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A Little Context, Please

To the Editors:

The Feature Article by Keith A. Webster, “Mitochondrial Death Channels” (September–October 2009) beautifully illustrates the strength and weakness of much contemporary biomedical research: The strength is its exquisite description of the molecular, cellular and physiological details of a clinically important phenomenon, myocardial infarction, in the contexts of apoptosis, oxidative stress and ischemia-hypoxia. Its weakness is the absence of broader contexts, a common feature of contemporary biomedical research in papers and seminars.

The context here is the role of innate immunity in triggering acute myocardial infarction (AMI). Innate immunity, which is the initial response of the body to infectious, traumatic and toxic stresses comprises many pathways. One of them, the complement pathway, consists of some 30 serum and membrane-bound proteins that protect against infections, but also damage tissues such as the heart. This pathway is triggered by ischemia, hypoxia and oxidative stress and also mediates apoptosis and myocardial infarction. Knowledge of the participation of this pathway in infarction is important not only because it helps to explain how the heart is damaged but also suggests treatments such as antagonists of this pathway. Moreover, knowledge of this pathway may help to predict and evaluate the success of various treatments. For instance, drug- eluting stents employed to reduce the narrowing of blood vessels in the heart can trigger the complement pathway and thereby induce significant inflammation that impairs vascular healing and leads to renarrowing of the vessels.

The absence of broader context in much contemporary biomedical research reflects either the lack of knowledge of that context (for example, innate immunity and the complement pathway), or failure to consider the context germane. In either case, a byproduct is failure to communicate the broader picture to graduate students, postdoctoral fellows and faculty. This failure is then reflected in the inadequate training that many of our graduate students and postdoctoral fellows receive and the eventual narrow teaching that they themselves do.

Abram B. Stavitsky
Cleveland, OH

Dr. Webster responds:

I appreciate Dr. Stavitsky’s comments. Unlike innate immunity, however, the role of the mitochondrial death channels in necrotic and apoptotic death during AMI are now quite well understood. The mitochondrial permeability transition pore (mPTP) is a clear therapeutic target and there are a number of candidates of which, in my opinion, cyclosporine A (CsA), volatile anesthetics and Viagra are the most promising. Each of these agents target the mPTP—CsA directly through its binding to cyclophilin D (CypD), volatile anesthetics and Viagra indirectly by activating ischemic preconditioning and inhibiting GSK3-* upstream of CypD. Clinical trials are underway for these agents, each of which is already approved for other indications. And successful results have already been reported where volatile anesthetics are used during angioplasty or CABG.

Innate immunity is a much more difficult target. We are not sure whether it is injurious or protective. It is not clear to what extent innate immunity is a consequence rather than a cause of AMI. A central role of innate immunity in coronary artery disease has been recognized for many years, and an exaggerated role of inflammation within damaged vessel walls after angioplasty with or without coronary stenting is indeed a serious clinical concern and the focus of intense research. Activation of innate immunity during myocardial infarction and remodeling has also been recognized for many years and is supported both by animal and patient studies that have demonstrated increased levels of circulating inflammatory cells, cytokines, and complement factors in patients with unstable angina, pre- and post AMI, and post-AMI progressing to heart failure.

Support for a direct role of innate immunity in AMI also includes the presence of neutrophils, macrophages and elevated levels of inflammatory cytokines within the infarct and peri-infarct regions of the myocardium. In addition, over-expression of inflammatory cytokines in mouse models can reproduce multiple features of post-MI contractile dysfunction, negative remodeling and heart failure. Despite this, clinical trials targeting either complement or inflammatory cytokines have been largely unsuccessful. This may be because the overall role of innate immunity during human AMI is protective. So, whereas I agree with Dr. Stavitsky that graduate students and postdocs should be made aware of the roles of innate immunity in cardiovascular disease—at the University of Miami, they are—I am not sure that I have missed a broader context in my article by focusing on the death channels.

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