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CARDIOLOGY CASEBOOK |
A 59-year-old housewife was initially examined 10 years ago because of angina pectoris and essential hypertension. At that time she was found to be moderately obese with blood pressures averaging 165/95 mm Hg and laboratory evidence of hyperlipidemia. The initial electrocardiogram (ECG) revealed nonspecific ST-T wave abnormalities and atrial enlargement. Supporting the diagnosis of atherosclerotic heart disease was a positive thallium exercise stress test. Coronary angiography at that time revealed 2-vessel obstructive disease with high grade lesions in the proximal circumflex artery and 75% occlusion of the first major diagonal branch of the left anterior descending artery. A secondary obtuse marginal branch was completely occluded at its origin with retrograde filling from the distal right coronary artery. The ejection fraction was 45%. The high sensitivity C-reactive protein (hs-CRP) level was 6 mg/dL (normal, 0.03–1.1 mg/dL). The implications of the positive hs-CRP test are that the coronary artery plaques noted on angiograms were inflammatory and consistent with increased probabilities of an imminent acute coronary event. Coronary bypass surgery was recommended, but promptly refused by both the patient and her family. Percutaneous transluminal coronary angioplasty (PTCA) was also refused out of hand. Evidently there had been unfortunate results in 2 close relatives following cardiac surgical procedures. With none of the interventional options acceptable to the patient, medical therapy was initiated. The patient was started on a low-cholesterol, low-calorie, low-sodium diet and a controlled exercise regimen. Drug therapy consisted of a ß-blocker, angiotensin-converting enzyme (ACE) inhibitor, low dose diuretic, statin, aspirin 325 mg, and fenofibrate. Sublingual nitrates were ordered to be taken hourly, routinely as tolerated and for attacks of angina. Progressive improvement occurred: blood pressures averaged 130/80 mm Hg in the right arm, heart rates averaged 68 to 70 beats per minute in the resting state, attacks of angina decreased, and she was asymptomatic after the twelfth day of therapy. After 5 months, the patient had a 10–lb (4.5 kg) weight loss. Diet and statin therapy normalized her lipid profile: cholesterol level improved from 252 to 162 mg/dL, triglycerides from 210 to 99 mg/dL, high-density lipoprotein (HDL) level increased from 39 to 56 mg/dL, the low-density lipoprotein (LDL) level decreased from 148 to 79 mg/dL and the very low density lipoprotein (VLDL) level decreased from 51 to 20 mg/dL; the cholesterol/HDL ratio decreased from 6.4 to 2.9 and the LDL/HDL ratio decreased from 3.7 to 1.4. At the end of 1 year, the patient remained symptom free and was walking 1 mile every day without any symptoms. This case, although stylized for publication and the patient’s privacy, was indeed an early and successful example of medical therapy in a patient with an acute impending myocardial infarction (MI). Medical therapy of the acute coronary event has come of age.
QUESTIONS
Answers
1. b. false
A seminal advance in evaluating CAD using selective coronary angiograms was first reported by Mason Sones in 1957. Up to the turn of the century, the severity of CAD was determined by coronary angiography, which revealed the degree of coronary luminal obstruction. These focal angiographic portraits of arterial diameter reduction due to plaque formation had become the basis for diagnosis and intervention. Cardiovascular (CV) disease was considered to be a mechanical problem that could be evaluated by an angiogram. However, the major pathology of atherogenesis lies within the arterial wall. Stenotic arterial lesions revealed by angiograms represent only 1% to 5% of the actual volume of atherosclerotic material present in the vessel wall. An angiogram is essentially a "lumenogram," the opacification of the lumen of an artery that enables the degree of obstruction of an artery to be evaluated. Angiograms reflect the degree of luminal obstruction; they do not define plaque morphology, plaque stability, or the extent of atherosclerosis in the arterial wall. Plaque morphology has a greater impact on predictability and prognosis of acute coronary events than do the size of the plaque and degree of arterial stenosis, since the majority of acute cardiac events are caused by lesions that are less than 50% stenotic on angiography. Evaluation of plaque morphology is critical in determining the severity and prognosis of CAD. Understanding endothelial function helps in our search for more effective care of the coronary patient.1
2. e. all of the above.
Reduction of LDL cholesterol to below 100 mg/dL with the use of statins (HMG coenzyme A reductase inhibitors) has been prospectively shown to reduce the incidence of major coronary events. Practitioners however were initially slow to implement and reinforce lipid lowering as a definitive treatment for CAD.1 Although currently lipid lowering with statins is more commonplace, their use is far from optimized. By restoring endothelial function, stabilizing vulnerable plaques, and retarding further plaque growth, statin use reverses endothelial dysfunction and can stabilize vulnerable plaques, thus lessening the chances for plaque rupture and coronary occlusion.2 Lipid lowering and restoration of normal endothelium affects not only major coronary lesions, but can stabilize minor lesions, which may appear as angiographically normal segments of the coronary or systemic vasculature. Angioplasty can improve the quality of life and exercise performance, however, the incidence of recurring ischemic events, and thus the need for repeat revascularization has always been a constant potential. In a 1999 study, the group of low-risk patients with stable CAD treated with atorvastatin had a longer period of time before their first ischemic event than the same group treated with angioplasty and routine medical care.3 In another study, the use of statins following acute MI reduced subsequent 1-year mortality in patients who had elevated cholesterol levels.4 However, it should be noted that increased skills gained through experience and the use of drug eluting stents have significantly reduced the number requiring repeat revascularization.
3. a. a discrete arterial lesion that can develop in infancy
It is well established that atherosclerosis is a gradual, progressive, and chronic process. The initial anlage of the atherosclerotic plaque seen in adults can be seen as a fatty streak on the surface of the arterial wall during infancy. Thus, it is reasonable to assume that uninhibited progression of this discrete coronary arterial lesion would result in the coronary atherosclerotic plaque seen in the adult. Endothelial dysfunction occurs long before its clinical manifestations and without anatomical alteration of the founding pathology; also, interventional revascularization does not deter progression of atherosclerosis, which will continue unabated unless risk factors are managed.5 Early atherosclerosis is manifested by an impaired endothelial response to vascular stimuli. The normal endothelial cells, which were previously thought to be merely a passive barrier between the vessel wall and lumen, are now known to be effective gatekeepers in mediating vasoactivity and reactivity. Hyperlipidemia and other atherogenic factors create pathological changes in endothelial cells that make them dysfunctional. Some of the clinical pathological responses mediated by impaired endothelial function include thrombogenesis, inflammation, increased vasomotor tone, and a decrease in vasodilator function.
4. b. metabolic with biomechanical manifestations
The simplistic mechanical obstructive aspect of CAD, which prevailed for 8 decades, has been replaced in the past decade by the complex metabolic abnormalities now known to occur in atherosclerosis. The metabolic hypothesis gained credibility when several trials showed a reduction in CV events and mortality following LDL cholesterol and risk factor reduction. The CV benefits manifested by the reversal of endothelial dysfunction were proportional to the LDL cholesterol reduction. Impaired endothelial function occurs early in atherosclerosis and results in impairment in vascular tone, myocardial perfusion, accumulation of oxidized LDL and increases in platelet adhesion, smooth muscle cell growth, and inflammatory cell migration. Lipid-lowering therapy reduces inflammation, increases collagen within the atheroma, improves endothelial function, and stabilizes the endothelial plaque. This has been demonstrated by objective markers of myocardial ischemia (ie, dipyridamole perfusion studies); and ST-segment monitoring on ambulatory electrocardiograms.5 The effects of lipid lowering also extend to the cerebral, renal, and systemic vascular beds. However, neither surgical nor percutaneous revascularization has any effect on the biological abnormalities of coronary atherosclerosis, nor do these invasive procedures have any effects on stabilizing atherogenic plaques in any of the coronary arteries.5
It has been suggested that conventional CV risk factors do not account for all CV disease. One factor thought to potentiate CV event risk is activation of the reninangiotensin-aldosterone system (RAAS). Inactivation of the RAAS is thought to retard progression of heart failure and atherosclerosis. The use of a long-acting ACE inhibitor agent, ramipril, demonstrated a significant reduction of mortality, MI, stroke, revascularization and heart failure in patients at high risk of CV events, but without low ejection fraction or known heart failure (Heart Outcomes Prevention Evaluation Study).6 The study focused on preventing events related to ischemia and atherosclerosis in patients treated with aspirin, ß-blockers and lipid lowering agents. The added benefit of ramipril suggests that reversal of the unstable plaque and thus reduction of the chances for acute coronary events were the results of ACE inhibition. Only a small percentage in the study trial improved as a result of blood pressure reduction.
5. c. pancoronaritis
In lipid-rich plaques, which are usually inflamed, the risk of instability and rupture increases. Most unstable lesions that rupture, however, have less than a 50% diameter stenosis on angiography and are not considered as requiring percutaneous coronary intervention. Only obstructive plaque size was and still is considered an indication for surgical or percutaneous intervention. In a recent study using coronary artery ultrasound, researchers reported that in the setting of acute MI or other acute coronary events more than one plaque rupture was found. The study suggests that there may be an overall destabilization of neighboring plaques in addition to the culprit lesion. This has been termed "pancoronaritis."7
SUMMARY
In the past era, we held high-grade arterial stenosis responsible for the acute complications of atherosclerosis. These concepts are being reassessed. Qualitative rather than quantitative aspects of plaques (eg, inflammation rather than plaque size) have been established as decisive determinants of their probabilities to cause acute complications.
Numerous beneficial effects of statins have been demonstrated. These include lipid lowering, plaque stability, enhanced endothelial function, and antiplatelet, antiatherothrombotic, and antimacrophage activities. However, the successful medical management of CAD is also multifactorial and in addition to use of statins includes ß-blockers, ACE inhibitors, and aspirin, as well as blood pressure control, diet, and exercise (see Figure). The results have been not only the preventions of acute complications of atherosclerosis, but also the successes in stabilizing acute coronary events and preventing infarctions.
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Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P O Box 016960, Miami, Fla 33101.
Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522–526.
Yusuf F, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153.
Futterman LG, Lemberg L. Peripheral arterial disease is only the tip of the atherosclerotic "iceberg." Am J Crit Care. 2002;11:390–394.
LaRosa JC. Prevention and treatment of coronary heart disease: who benefits? Circulation. 2001;104:1688–1692.
Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hyper-cholesterolemia (ASAP): a prospective, randomized, double-blind trial. Lancet. 2001;357:577–581.[Medline]
Sternberg D, Grotto AM. Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside. JAMA. 1999;282:2043–2050.
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