No Pain, No Gain
The Useful Function of Angina
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Myocardial ischemia, the major cause of mortality and morbidity in the United States, accounts for nearly 20% of all deaths.1 The prognosis of patients with acute myocardial infarction is strongly related to the amount of tissue destroyed during ischemia/reperfusion; hence, limiting this injury is of paramount importance for reducing the morbidity and mortality associated with ischemic heart disease.2,3 Over the past 40 years, several hundred pharmacological or nonpharmacological therapies have been reported to alleviate ischemia/reperfusion injury in experimental animal models; unfortunately, few of these results have been reproducible, and, with the exception of early reperfusion, none have been translated into clinical therapies.4 These sobering facts provide a cogent rationale for a reassessment of the models and methodologies that have been used heretofore to test the efficacy of putative cardioprotective interventions. The obvious translational failure in this field calls for a new paradigm in which preclinical studies must be done as rigorously as their clinical counterparts, that is, using clinically relevant animal models, appropriate statistical methods, and a multicenter, randomized, blinded design using centralized core laboratories for data analysis.4 This paradigm would also improve our understanding of the mechanism of cardiomyocyte death during ischemia/reperfusion.
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One facet of ischemic biology that has received relatively little attention is the role of cardiac sensory nerves. Myocardial ischemia/reperfusion is known to cause the release of bradykinin and protons, both of which activate the vanilloid receptor 1 (VR1, also known as transient receptor potential vanilloid type 1 [TRPV1]) on the capsaicin-sensitive cardiac sensory nerves (unmyelinated [type C] or thinly myelinated [A-δ] fibers).5 The VR1 is a nonselective cation channel that plays an important role in the polymodal detection of noxious stimuli such as low pH and heat.6 It can also be activated by chemicals such as capsaicin …