(Circulation. 1997;95:324-328.)
© 1997 American Heart Association, Inc.
Articles |
Effect of Cholesterol Reduction on Myocardial Ischemia in Patients With Coronary Disease
Cardiovascular Division and Vascular Medicine Section, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Department of Neuroepidemiology, Children's Hospital, Boston, Mass.
Correspondence to Andrew P. Selwyn, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
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Abstract |
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Background Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life.
Methods and Results We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (P<.001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution.
Conclusions Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients.
Key Words: ischemia • lipoproteins • arteriosclerosis
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Introduction |
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Elevated serum cholesterol in general and serum LDL cholesterol in particular are well-established risk factors for the development of coronary artery disease and cardiac events.1 2 In addition, trials of aggressive LDL cholesterol lowering have shown a reduction in the incidence of adverse cardiac events.3 4 Curiously, this reduction in cardiac events is disproportionate to the small degree of angiographic regression of coronary atherosclerosis, which suggests that physical regression of atheroma may not be the principal mechanism by which cholesterol lowering alters cardiac risk.5 6 7 New data suggest that LDL cholesterol lowering results in improvement of characteristiccellular dysfunctions affecting atherosclerotic arteries (eg, endothelial dysfunction) in hypercholesterolemic animals and patients.8 9 10 11 12 Hyperlipidemia is associated with endothelial dysfunction, which leads to unopposed constriction at coronary stenoses.13 14 This constriction plays a role in triggering myocardial ischemia, which is known to be a sign of increased cardiac risk.15 16 Hence, we sought to determine the effect of cholesterol lowering on myocardial ischemia as measured by ST-segment depression on ambulatory ECG monitoring in patients with coronary artery disease.
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Methods |
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This study was a single-blind, placebo-controlled, randomized prospective parallel design comparing the effects of cholesterol lowering by diet with cholesterol lowering by diet plus lovastatin.
Patient Identification
A total of 96 patients with known coronary artery disease and measured serum cholesterol were screened with ambulatory ECG monitoring for ST-segment depression. Coronary artery disease was documented in all patients by at least one of the following: prior history and ECG evidence of myocardial infarction; >50% stenosis of at least one major epicardial coronary artery documented by angiography; exercise treadmill test independently judged to be positive for myocardial ischemia with associated reperfusion abnormality on thallium/2-methoxy-2-isobutyl isonitrile (MIBI) imaging; or independently documented angina pectoris in association with age >60 years, at least two coronary artery disease risk factors, and infrainguinal arterial occlusive disease shown by angiography. Patients were not screened with ambulatory monitoring if they had any of the following: a history of myocardial infarction within 3 months, symptoms of unstable angina or heart failure, or baseline ECG changes that precluded accurate ambulatory monitoring (left bundle-branch block, left ventricular hypertrophy with ST/T-wave changes, or chronic digoxin therapy). We enrolled patients with serum cholesterol levels between 190 and 330 mg/dL. Of the 96 patients, 40 had at least 1 minute of 1-mm ST-segment depression during 48 hours of ambulatory monitoring and consented to enroll in this randomized trial, which was approved by the Brigham and Women's Hospital Institutional Review Committee.
Randomization
All patients provided a detailed history and underwent a physical examination and baseline ECG. Fasting total serum cholesterol, LDL cholesterol, and HDL cholesterol were measured at the onset of the study. In 9 of the 40 patients, it was not possible to secure measurement of serum LDL and HDL at the start of each study because of logistic difficulties and/or expense. Ambulatory ECG monitoring was performed for 48 hours on entry and at the end of the study on the same medications. Ambulatory monitoring at entry and end of each study was always performed during a customary working day in each patient, avoiding weekends and holidays. Care was taken to repeat the monitoring on days when each patient repeated a familiar pattern of activities. After the above evaluation, patients were randomized to (1) American Heart Association Step 1 diet plus placebo or (2) Step 1 diet plus lovastatin. Instructions about the Step 1 diet were reviewed in detail with each patient by a dietician or one of the investigators. Lovastatin (or placebo) was initiated at a minimum of 20 mg/d and increased to a maximum of 40 mg/d if a 20% reduction of LDL cholesterol was not achieved by 6 weeks. Compliance was monitored with pill counts during follow-up visits at 6 weeks, 3 months, and 6 months. Medications were discontinued if side effects occurred. In the case of mild side effects (eg, dyspepsia), medications were restarted after 2 weeks with close monitoring for recurrence.
Follow-up
Serum cholesterol and LDL and HDL cholesterol were determined at the end of each study at the time of repeat ambulatory ECG monitoring. In 1 of 40 patients, it was not possible to secure measurement of serum LDL and HDL at the end of the study because of logistic difficulties and expense. Before repeat monitoring, the patients were reinterviewed and examined to establish that no intercurrent adverse cardiac events had occurred. Patients returned with their study medications for pill counts to ensure compliance. Monitoring was carried out on the identical medical regimen that patients were receiving at study entry (2 patients had been placed on ß-blocker therapy during the study, and this was tapered over 48 hours before monitoring was repeated).
Ambulatory Monitoring Analysis
All patients wore calibrated digital recorders to continuously record the ECG from a modified inferior bipolar lead and bipolar lead V5. All patients were monitored as outpatients during 2 customarily active days. The patients were monitored with calibrated full-disclosure devices that provided low-frequency fidelity from digital recording for ST-segment analysis, high signal-to-noise ratio, and a permanent analog ECG record of each event (Oxford MR45 in 28 patients and QMed Tc 350 in 12). Ambulatory monitoring data were analyzed by an expert blinded to patient information and the randomization process. Episodes of ST-segment depression were defined as the onset of >1 mm of downward change from baseline at the J-point and at 60 ms lasting for 
1 minute in consecutive beats. A new episode was recorded if the ST segment returned to baseline for 3 minutes. The number of episodes per 48 hours was recorded.16 17 18 19 20
Statistical Analysis
All patients were analyzed with their groups (intention to treat). Total, LDL, and HDL cholesterol; the number of ischemic episodes at the start and end of the study; and the difference between the two (end value minus start value) for the diet plus placebo group were compared with those values for the diet plus lovastatin group by the Wilcoxon rank-sum test. The change in ischemia was also dichotomized (into outcome groups), forming an "improved" group (fewer episodes at the end of the study than at the start) and an "unchanged/worse" group (the same or more episodes at the end). The treatment groups and the outcome groups were compared with regard to potential confounders, such as age, sex, smoking status, medical history, severity of coronary artery disease, and use of medications, by Fisher's exact test and the Wilcoxon rank-sum test. Logistic regression was used to evaluate the risk of "improvement" in ischemia associated with assignment to diet plus lovastatin, controlling for confounders that were positive in the univariate analysis (see Tables 1 and 3
).
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Results |
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All patients completed the study. One patient receiving lovastatin stopped the medication for 2 weeks secondary to dyspepsia and resumed it uneventfully. Of the 40 patients, there were 28 men and 12 women 49 to 85 years old (median, 67 years). Coronary artery disease was documented by coronary angiography in 24 patients. Among the 16 remaining patients, 9 had a prior history of myocardial infarction, 2 others had a positive treadmill exercise test with abnormal thallium/MIBI redistribution diagnostic of ischemia, and the remaining 5 were >60 years old and had a history of angina pectoris, two clear-cut risk factors, and symptomatic angiographically proven peripheral vascular disease. A total of 18 patients were asymptomatic, 14 patients had NYHA functional class I angina, 5 patients had class II, and 3 patients had class III symptoms. Thirty-six patients were on antianginal therapy, including ß-blockers, calcium antagonists, and long-acting nitrate therapy. Thirty-four patients were on aspirin therapy. Baseline cholesterol levels ranged from 191 to 327 mg/dL, with a median of 244 mg/dL. Baseline LDL cholesterol ranged from 121 to 236 mg/dL, with a median of 169 mg/dL. At baseline, the number of episodes of ST-segment depression ranged from 1 to 24, with a median of 4.
Patient characteristics in the placebo and treatment groups showed that patients randomized to diet plus lovastatin were more likely to have a history of prior myocardial infarction (Table 1
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Patients randomized to diet plus lovastatin had more significant total serum cholesterol and LDL cholesterol lowering (Table 2). None of the patients reported angina during the two monitoring sessions in this study. The median baseline number of ST-segment depression episodes was the same in the two groups (Table 2). Although the median number of episodes of ST-segment depression did not change appreciably in the group randomized to diet plus placebo, there was a substantial reduction in the number of episodes in the group randomized to diet plus lovastatin (Table 2). More specifically, a total of 13 of 20 patients randomized to diet plus lovastatin had total resolution of ST-segment depression, whereas only 2 of 20 patients randomized to diet plus placebo had resolution (Figure). In addition, only 3 of the 20 patients randomized to diet plus lovastatin had unchanged or increased numbers of ST-segment depression episodes at follow-up, compared with 11 of the 20 patients randomized to diet plus placebo (Figure).
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The total duration of ischemic ST-segment depression for 48 hours at entry was 52 minutes (median) in the placebo group (interquartile range, 18 to 172; range, 1 to 526 minutes) and 45 minutes (median) in the treatment group (interquartile range, 21 to 126; range, 4 to 588 minutes). At the end of the study, total duration of ischemic ST-segment depression per 48 hours was unchanged at 52 minutes (median) in the placebo group (interquartile range, 11 to 93; range, 0 to 1048 minutes), significantly different from the treated group, which showed a reduced duration to 0 minutes (median) and interquartile range, 0 to 30; range, 0 to 150 minutes; P=.001.
Comparison of patient characteristics in the unchanged/worse versus the improved groups showed that patients who showed improvement in ischemia were less likely to be male and more likely to have angina (Table 3).
The logistic regression model shows that assignment to treatment was the most significant predictor of improvement in measured ischemia (odds ratio, 6.9; CI, 1.5 to 31.4; P=.01). The presence of angina did not predict a reduction in ischemia (Table 4).
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No intercurrent adverse cardiac events occurred during the 6-month follow-up.
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Discussion |
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This study has shown that lowering of total and LDL cholesterol can result in resolution of myocardial ischemia recorded as episodes of ST-segment depression in ambulatory monitoring of the ECG.
In patients with either proven or a high likelihood of coronary artery disease, episodes of ST-segment depression on ambulatory monitoring have been shown to be a reliable measure of transient myocardial ischemia.19 This signal has also been shown to predict cardiac risk and outcomes in patients with coronary artery disease in a variety of clinical settings.16 21 22 23 Recent trials using medical therapy or revascularization have provided preliminary evidence to support the hypothesis that the elimination of ischemia detected by ambulatory monitoring will lead to a decrease in adverse coronary events.24 25
Prior studies have demonstrated that ischemia during exercise and ambulatory monitoring is found more often in patients with angina but does occur in asymptomatic subjects. In addition, the ischemia found during both tests is frequently asymptomatic. The majority of patients in this study were on antianginal medications, had mild or no angina pectoris during daily life, and did not report any symptoms during the two monitoring sessions.16 17 19 24 25
In epidemiological studies, the serum levels of total and LDL cholesterol are positively related to the risk of clinical coronary heart disease and adverse coronary outcomes.1 2 In addition, large-scale clinical trials have now shown that when 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are used to lower cholesterol in patients with coronary disease and/or hypercholesterolemia, there is a significant reduction in the occurrence of coronary death and myocardial infarction.3 4 Interestingly, these clinical trials also showed a significant reduction over 4 years in the need for coronary angioplasty or bypass graft surgery, interventions usually performed to manage refractory ischemia.3 The coronary regression and clinical outcome trials all showed effects after 2 years. The study presented here shows directly that cholesterol lowering can beneficially change evidence of active myocardial ischemia in a relatively short time frame. This is in agreement with previous studies of cholesterol lowering that have also shown a rapid improvement in regional perfusion abnormalities that were provoked in a laboratory setting and measured by radionuclide imaging.26
The search for possible mechanisms underlying this improvement in transient ischemia with cholesterol lowering must consider the causes of ischemia and the effects of cholesterol lowering on the biology of atherosclerotic coronary arteries. Episodes of transient myocardial ischemia are usually preceded by sympathetic arousal, an increase in myocardial demand, and a varying degree of constriction of atherosclerotic stenoses.14 15 17 The constriction is closely related to the loss of dilation and appearance of paradoxical constriction due to endothelial dysfunction in the atherosclerotic coronary artery.27 In animal studies, cholesterol lowering has been shown to improve endothelial function, lessen the abnormal constriction that is provoked by acetylcholine, and decrease the infiltration of inflammatory monocytes in subintimal lesions.10 It is important to note that these changes occur within months and before any physical regression of atherosclerosis. Clinical studies in patients have also shown that cholesterol lowering causes very little physical regression but can improve endothelium-dependent vasomotor function in atherosclerotic epicardial arteries within 6 to 12 months.5 7 12 28 29
In conclusion, serum lipids are closely related to the clinical manifestations of coronary heart disease. Cholesterol lowering can improve the endothelial dysfunction in atherosclerotic coronary arteries in patients, cause modest physical regression of atheroma, and significantly decrease the occurrence of coronary death and myocardial infarction over 2 years. This study has shown that the same treatment strategy (cholesterol lowering) that is known to reduce cardiac risk in the medium term and long term can also improve clinical signs of disease activity and increased risk (ischemia) in a much shorter time frame.
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Acknowledgments |
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This study was supported by grants RO1-HL-38780 (Dr Selwyn), 1K04-HL-02566 (Dr Ganz), and 5PO1-HL48743 (Drs Ganz and Selwyn) from the National Institutes of Health and a Merck-ACC Fellowship Award (Dr Andrews).
Received May 20, 1996; revision received September 26, 1996; accepted October 7, 1996.
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S. J Duffy, G. New, R. W Harper, and I. T Meredith Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation Cardiovasc Res, August 15, 1999; 43(3): 721 - 730. [Abstract] [Full Text] [PDF]
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A. M Dart and J. P.F Chin-Dusting Lipids and the endothelium Cardiovasc Res, August 1, 1999; 43(2): 308 - 322. [Abstract] [Full Text] [PDF]
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J. Dupuis, J.-C. Tardif, P. Cernacek, and P. Theroux Cholesterol Reduction Rapidly Improves Endothelial Function After Acute Coronary Syndromes : The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial Circulation, June 29, 1999; 99(25): 3227 - 3233. [Abstract] [Full Text] [PDF]
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D. Baller, G. Notohamiprodjo, U. Gleichmann, J. Holzinger, R. Weise, and J. Lehmann Improvement in Coronary Flow Reserve Determined by Positron Emission Tomography After 6 Months of Cholesterol-Lowering Therapy in Patients With Early Stages of Coronary Atherosclerosis Circulation, June 8, 1999; 99(22): 2871 - 2875. [Abstract] [Full Text] [PDF]
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R. R. Arora, T. M. Chou, D. Jain, B. Fleishman, L. Crawford, T. McKiernan, and R. W. Nesto The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes J. Am. Coll. Cardiol., June 1, 1999; 33(7): 1833 - 1840. [Abstract] [Full Text] [PDF]
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G. Dangas, J. J. Badimon, D. A. Smith, A. H. Unger, D. Levine, J. H. Shao, P. Meraj, C. Fier, J. T. Fallon, and J. A. Ambrose Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1294 - 1304. [Abstract] [Full Text] [PDF]
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H. Drexler Endothelium as a Therapeutic Target in Heart Failure Circulation, December 15, 1998; 98(24): 2652 - 2655. [Full Text] [PDF]
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R A Archbold and A D Timmis Cholesterol lowering and coronary artery disease: mechanisms of risk reduction Heart, December 1, 1998; 80(6): 543 - 547. [Full Text]
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G. S. Huggins, R. C. Pasternak, N. M. Alpert, A. J. Fischman, and H. Gewirtz Effects of Short-Term Treatment of Hyperlipidemia on Coronary Vasodilator Function and Myocardial Perfusion in Regions Having Substantial Impairment of Baseline Dilator Reverse Circulation, September 29, 1998; 98(13): 1291 - 1296. [Abstract] [Full Text] [PDF]
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F.-C. Schoebel, T. W. Jax, B.-E. Strauer, M. Leschke, and W. R. M. A. A. J. v. B. A. H. Z. J. W. J. A. V. G. van der Werf Functional Evaluation of Lipid-Lowering Therapy by Pravastatin • Response Circulation, May 12, 1998; 97(18): 1874 - 1875. [Full Text]
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P. Di Napoli and P. A. Barsotti Does 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor Therapy Exert a Direct Anti-Ischemic Effect? Circulation, March 10, 1998; 97(9): 937 - 937. [Full Text]
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M. Gheorghiade and R. O. Bonow Chronic Heart Failure in the United States : A Manifestation of Coronary Artery Disease Circulation, January 27, 1998; 97(3): 282 - 289. [Full Text] [PDF]
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A. M. Gotto Jr Cholesterol Management in Theory and Practice Circulation, December 16, 1997; 96(12): 4424 - 4430. [Abstract] [Full Text]
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R. L. Frye Clinical Reality of Lowering Total and LDL Cholesterol Circulation, January 21, 1997; 95(2): 306 - 307. [Full Text]
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