Abstract & Commentary
Synopsis: Systemic anti-inflammatory therapy may be superior to focal angioplasty for preventing future coronary events in patients with unstable angina.
Source: Buffon A, et al. N Engl J Med. 2002;347:5-12.
For much of the last decade, dr. a. maseri’s group in Rome, Italy, have been exploring the hypothesis that acute coronary disease is related to an inflammatory process. Beginning in 1994, with multiple subsequent publications since, they have demonstrated activation of the coronary bed with increased leukocyte CD11b and CD18; activated monocytes and neutrophils; cytokine elevations; and increases in the metalloproteinase and collagenases. Other workers have corroborated their data. In an intriguing report from William Beaumont Hospital 2 years ago (Goldstein J, et al. N Engl J Med. 2000;343:2115-2122), it was demonstrated that patients with acute myocardial infarction (MI) frequently had multiple complex coronary lesions in coronary vessels not involved with the infarction itself, suggesting widespread activation of the coronary tree. In the present study, Maseri et al used an intricate protocol involving measurements of white blood cell and neutrophil myeloperoxidase (NM) content in the coronary arteries and the cardiac and femoral venous circulations in 5 different patient groups to determine whether there is widespread vs. localized inflammation in the coronary arterial bed during episodes of unstable angina pectoris. During cardiac catheterization, catheters were placed in the right femoral vein, aorta, great cardiac vein, as well as in the right and left anterior descending coronary arteries. Simultaneous sampling was obtained from all sites for NM concentration analyzed by automated flow cytochemistry. A low NM index indicates neutrophils that are depleted of myelperoxidase due to activation; a zero or positive index is consistent with nonactivation. If the index is low in the great cardiac and femoral veins compared to the aorta, this supports neutrophil activation across the coronary bed. C-reactive protein was measured in all subjects. The left and right coronary circulations were evaluated for the presence of plaque. The patient cohorts included 24 subjects with unstable angina and LAD stenosis and 9 with an RCA stenosis; 13 individuals with chronic stable angina; 13 with variant angina and recurrent ischemia; and 6 controls. The great cardiac vein drainage comes from the LAD but not the RCA, allowing assessment of localized neutrophil activation. Sampling from the femoral vein allowed the assessment of more generalized neutrophil activation in patients with unstable or variant angina who had typical clinical symptoms.
The leukocyte and neutrophil counts in the aorta, great cardiac vein, and femoral vein were similar among all 5 groups. RCA lesions were associated with minimal LAD disease, whereas LAD unstable angina subjects had little to no RCA disease. Median aortic myeloperoxidase levels did not differ between patients with unstable angina who had left or right coronary lesions, but their NM levels were substantially lower than in individuals with stable angina, variant angina, or controls. There was a significant transcoronary decrease in the NM index only in the unstable angina patients. CRP levels were markedly elevated in the unstable angina group at 4.5- 6.5 mg/L, compared to 2.1 mg/L in stable angina subjects, 2 mg/L in patients with stable or variant angina, and 1.2 mg/L in controls. There was a significant negative correlation between systemic CRP levels and aortic and great cardiac vein NM concentration. Buffon and colleagues conclude that "leukocytes become activated as they traverse the coronary vascular bed" in unstable angina but not in variant or stable angina. Furthermore, transcoronary neutrophil activation was not found solely in the vascular bed perfused by a single decreased coronary artery but was found in both the right and left sides of the coronary circulation. Buffon et al speculate that "multifocal or widespread inflammatory activation of the endothelium" relates to a change in the "interface between the blood and the vessel walls from anticoagulant and vasodilative to prothrombotic and vasoconstrictive." Activation of metalloproteinase and collagenases are believed to be related to severe endothelial dysfunction and even lysis within the plaque capsule. Buffon et al cite a number of other reports that are consistent with widespread coronary inflammation in ACS, including autopsy analyses of Falk and Davies; postmortem plaque analyses demonstrating inflammatory-cell infiltrates with high content of proinflammatory cytokines; and studies of coronary flow and labeled deoxyglucose uptake in myocardial beds served by normal coronary arteries during unstable angina. Elevated CRP and interleukin-6 have been documented by Maseri et al’s in more than two thirds of patients with severe unstable angina, declining somewhat by 6 months. Such levels are associated with unstable coronary plaque activation and an increase in subsequent clinical events, including MI. These findings are much less common in individuals who present with an acute MI not preceded by unstable angina, suggesting that "triggers of coronary thrombosis and vasoconstriction are not necessary the same in all patients with ACS." Finally, Buffon et al conclude that their work challenges the well known hypothesis that a single activated or vulnerable plaque is "the genesis of coronary instability."
A companion editorial by Keaney and Vita discusses the implications of this study (Keaney JF, Vita JA. N Engl J Med. 2002;347:55-57). They emphasize the well-known fact that coronary angiography has not been very useful in identifying inflammed athroscoletic plaque, and that many acute coronary syndromes arise from nonstenotic vessels. They suggest that "systemic medical therapy is superior to focal angioplasty in preventing future coronary events in patients with unstable angina." They point out that considerable research is currently underway to try to identify unstable plaque and widespread coronary inflammation in a noninvasive fashion, which may result in new therapies with potentially enormous public health implications.
Comment by Jonathan Abrams, MD
The inflammation concept was advanced many years ago and was particularly emphasized in an early publication by the Rome group demonstrating increased CRP and serum amyloid A protein in severe unstable angina (N Engl J Med. 1994;331:317-324). The CRP story is now well known, with elevations documented in a wide variety of conditions. In both chronic and acute coronary syndromes, high CRP is associated with adverse short- and long-term prognosis. This is completely consistent with the inflammatory hypothesis. In the report from Goldstein et al, multiple complex plaques were found in coronary arteries away from the culprit lesion, suggesting an activated vascular state. Angioplasty with or without stenting is obviously not a "complete" therapy in such a situation. A variety of laboratories, including those of Libby, Ridker, and others, indicate that inflammation is tightly linked to atherosclerosis as well as to instability of atherosclerotic plaque. Many imaging techniques are currently being evaluated, including plaque thermography assays of multiple markers of inflammation, intravascular ultrasound, and MRI. It is widely believed that statin therapy plays a role in quenching coronary inflammation, and these drugs may work in part due to the nonlipid effects. Furthermore, the substantial benefits of aspirin in unstable coronary syndromes may be linked to the inflammatory hypothesis. Measurements of CRP are not advocated at the present time, but it is likely that, in the near future, widespread use of high sensitivity-CRP levels and perhaps other cytokines will be part of the evaluation of acute coronary syndromes to determine the presence and degree of inflammation. In spite of all this exciting research, the precise causes of the inflammatory stimuli are yet to be determined.
Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, NM.