Abstract
Ischemic heart disease remains a leading cause of morbidity and mortality in the United States and other industrialized countries [1]. Ongoing research efforts within the biomedical science community seek to discover counter therapies that will mitigate ischemic damage in those with coronary artery disease. Candidate therapies are intended to invoke cardioprotection by pharmacologic activation of endogenous mechanisms of cellular protection [2]. In concept the process of pharmacologic development is fundamentally simple: a cardioprotective pathway against ischemic injury is discovered, animal-based experiments provide proof of concept for pharmacologic induction of cardioprotection, and then clinical trials are undertaken. The reality, however, is somewhat more complicated. Within the context of discovery at different organizational levels (isolated cells, isolated organs, whole animal), numerous cellular pathways that elicit robust cardioprotection against ischemic injury are now well characterized [3]. Translation of this knowledge into clinical practice has proven far more difficult than expected. The point is famously articulated in a 2004 position paper by preeminent physicians and scientists is Circulation Research, “over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice” [4]. Given the collective effort to date, this is the central question: What scientific breakthrough is needed to translate our understanding of cardiac preconditioning into clinical practice? The underlying premise of this editorial is that the major limitation of cardiac preconditioning research is the nature of the stimulus, which traditionally has been derived from ischemia-induced adaptations.
Highlights
Ischemic heart disease remains a leading cause of morbidity and mortality in the United States and other industrialized countries [1]
Ischemic preconditioning research is historically founded on the classic 1986 Murry study, which was the first to demonstrate that brief intervals of sub-lethal ischemia conferred a subsequent window of protection against an ischemic insult of longer duration [5]
The ischemic preconditioning phenotype is well characterized as a polygenic response with redundant protective mediators including up-regulation of myocardial inducible nitric oxide synthase, heat shock proteins (HSP) including HSP72, cyclooxygenase-2 (COX-2), and the sarcolemmal ATP-sensitive potassium channel (KATP)
Summary
Ischemic heart disease remains a leading cause of morbidity and mortality in the United States and other industrialized countries [1]. Ischemic preconditioning research is historically founded on the classic 1986 Murry study, which was the first to demonstrate that brief intervals of sub-lethal ischemia conferred a subsequent window of protection against an ischemic insult of longer duration [5]. The ischemic preconditioning phenotype is well characterized as a polygenic response with redundant protective mediators including up-regulation of myocardial inducible nitric oxide synthase (iNOS), heat shock proteins (HSP) including HSP72, cyclooxygenase-2 (COX-2), and the sarcolemmal ATP-sensitive potassium channel (KATP) (reviewed in [6]).
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