J Appl Physiol 103: 1436–1437, 2007;

Editorial doi:10.1152/japplphysiol.00834.2007.

HIGHLIGHTED TOPIC Perspectives in Innate and Acquired Cardioprotection

Acquired and innate cardioprotection

Andre Terzic,1 Russell L. Moore,2 and Scott A. Waldman3
1
Marriott Heart Disease Research Program, Divisions of Cardiovascular Diseases and Clinical Pharmacology, Departments
of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester,
Minnesota; 2Department of Integrative Physiology and Regent Administrative Center, University of Colorado, Boulder,
Colorado; 3Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Department of
Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

WITH AGING OF THE POPULATION, cardiovascular disease is the function, and lower in-hospital mortality rates. Dissection of
leading cause of death, disability, and morbidity across conti- disease processes thus offers an unprecedented opportunity to
nents. In a series of mini-reviews, the Journal of Applied identify and intervene in the earliest preclinical stages of

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Physiology highlights the most recent advances in molecular disease, prior to irreversible disruption of tissue and decom-
and integrative physiology that have provided new insights in pensation of organ function (7).
understanding the pathobiology of cardiovascular disease, es- Advances in the new biology have opened a window on
tablishing platforms for novel strategies of care, including the molecular ontogeny of heart disease syndromes, defining
disease risk prediction and prevention. Despite current aggres- the spatiotemporal sequence of genetic and molecular alter-
sive approaches in patient management, including reperfusion ations integrated at the systems level to form the mechanis-
therapy in the context of acute coronary syndrome, a limiting tic foundation from risk burden to development of overt
factor in averting poor outcome is the inherent susceptibility of disease. New emphasis placed on systems-based genomic
the myocardium to ischemic insult and lethal cell injury (3). approaches aims to stratify individual risk for coronary
Therefore the concept of cardioprotection has emerged as an artery disease and achieve targeted interventions for en-
important new direction aimed at protecting cardiac cells under hanced myocardial tolerance to injury. As pathways of
stress. Collectively, the confluence of genomics, proteomics, endogenous cardioprotection are increasingly deciphered,
metabolomics, molecular imaging, and applied systems biol- population-based validation of disease susceptibility has
ogy has enabled the resolution of the transcriptome and the created the prospect for implementation of the principles of
downstream signaling pathways, effectors, and mediators cen- personalized medicine. The sciences of molecular medicine
tral to innate or acquired myocardial protection, which are have indeed provided a powerful catalyst to generate inte-
corrupted in aging or with disease (4, 6). grated diagnostic and therapeutic paradigms tailored to the
In particular, the dissection of intimate processes fundamen- genetic and molecular profile of the individual patient to
tal to endogenous protective mechanisms has revealed that the enhance specificity of care, reduce therapeutic variability,
heart cannot simply be viewed as a collateral casualty of an and minimize adverse drug effects.
environmental challenge. Rather the myocardium senses and Concomitantly, the emergence of stem cell technology pro-
responds to stress, actively adapting its phenotype to secure vides a unique opportunity for myocardial regeneration (1).
self-preservation. Mapping the nucleocytoplasmic circuits of Cell-based clinical trials use adult stem cell approaches to
the stress response has led to the identification of biosensors repair damage sustained following acute myocardial infarction
and metabolic pathways responsible for decoding and trans- or restore pump function in congestive heart failure. While
ducing signals of distress, triggering a systems-level homeo- improvement in ejection fraction has been demonstrated, dis-
static reaction (5). This previously unrecognized myocardial crepancies in outcome raise the issue of cellular competence
plasticity underscores the paradigm of preventive therapy or and intertrial variability. It remains uncertain whether im-
“vaccination” against the sequelae of ischemia-reperfusion planted somatic stem cells reliably contribute to regeneration,
injury (2). Exposure to episodes of mild ischemia precon- whether the benefit of cellular therapy is derived from contri-
ditions the myocardium, reducing the impact of subsequent bution to myocardial contractility, or whether implanted cells
prolonged insult. Ischemic preconditioning underlies the create an environment promoting self-repair. A limiting factor
“warm-up” phenomenon first described by Heberden in the to establishing the benefit of a stem cell-based approach is the
18th Century. Severe angina during initial effort decreases in lack of appreciation of the most efficacious cell and the specific
intensity with subsequent exercise, a phenomenon also ob- underlying repair mechanism. With validation of cellular phe-
served in serial exercise testing. In fact, in certain patients, the notypes and optimizing performance, the next generation of
presence of angina before myocardial infarction has been clinical trials should achieve increasing intertrial consistency
associated with reduced infarct size, preservation of ventricular translating a novel cardioprotective modality from the bench to
the bedside (1).
Address for reprint requests and other correspondence: A. Terzic, Mayo
The promise that lies ahead is in the translation of funda-
Clinic, 200 First St. SW, Rochester, MN, 55905 (e-mail: terzic.andre mental principles of stress adaptation, probed in the experi-
@mayo.edu). mental setting and tested in discrete patient cohorts, into
1436 8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society http://www. jap.org
 Editorial
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ACKNOWLEDGMENTS 8. Yellon DM, Hausenloy DJ. Realizing the clinical potential of ischemic
A. Terzic is Marriott Family Professor of Cardiovascular Research of the preconditioning and postconditioning. Nat Clin Pract Cardiovasc Med 2:
Mayo Clinic. R. L. Moore is Associate Vice Chancellor for Research, Uni- 568 –575, 2005.

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J Appl Physiol • VOL 103 • OCTOBER 2007 • www.jap.org