Ann Thorac Surg 2004;78:889
© 2004 The Society of Thoracic Surgeons
Invited commentary
Daniel R. Meldrum, MD
Departments of Surgery and Physiology, Indiana University Medical Center, 545 Barnhill Dr, Emerson 215, Indianapolis, IN 46033 USA
dmeldrum{at}iupui.edu
Vogt and colleagues present a brilliant, quantifiable method of determining the severity, and possibly the duration, of angina in patients. Additionally, Vogt and colleagues provide a basic science explanation for some of the observations of the TIMI-9B. Experimentally, it appears as though any severe stress, whether it is trauma, shock, ischemia, near-drowning, extreme exercise (marathons), or even a prolonged exposure to deafening noises, induces endogenous stress proteins that provide protection against a subsequent insult. Some of these proteins are called heat shock proteins, their name harkening back to the stress first known to induce their expression. Although stress proteins, such as the heat shock protein 70 (HSP-70) referred to here, provide potent tissue protection, capturing their therapeutic potential has proven elusive. For instance, using the above severe stressors to induce protection may leave one wondering whether the treatment is worse than the disease. Brilliant translational researchers are circumventing the unappealing prerequisite stress by pharmacologic means of inducing expression, or by transfection of the protein or gene.
Vogt and associates present a clever way of determining which patients have "seen" the protein even if expression of the protein may have already faded. At first, it is somewhat surprising that patients make antibody to an endogenous, "self" protein whose expression is limited to the intracellular space. However, patients who make antibody to HSP-70 may not only require stress sufficient to induce the protein but they may also require cell death for its release. In concert with animal data, patients whose preoperative stress levels reached the threshold for anti–HSP-70 antibody production, were relatively protected from the subsequent coronary artery bypass grafting procedure. The time required for heat shock protein production and antibody formation also implies that a window of recovery from the extreme stress is required. This finding also coincides with experimental data that have demonstrated that the temporal placement of the "second hit" too close to the "first hit" is destructive rather than adaptive.
The mechanisms of heat shock protein mediated protection are intensely studied and clearly described by the authors. Questions that are equally fascinating include the following: why don't our cells continuously produce these protective proteins? Why do antibodies to protective proteins confer protection rather than increased vulnerability? And what led to the evolution of their precisely timed expression? The fact that we do not constitutively (chronically) express HSP-70 may imply that there is a physiologic downside to its expression. This fact perhaps suggests some caution concerning long-term consequences of genetic manipulation designed to induce constitutive expression. In lieu of genetic manipulation, intracellular protein delivery strategies through liposomes have been effective in the treatment of acute injury. This mode of delivery has the advantages of rapid delivery and little stress, while avoiding the potential deleterious effects of constitutive expression.
In regard to the second question, it appears that these antibodies simply indicate that the protective proteins were released. Indeed these protective proteins, once induced, are active inside the cell, out of the reach of the antibodies to them. In regard to the evolution of heat shock protein production, several investigators have suggested that the stress associated with the "fight or flight" response may have led to the evolution of these proteins; ie, this adaptive response was conserved because it allowed the bearer to produce heat shock proteins as a survival advantage. In any case, Vogt and colleagues are to be congratulated for bringing us one step closer to understanding the mystery of HSP-70, and to unlocking its therapeutic potential for our patients.
Related Article
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Detection of anti-hsp70 immunoglobulin G antibodies indicates better outcome in coronary artery bypass grafting patients suffering from severe preoperative angina
- Sebastian Vogt, Irene Portig, Björn Kusch, Sabine Pankuweit, Abdul Sami Sirat, Dirk Troitzsch, Bernhard Maisch, and Rainer Moosdorf
Ann. Thorac. Surg. 2004 78: 883-889.
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