Immune System Activation Follows Inflammation in Unstable Angina: Pathogenetic I
January 1, 1999
Immune System Activation Follows Inflammation in Unstable Angina: Pathogenetic Implications
ABSTRACT & COMMENTARY
Synopsis: This study supports the hypothesis that an inflammatory process is associated with unstable angina pectoris.
Source: Caligiuri G, et al. J Am Coll Cardiol 1998;32:1295-1304.
A new study from caligiuri and colleagues is consistent with a putative role for inflammation and especially immune responses in unstable angina. Caligiuri et al carefully studied a cohort of patients with unstable angina as well as a control group with chronic stable angina; they measured a variety of immune markers at several time intervals. The study was stimulated by prior work from this group as well as others indicating that elevated systemic levels of inflammatory and immune markers were common in unstable angina, and indicated a poorer outcome in such individuals. Thirty-five patients with severe unstable angina underwent serial studies for six months. This cohort was subdivided into a group that quickly stabilized and another that had more than two unstable ischemic episodes after 48 hours on maximum medical therapy. Thirty-five individuals with stable effort angina, a positive stress test, and a documented coronary obstruction served as the controls. Analyses were carried out for C-reactive protein, immunoglobulins and complement fractions, IgG and IgM titers for C. pneumoniae, interleukin-2 levels, and a variety of lymphocyte subpopulations. The results indicated that unstable angina patients as a group had higher admission CRP levels and a higher percentage of circulating T-helper lymphocytes (CD4 +) than in chronic stable angina, as well as less circulating T-suppressor cells. CRP levels tended to fall in the unstable patients, although IgM levels increased at 7-15 days. Unstable angina patients who had persistent and severe ischemia had higher CRP levels than those who responded to therapy, and these patients also had higher IgM levels and activated T-cells at two weeks. Interleukin-2 levels were increased in unstable angina patients; activation of lymphocytes in general was greater in the unstable patients, but not in the chronic stable angina. Caligiuri et al conclude that the unstable angina cohort manifests a "transient specific immune response" within 1-2 weeks, and that increases in circulating activated T-cells and IgM levels were associated with a more favorable short-term clinical outcome. Caligiuri et al believe that the elevated CRP levels, declining rapidly but remaining high in the unfavorable unstable angina cohort, support the hypothesis that an inflammatory process is associated with unstable angina pectoris. This inflammation may come from the complex culprit plaque and/or systemic activation. Furthermore, their data are consistent with the view that the inflammatory process is not related to thrombosis or reperfusion injury. Caligiuri et al suggest that this inflammatory response may be antigen-stimulated, although the precise antigens that might be implicated are not identified in this study. These could be "self-modified proteins" or infectious agents, as has been suggested in previous studies. However, antibody levels in this study did not support a reaction to C. pneumoniae. In fact, Caligiuri et al conclude that an increase in total antibody titers as well as a presumed polyclonol origin of plaque T-cells suggest that different antigenic stimuli might play a role in different patients or even the same patient over time. In the chronic stable angina patients, T-cell activation was noted, particularly in the individuals that had severe effort angina, but none of the other immune parameters, such as CRP, IgM, or interleukin-2, appeared to be important in stable angina cohorts.
Comment by Jonathan Abrams, MD
These data are fascinating and lend credence to the many reports suggesting that inflammatory and/or immune activation are present in unstable angina patients and even to some degree in chronic stable angina. The dynamic nature of the rise and fall of a number of parameters in the unstable angina cohort, particularly the differences between the stable vs. less stable subjects, further supports the possibility of a causal contribution of the immune system in unstable angina. Obviously, a great deal of additional research is necessary, and no immediate therapeutic implications can be identified. However, as Eugene Braunwald (Circulation 1998;98:2219-2222) points out in his editorial, it is time that physicians become more comfortable with these interesting pathogenetic phenomena. The evidence that coronary events may be in part related to immune phenomena appears to be solid. There is considerable evidence that elevated CRP levels are associated with adverse prognosis in ischemic heart disease cohorts; these data in unstable angina patients begin to explore the immune system in much greater detail than simply measuring common acute phase reactants.
The syndrome of unstable angina pectoris is variably defined as heterogeneous with respect to pathogenesis as well as clinical manifestations. Braunwald suggests that more effort be made to identify the various etiologies of unstable angina, and that specific therapies should be appropriately chosen depending on causation. He defines five different causes—not necessarily mutually exclusive. These include the most common etiology, nonocclusive thrombus on a pre-existing coronary lesion; dynamic obstruction of a normal or abnormal coronary artery, with focal or diffuse vasoconstriction/spasm resulting in myocardial ischemia; progressive atherosclerosis with luminal narrowing, such as has been documented to occur at the site of the "culprit lesion" or in restenosis following PTCA; inflammation and possible systemic infection; and, finally, "secondary unstable angina" (i.e., myocardial ischemia rated to exogenous factors, such as tachycardia, hypertension, thyrotoxicosis, etc.). Clearly, identification of the etiology of unstable angina in a specific patient might influence therapy. For instance, the thrombotic cause would benefit from antiplatelet and antithrombotic agents; the severe obstruction requires revascularization; a variety of potential therapies might be appropriate for an inflammatory-infectious causation, etc. It is conceivable that short- and long-term prognosis might be different among the various causes of unstable angina. Braunwald’s construct, while not new, should assist clinicians as well as investigators regarding their thoughts about unstable angina and its therapy.
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