Journal of Applied Physiology Watch the video to see how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 103: 2120-2128, 2007. First published August 23, 2007; doi:10.1152/japplphysiol.00647.2007
8750-7587/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
103/6/2120    most recent
00647.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jahangir, A.
Right arrow Articles by Terzic, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jahangir, A.
Right arrow Articles by Terzic, A.

INVITED REVIEW

HIGHLIGHTED TOPIC
Perspectives in Innate and Acquired Cardioprotection

Aging and cardioprotection

Arshad Jahangir, Sandeep Sagar, and Andre Terzic

Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, and Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics Mayo Clinic, Rochester, Minnesota


   ABSTRACT
TOP
 ABSTRACT
AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Advanced age is a strong independent predictor for death, disability, and morbidity in patients with structural heart disease. With the projected increase in the elderly population and the prevalence of age-related cardiovascular disabilities worldwide, the need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability, and the development of strategies to limit myocardial dysfunction in the elderly have never been more urgent. Experimental evidence in animal models indicate attenuation in cardioprotective pathways with aging, yet limited information is available regarding age-related changes in the human heart. Human cardiac aging generates a complex phenotype, only partially replicated in animal models. Here, we summarize current understanding of the aging heart stemming from clinical and experimental studies, and we highlight targets for protection of the vulnerable senescent myocardium. Further progress mandates assessment of human tissue to dissect specific aging-associated genomic and proteomic dynamics, and their functional consequences leading to increased susceptibility of the heart to injury, a critical step toward designing novel therapeutic interventions to limit age-related myocardial dysfunction and promote healthy aging.

senescence; ischemia; preconditioning; postconditioning; ATP-sensitive K+ channel; mitochondria; human

DESPITE ADVANCES IN PREVENTIVE and therapeutic strategies, cardiovascular disease remains the leading cause of death, disability, and morbidity in the elderly (133). The elderly account for >80% of patients with ischemic heart disease (Fig. 1), >75% of patients with congestive heart failure, and >70% of patients with atrial fibrillation (133). More than 80% of all acute myocardial infarction-related death occur in those 65 yr or older (9, 10, 113), with advanced age consistently identified as one of the strongest independent predictor for poor outcome in the population (55, 97, 151). It is projected that the number of elderly in the United States will double in the next 25 yr, and by the year 2030 >70 million people (~20% of the population) will be 65 yr and older (11). This change in population demographics, a worldwide phenomenon (Fig. 2), will result in a large increase in the prevalence of age-related cardiovascular disabilities (141) with a severe impact on the utilization of health care resources (49), underscoring the need to implement strategies that limit myocardial dysfunction in the elderly (Fig. 3). A critical step in the development of such approaches is the further understanding of mechanisms underlying age-dependent increase in the susceptibility of the heart to injury.


Figure 1
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 1. Number of patients in the United States of America diagnosed yearly with a heart attack according to age (in years) and sex. With data obtained from the Center for Disease Control, National Center for Health Statistics, and National Heart, Lung, and Blood Institute (Circulation 115: e69–e171, 2007). With permission from Lippincott Williams and Wilkins.

 

Figure 2
View larger version (55K):
[in this window]
[in a new window]

  		Fig. 2. World Health Organization projection of the geographical distribution of the elderly population. Today (A), and in year 2025 (B). Color code indicates the proportion of the country population exceeding 60 yr of age. The blue shade indicates countries with >20% of the population above 60 yr.

 

Figure 3
View larger version (48K):
[in this window]
[in a new window]

  		Fig. 3. Strategies to reduce aging-associated risk for coronary atherosclerosis, limit myocardial ischemia, and salvage myocardium by restoration of endogenous cardioprotective responses during stress. IPC, ichemic preconditioning; PCI, percutaneous coronary intervention; Ado, adenosine; BK, bradykinin, NE, norepinephrine; NO, nitric oxide; GPCR, G-protein-coupled receptors; KATP, ATP-sensitive K+ channel; mPTP, mitochondrial permeability transition pore.

 
Elderly are prone to myocardial dysfunction due to multiple factors, including greater severity of atherosclerosis and the negative impact of comorbidities such as hypertension, diabetes mellitus, renal dysfunction, and age-related cardiovascular structural and physiological changes (50, 96). These include degenerative changes in myocytes, as well as alterations in structure and composition of the extracellular matrix, rheostatic factors, and neurohormonal and autonomic influences (13, 33, 50, 95). Furthermore, the responsiveness of the aged heart to stress is altered with a concomitant attenuation of endogenous protective mechanisms increasing vulnerability to injury (5, 23, 143). The fundamental processes underlying aging and increased vulnerability, however, remain ill defined (107). This synopsis summarizes clinical and experimental evidence implicating the increased vulnerability of the aging heart, and highlights potential mechanisms underlying loss of endogenous cardioprotective responses.


   AGING WORSENS CLINICAL OUTCOMES IN ISCHEMIA-REPERFUSION
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Advanced age is one of the major independent predictor of adverse events in patients with ischemic heart disease (28). With each 10-yr increase in age, the odds for in-hospital death following an acute coronary event augments by 70% (55). In clinical trials of acute myocardial infarction and thrombolytic therapy, age has been shown to be one of the strongest independent variables associated with increased mortality after a heart attack (151, 154). The overall mortality rate in the European Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-2 trial was <2% among patients younger than 40 yr, compared with >30% in those 80 yr and older (151). In the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial patients at the upper quartile of the age distribution (~70 yr) with acute myocardial infarction treated with a thrombolytic agent were nearly four times more likely to die within 30 days than patients at the lowest quartile (~50 yr) (103). Advanced age in patients is associated with a more severe hemodynamic compromise, left ventricular dysfunction, heart failure, electromechanical dissociation, and cardiac rupture compared with younger age in patients presenting with acute myocardial infarction (113, 115, 125), despite the fact that the infarct size and the extent of coronary artery disease may not be different between the different age groups (103). During follow-up after an acute myocardial infarction, the mortality rate is about six times higher among those 70 yr and older compared with those 60 yr or younger. The relationship between advanced age and increased mortality is independent of other clinical and angiographic variables, such as gender, presence of hypertension, diabetes mellitus, time to treatment, previous myocardial infarction, infarct location, number of diseased coronary arteries, and patency of the infarct-related vessel (97, 113). These and other studies (9, 97, 108, 113) moreover indicate that the aged myocardium displays a higher vulnerability to metabolic insults with a reduced ability to recover. The mechanisms for a higher susceptibility to damage resulting in increased mortality, greater ventricular dysfunction, heart failure, and arrhythmias in the elderly are not fully understood.


   AGING REDUCES ENDOGENOUS CARDIOPROTECTION
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
The greater vulnerability of the aged heart to metabolic insults has also been demonstrated in animal models. In isolated perfused heart preparations controlling for variables, such as collateral flow, cellular blood elements, and hemodynamic factors, the greater susceptibility of the senescent heart to ischemia-reperfusion injury has been confirmed in a number of species (5, 45, 96, 101, 144). This occurs without change in the threshold for myocardial ischemia, collateral flow, or area at risk for infarction, indicating an aging-related decreases in intrinsic myocardial resistance to ischemic injury (3, 45, 155). Two major endogenous protective responses, ischemic preconditioning and postconditioning, have been identified in the heart. Ischemic preconditioning has been recognized as one of the most powerful endogenous cardioprotective mechanisms, whereby transient non-lethal ischemic events render the myocardium resistant to subsequent prolonged ischemia limiting infarct size, myocardial dysfunction, and arrhythmogenesis following reperfusion (59, 119, 158). This protective response can also be activated by other noxious stimuli, such as heat-stress, rapid pacing, or exposure to endotoxin, cytokines or reactive oxygen species (ROS) (29). Brief exposure to ischemia results in two distinct phases of preconditioning: an early phase that develops within a few minutes and last for ~1–2 h and a late phase that develops over 6–12 h but may last for up to 4 days (29, 42, 109, 158). Complex signaling cascades are activated by a preconditioning stimulus, and they may involve rapid posttranslational modification of preexisting proteins that in turn activate effectors of the early preconditioning response (42, 58, 92). The late-phase protection occurs due to stress induced alteration in expression of a number of stress-responsive and protective proteins that act in concert to mediate cardioprotection (9, 29, 42). Brief repetitive interruptions in blood flow in the early minutes of reperfusion, the so-called postconditioning response have also been shown to be cardioprotective against reperfusion injury by limiting infarct size (58, 88, 140, 160). It appears that cardioprotection by both ischemic preconditioning and postconditioning recruit similar signaling pathways (34, 58, 68, 89).

Although the cardioprotective ischemic preconditioning response has been documented in every species tested (131), it is attenuated in the senescent heart (5, 45, 137, 144). Indirect evidence also indicate that the cardioprotective effect of transient ischemia before subsequent prolonged ischemia is attenuated in the aging human heart (23). Protection due to preinfarction angina within 48 h of the onset of myocardial infarction, a clinical correlate of ischemic preconditioning associated with a lower incidence of in-hospital mortality, heart failure, cardiogenic shock, and myocardial necrosis observed in younger patients has been reported to be lost in the elderly by most (3, 74, 89) but not all (107, 131) investigators. In addition, studies with biochemical markers of injury (31, 98), warm-up angina (120) or electrocardiographic ischemic changes during coronary angioplasty (78, 98) are also supportive of the apparent attenuation of the ischemic preconditioning response in the aging human heart.


   MECHANISMS UNDERLYING INCREASED SUSCEPTIBILITY OF SENESCENT HEART
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Advanced age is a major risk factor associated with poor cardiovascular outcome (9, 10, 95, 132), with aging associated with multiple comorbidities that increases the likelihood of myocardial damage (13, 96). Yet, the fundamental processes that lead to cardiac senescence and to loss of myocardial capacity to protect itself are not fully understood (6, 112, 142). Notwithstanding, elucidation of mechanisms underlying increased tolerance of the heart to ischemia and its loss with aging are of major clinical significance (159). Abnormalities in mitochondrial function, calcium handling, oxidative stress, and cardioprotective signaling have all been proposed to be potentially implicated (26, 39, 102, 105, 118, 126). A number of transducers of the cardioprotective pathway have been identified, including receptor- and protein kinase-mediated signal cascades that activate effectors of cardioprotection, yet a single final effector remains elusive (41, 67, 153, 156, 158). Considered critical in myopreservation is the preservation of ionic and energetic homeostasis, with mitochondria and cellular metabolic sensors playing a vital role (59, 84, 91, 118, 153, 159).


   MITOCHONDRIAL DYSFUNCTION AND IMPAIRED ENERGETIC RESERVE IN AGING
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Age-associated deficits in myocardial performance, which typically manifest on exposure to increased metabolic demand during stress, are multifactorial. Heart muscle, an aerobic tissue with high energy demand is dependent on adequate energy supply from mitochondrial oxidative phosphorylation that provides >70% of ATP (135). A dysfunction in mitochondrial electron transport or oxidative phosphorylation increases the susceptibility to injury by limiting energetic reserves under conditions of increased demand (39, 122). In addition mitochondria also help regulate cellular ionic homeostasis, ROS, generation and cell death-survival signals that initiate necrosis or apoptosis following injury (39, 46, 65, 121). An age-associated decrease in mitochondrial substrate oxidation and activity of the oxidative phosphorylation pathway has been documented (21, 63, 76) with reduction in the activity of the respiratory chain components, adenine nucleotide translocase activity and changes in mitochondrial matrix and membrane lipid pattern (35, 43, 100, 127). These changes are associated with a reduced energetic reserve and an increase in myocardial susceptibility to calcium overload and oxidative injury during stress precipitating myocardial dysfunction (20, 39, 47, 54, 76, 94, 157). Mitochondria are also central to endogenous cardioprotection and play a critical role in defining tolerance of the heart to noxious stimuli (34–36, 40, 118). A critical process in initiating cell death is the opening of the mitochondrial permeability transition pore (mPTP), a nonspecific high conductance channel in the inner mitochondrial membrane (40) that causes mitochondrial uncoupling and swelling resulting in energetic failure, disruption of ionic homeostasis, and promotion of cell death following ischemia-reperfusion injury (39, 54, 65). Prevention of mPTP opening protects the myocardium against lethal injury and appears to be involved in cardioprotection by ischemic preconditioning, but exact mechanisms underlying protection are not known (34–36, 64, 104, 138). An increased sensitivity to stress-mediated opening of mPTP has been demonstrated in senescent mitochondria from lymphocytes (134), liver and brain (53, 110), as well as heart (75); however, the underlying mechanisms are not known and could be related to aging-associated impairment in calcium handling capacity (76) or alteration in adenine nucleotide translocase (157), voltage-dependent anion channel (85), or cyclophilin D (90) structure or function. Whether aging-associated changes in mPTP sensitivity described in rodent mitochondria (53, 76, 110, 134) also occur in human cardiac mitochondria is not known, and it is unclear whether interventions that prevent mitochondrial calcium overload or mPTP opening during stress (36, 39, 69, 72) are effective in protecting the senescent human heart.


   INCREASED OXIDANT DAMAGE IN AGING
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Oxidative stress plays a major role in disease processes, especially in the senescent heart. Normally, a balance exists between oxidant production as a by-product of normal intracellular metabolism and the antioxidant defense system that counteracts and regulates overall free radical levels maintaining physiological homeostasis (46). The level of oxygen radical production increases following ischemia-reperfusion, perturbing the normal redox balance and shifting the cell into a state of oxidative stress (46, 130). The interruption of oxygen delivery to mitochondria during ischemia results in accumulation of electrons in the respiratory chain at redox centers susceptible to electron leak, such as the NADH dehydrogenase in the respiratory chain complex I and the ubiquinone in the respiratory chain complex III, which is then partially reduced to ubisemiquinone, which on reperfusion reacts with oxygen to produce superoxide anion. This in turn is rapidly transformed into hydrogen peroxide by superoxide dismutases (SOD) (99), and hydrogen peroxide is further reduced to the hydroxyl group. Superoxide anion, hydrogen peroxide, or hydroxyl group can directly affect respiratory chain components (complex I and III, ATPase and the adenine nucleotide translocase) or cause mitochondrial genomic damage that over time creates a progressive decline in mitochondrial function in the aging heart (66, 148, 149). Free radicals also react with key cellular constituents, including proteins, lipids, and nucleic acids, increasing their susceptibility to injury (46, 130). Activation of signaling pathways contributes to additional cellular dysfunction further impairing functional reserves and the responsiveness of cardiomyocytes to metabolic stress, compromising thereby their viability (46, 149). Interaction of ROS with nitric oxide causes incremental damage by generation of peroxynitrite and other reactive nitrogen species that produce irreversible nitration of mitochondrial and cellular proteins (24, 37). Among antioxidant defenses, the mitochondrial form of SOD or MnSOD (SOD-2) is particularly important in securing ROS clearance and its lack results in generalized mitochondrial dysfunction and organ damage (117). Similarly, the cytosolic isoform CuZnSOD (SOD-1) reduces superoxide anion to hydrogen peroxide, whereas catalase and glutathione peroxidase catalyze the reduction of hydrogen peroxide to water. Quinones, ascorbates, and tocopherols also form part of this antioxidant system and act as strong scavengers of free radicals. With aging, a decrease in the antioxidative capacity along with increased oxidant production occurs. A shift in the oxidant-antioxidant balance in favor of enhanced oxidation contributes to the increased sensitivity of cellular and subcellular structures to damage, overwhelming the cardioprotective signaling function of otherwise low ROS levels (46, 51, 80, 114, 150, 152).


   CALCIUM OVERLOAD SUSCEPTIBILITY IN AGING
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 
Aging results in a reduced threshold for calcium overload (20, 47). Postreperfusion, a greater myocardial dysfunction occurs in the senescent compared with adult hearts, with a delayed recovery of contractile function and increased susceptibility to arrhythmias (20). The functional recovery of the ventricle is inversely related to intracellular calcium loading during ischemia, and this appears more severe in aged heart (20, 81). Altered cytosolic calcium handling in the senescent heart is due to reduction in the density and activity of calcium regulating proteins both in the sarcolemma (Na+/Ca2+ exchanger), and the sarcoplasmic reticulum (Ca2+-ATPase and ryanodine receptor) (18, 26, 32, 86). This results in a reduction in calcium extrusion and impaired sequestration into sarcoplasmic reticulum, both at baseline and during stress leading to greater calcium overload (18, 87, 111). The increased calcium in the aged heart is deleterious because of direct cellular injury with activation of calcium-dependent phospholipases, proteases, and nucleases, and indirectly through depletion of cellular ATP by inhibition of oxidative phosphorylation (71) and enhanced consumption of ATP due to activation of calcium ATPases. In addition, modification of cardiolipin content and composition in mitochondria (128) impair calcium homeostasis, predisposing to increased mitochondrial calcium load and mitochondrial damage due to opening of the mPTP (64) precipitating energetic failure and cellular injury (39, 65, 118).


   PROTECTION OF THE SENESCENT HEART FROM INJURY
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
GRANTS
 REFERENCES
 
Strategies to protect the heart against ischemic injury currently involve early reperfusion following acute myocardial infarction (9, 10) or interventions that reduce energy demands during ischemia, such as hypothermia or cardioplegic solutions during cardiac surgery or drugs, such as β-adrenergic receptor blockers that reduce cardiac workload by decreasing heart rate, afterload, and contractility (Fig. 3) (12). In addition to these established therapeutic strategies, activation of endogenous protective responses by stimuli applied immediately before ischemia (ischemic preconditioning) or at reperfusion (postconditioning) have been demonstrated to increase myocardial tolerance to ischemia-reperfusion injury (58, 80, 140). These innate cardioprotective responses that persist even after the initiating stimulus is withdrawn are attractive targets to achieve persistent cardioprotection by activating receptors, signaling cascade or effector(s) mediating cardioprotection (29, 34, 58, 68). Insights into mechanisms underlying ischemic preconditioning or postconditioning have resulted in the exploration of novel therapeutic avenues. This has included administration of exogenous or promotion of endogenous production of cardioprotective adenosine, nitric oxide, or opioids that trigger protective signal transduction pathways (29, 42, 52, 57). Similarly, drugs that directly activate or increase the synthesis of cardioprotective proteins have been considered to enhance tolerance of the senescent heart against injury. In this way, the cardioprotective effects of ischemic preconditioning can be mimicked by treatment with various drugs that precondition the heart to produce a similar degree of protection against ischemic injury as induced by transient ischemia (Fig. 3) (60, 61). These drugs, which include potassium channel openers (56, 77), volatile anesthetics (142) and various agonists of G protein-coupled receptors (29, 42, 93), need to be further evaluated in randomized clinical trials to assess their effectiveness in protecting the senescent human heart against ischemia-reperfusion injury (30, 77, 88, 159).

Recent findings that both short- and long-term regular exercise partially reinstate the ability of the senescent myocardium to tolerate ischemia-reperfusion injury reducing infarct size in animal models as well as improve outcomes following myocardial ischemia in humans and the improvement in cardiac tolerance with short-term caloric restriction (1, 4, 6, 7, 139) opens up an additional opportunity for lifestyle and dietary modulation to limit myocardial dysfunction in elderly patients (139). Interventions that target signaling cascades or receptors that restore endogenous cardioprotective responses with exercise, caloric restriction or ischemic pre- or postconditioning responses such as upregulation of heat shock proteins and regulatory kinases, ROS production, mPTP inhibition, and improvement in energetics of the heart during stress are all potential strategies that needs to be systematically studied in humans to identify their beneficial effect in reducing morbidity in the elderly following an acute coronary event (17, 29, 34, 38, 42, 104, 129).

A case in point is the modulation of the cardioprotective potential of ATP-sensitive K+ (KATP) channels. A value for targeting KATP channels, metabolic sensors that by virtue of nucleotide-dependent gating link cellular metabolic state to cellular excitability (59, 84, 123, 145), have been demonstrated through use of KATP channel openers that mimic and inhibitors that abolish protection afforded by ischemic preconditioning (59, 77, 83, 161). Overexpression of KATP channel genes confers increased resistance to cells otherwise vulnerable to stress (17, 62, 82, 116, 161), whereas deletion results in maladaptation and loss of protection (27, 62, 82, 106). In humans, KATP channel mutations have been associated with increased susceptibility to heart failure and/or increased arrhythmogenesis (106, 124). Therefore, further studies to delineate the role of modulators of KATP channel function in aging-associated loss of preconditioning are warranted (32, 76, 77, 79).

Mitochondrial uncoupling by protonophores (73) and potassium channel openers (48, 71) also protects against metabolic stress by reduction in mitochondrial calcium overload, inhibition of mPTP opening, and decrease in stress-induced increase in ROS production that translate into improved cardioprotection against ischemia-reperfusion injury (48, 70–72). A mitochondrial potassium conductance has been proposed within the inner mitochondrial membrane that contributes to cardioprotection against ischemia reperfusion injury (16, 48, 59). A multiprotein complex consisting of succinate dehydrogenase, mitochondrial ATP-binding cassette protein 1, phosphate carrier, adenine nucleotide translocase, and ATP synthase has been proposed to reconstitute this channel (15), providing additional opportunity for therapy.

The identification of stem cells in the heart or in peripheral tissues such as the bone marrow that have the potential to differentiate into myocardial, endothelial, and vascular tissue has provided the impetus for cell-based therapies as a strategy to replace damaged myocardium and/or promote endogenous cardioprotective responses (22, 25). These multipotent cells have been shown to improve cardiac function when transplanted in to scarred myocardium in experimental models (25, 44) and to be safe in human clinical trials indicating their potential usefulness as cell-based therapy (19, 136, 146). However, because of genomic instability from decreased telomerase activity and increased oxidant injury with aging, the ability of the progenitor cells to differentiate or replicate may decrease and limit their utility for cell-replacement therapy in the elderly (14, 22, 147). Therefore, long-term efficacy in improving clinical outcomes under physiological and pathological stresses associated with pressure or volume overload and atherosclerotic vascular disease present in the elderly needs to be further defined.

As the life expectancy increases and demographics continue to shift with increase in the number of elderly suffering from cardiovascular diseases (132, 133), there is a greater need to understand the biology of the aging heart and to apply strategies to limit the burden of cardiovascular disabilities in our most rapidly growing population, ultimately reducing the impact on health care resources. A wealth of information has been accumulated on the effect of aging on cardiovascular function in animal models and humans, yet the molecular basis for age-associated alteration in myocardial function and tolerability to stress is not fully understood. Because human cardiac aging is associated with a complex phenotype that cannot be completely replicated in animal models, key determinants of aging-associated myocardial dysfunction can be missed, necessitating a direct assessment of human tissue to detect aging-associated changes in gene expression, protein modification and functional alteration to understand the basis for increased susceptibility of the heart to injury and disease progression in elderly patients. Insights into age-associated molecular changes underlying altered cardiac energetics, sensitivity to oxidative stress and cardioprotective pathways will advance our understanding of the biology of aging and provide targets for the development of novel therapeutics to prevent, slow, or reverse changes that increases vulnerability of the senescent heart to injury.


   GRANTS
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
REFERENCES
 
This work was supported by National Institute on Aging Grant AG-21201; National Heart, Lung, and Blood Institute Grants HL-64822 and HL-83439; the Mayo Clinic Robert and Arlene Kogod Program on Aging; and the Marriott Heart Disease Research Program, Marriott Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Jahangir, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (e-mail: jahangir.arshad{at}mayo.edu)


   REFERENCES
TOP
 ABSTRACT
 AGING WORSENS CLINICAL OUTCOMES...
 AGING REDUCES ENDOGENOUS...
 MECHANISMS UNDERLYING INCREASED...
 MITOCHONDRIAL DYSFUNCTION AND...
 INCREASED OXIDANT DAMAGE IN...
 CALCIUM OVERLOAD SUSCEPTIBILITY...
 PROTECTION OF THE SENESCENT...
 GRANTS
 REFERENCES
 

  1. Abete P, Calabrese C, Ferrara N, Cioppa A, Pisanelli P, Cacciatore F, Longobardi G, Napoli C, Rengo F. Exercise training restores ischemic preconditioning in the aging heart. J Am Coll Cardiol 36: 643–650, 2000.[Abstract/Free Full Text]
  2. Abete P, Cioppa A, Calabrese C, Pascucci I, Cacciatore F, Napoli C, Carnovale V, Ferrara N, Rengo F. Ischemic threshold and myocardial stunning in the aging heart. Exp Gerontol 34: 875–884, 1999.[CrossRef][Web of Science][Medline]
  3. Abete P, Ferrara N, Cacciatore F, Madrid A, Bianco S, Calabrese C, Napoli C, Scognamiglio P, Bollella O, Cioppa A, Longobardi G, Rengo F. Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart? J Am Coll Cardiol 30: 947–954, 1997.[Abstract]
  4. Abete P, Ferrara N, Cacciatore F, Sagnelli E, Manzi M, Carnovale V, Calabrese C, de Santis D, Testa G, Longobardi G, Napoli C, Rengo F. High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients. J Am Coll Cardiol 38: 1357–1365, 2001.[Abstract/Free Full Text]
  5. Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol 27: 1777–1786, 1996.[Abstract]
  6. Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol 282: H1978–H1987, 2002.[Abstract/Free Full Text]
  7. Abete P, Testa G, Galizia G, Mazzella F, Della Morte D, de Santis D, Calabrese C, Cacciatore F, Gargiulo G, Ferrara N, Rengo G, Sica V, Napoli C, Rengo F. Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart. Exp Gerontol 40: 43–50, 2005.[CrossRef][Web of Science][Medline]
  8. Ahmad N, Wang Y, Haider KH, Wang B, Pasha Z, Uzun O, Ashraf M. Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning. Am J Physiol Heart Circ Physiol 290: H2402–H2408, 2006.[Abstract/Free Full Text]
  9. Alexander KP, Newby LK, Armstrong PW, Cannon CP, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation 115: 2570–2589, 2007.[Abstract/Free Full Text]
  10. Alexander KP, Newby LK, Cannon CP, Armstrong PW, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM. Acute coronary care in the elderly, part I: Non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation 115: 2549–2569, 2007.[Abstract/Free Full Text]
  11. Anonymous. Trends in aging–United States and worldwide. MMWR Morb Mortal Wkly Rep 52: 101–104, 106, 2003.[Medline]
  12. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 110: e82–e292, 2004.[Free Full Text]
  13. Anversa P, Hiler B, Ricci R, Guideri G, Olivetti G. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol 8: 1441–1448, 1986.[Abstract]
  14. Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A, Kajstura J, Bolli R. Myocardial aging–a stem cell problem. Basic Res Cardiol 100: 482–493, 2005.[CrossRef][Web of Science][Medline]
  15. Ardehali H, Chen Z, Ko Y, Mejia-Alvarez R, Marban E. Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Proc Natl Acad Sci USA 101: 11880–11885, 2004.[Abstract/Free Full Text]
  16. Ardehali H, O'Rourke B. Mitochondrial K(ATP) channels in cell survival and death. J Mol Cell Cardiol 39: 7–16, 2005.[CrossRef][Web of Science][Medline]
  17. Ashraf M, Suleiman J, Ahmad M. Ca2+ preconditioning elicits a unique protection against the Ca2+ paradox injury in rat heart. Role of adenosine fixed. Circ Res 74: 360–367, 1994.[Abstract/Free Full Text]
  18. Ashton KJWL, Holmgren K, Ferreira L, Headrick JP. Age-associated shifts in cardiac gene transcription and transcriptional responses to ischemic stress. Exp Gerontol 41: 189–204, 2006.[CrossRef][Web of Science][Medline]
  19. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 355: 1222–1232, 2006.[Abstract/Free Full Text]
  20. Ataka K, Chen D, Levitsky S, Jimenez E, Feinberg H. Effect of aging on intracellular Ca2+, pH, and contractility during ischemia and reperfusion. Circulation 86: 371–376, 1992.
  21. Bak MI, Wei JY, Ingwall JS. Interaction of hypoxia and aging in the heart: analysis of high energy phosphate content. J Mol Cell Cardiol 30: 661–672, 1998.[CrossRef][Web of Science][Medline]
  22. Ballard VL, Edelberg JM. Stem cells and the regeneration of the aging cardiovascular system. Circ Res 100: 1116–1127, 2007.[Abstract/Free Full Text]
  23. Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg 76: 105–111, 2003.[Abstract/Free Full Text]
  24. Beckman K, Ames B. The free radical theory of aging matures. Physiol Rev 78: 547–581, 1998.[Abstract/Free Full Text]
  25. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763–776, 2003.[CrossRef][Web of Science][Medline]
  26. Besse S, Delcayre C, Chevalier B, Hardouin S, Heymes C, Bourgeois F, Moalic JM, Swynghedauw B. Is the senescent heart overloaded and already failing? Cardiovasc Drugs Ther 8: 581–587, 1994.[CrossRef][Web of Science][Medline]
  27. Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 36: 382–387, 2004.[CrossRef][Web of Science][Medline]
  28. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, Lincoff AM, Califf RM, Topol EJ, Simoons ML. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients The PURSUIT Investigators. Circulation 101: 2557–2567, 2000.[Abstract/Free Full Text]
  29. Bolli R. Preconditioning: a paradigm shift in the biology of myocardial ischemia. Am J Physiol Heart Circ Physiol 292: H19–H27, 2007.[Abstract/Free Full Text]
  30. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 95: 125–134, 2004.[Abstract/Free Full Text]
  31. Buyukates M, Kalaycioglu S, Oz E, Soncul H. Effects of ischemic preconditioning in human heart. J Card Surg 20: 241–245, 2005.[CrossRef][Web of Science][Medline]
  32. Cabrera Aguilera C, Oberlin A, Raghavakaimal S, Morlan B, Jahangir A. Aging-induced reprogramming of genes regulating cardiac excitability and refractoriness. Heart Rhythm 2: S262, 2005.
  33. Capasso JM, Palackal T, Olivetti G, Anversa P. Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts. Am J Physiol Heart Circ Physiol 259: H1086–H1096, 1990.[Abstract/Free Full Text]
  34. Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol 292: C137–C147, 2007.[Abstract/Free Full Text]
  35. Chicco AJ, Sparagna GC. Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292: C33–C44, 2007.[Abstract/Free Full Text]
  36. Crompton M. Mitochondria and aging: a role for the permeability transition? Aging Cell 3: 3–6, 2004.[CrossRef][Web of Science][Medline]
  37. Davidson SM, Duchen MR. Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance. Cardiovasc Res 71: 10–21, 2006.[Abstract/Free Full Text]
  38. Demirel HA, Hamilton KL, Shanely RA, Tumer N, Koroly MJ, Powers SK. Age and attenuation of exercise-induced myocardial HSP72 accumulation. Am J Physiol Heart Circ Physiol 285: H1609–H1615, 2003.[Abstract/Free Full Text]
  39. Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing a hole. Cardiovasc Res 70: 191–199, 2006.[Abstract/Free Full Text]
  40. Di Lisa F, Bernardi P. Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition. Cardiovasc Res 66: 222–232, 2005.[Abstract/Free Full Text]
  41. Downey JM, Cohen MV. Unraveling the mysteries of classical preconditioning. J Mol Cell Cardiol 39: 845–848, 2005.[CrossRef][Web of Science][Medline]
  42. Downey JM, Davis AM, Cohen MV. Signaling pathways in ischemic preconditioning. Heart Fail Rev 12: 181–188, 2007.[CrossRef][Web of Science][Medline]
  43. Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25: 365–451, 2004.[Medline]
  44. Ellison GM, Torella D, Karakikes I, Nadal-Ginard B. Myocyte death and renewal: modern concepts of cardiac cellular homeostasis. Nat Clin Pract Cardiovasc Med 4, Suppl 1: S52–S59, 2007.[CrossRef][Medline]
  45. Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 32: 1371–1375, 2000.[CrossRef][Web of Science][Medline]
  46. Finkel T, Holbrook N. Oxidants, oxidative stress and the biology of ageing. Nature 408: 239–247, 2000.[CrossRef][Medline]
  47. Frolkis V, Frolkis R, Mkhitarian L, Shevchuk V, Fraifeld V, Vakulenko L, Syrovy I. Contractile function and Ca2+ transport system of myocardium in ageing. Gerontology 34: 64–74, 1988.[Web of Science][Medline]
  48. Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P. Mitochondrial potassium transport: the role of the mitochondrial ATP-sensitive K(+) channel in cardiac function and cardioprotection. Biochim Biophys Acta 1606: 1–21, 2003.[Medline]
  49. Garrett N, Martini EM. The boomers are coming: a total cost of care model of the impact of population aging on the cost of chronic conditions in the United States. Dis Manag 10: 51–60, 2007.[CrossRef][Medline]
  50. Gerstenblith G, Frederiksen J, Yin FC, Fortuin NJ, Lakatta EG, Weisfeldt ML. Echocardiographic assessment of a normal adult aging population. Circulation 56: 273–278, 1977.[Abstract/Free Full Text]
  51. Gil L, Siems W, Mazurek B, Gross J, Schroeder P, Voss P, Grune T. Age-associated analysis of oxidative stress parameters in human plasma and erythrocytes. Free Radic Res 40: 495–505, 2006.[CrossRef][Web of Science][Medline]
  52. Gong L, Pitari GM, Schulz S, Waldman SA. Nitric oxide signaling: systems integration of oxygen balance in defense of cell integrity. Curr Opin Hematol 11: 7–14, 2004.[CrossRef][Web of Science][Medline]
  53. Goodell S, Cortopassi G. Analysis of oxygen consumption and mitochondrial permeability with age in mice. Mech Ageing Dev 101: 245–256, 1998.[CrossRef][Web of Science][Medline]
  54. Gottlieb RA. Mitochondrial signaling in apoptosis: mitochondrial daggers to the breaking heart. Basic Res Cardiol 98: 242–249, 2003.[Web of Science][Medline]
  55. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 163: 2345–2353, 2003.[Abstract/Free Full Text]
  56. Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res 70: 212–221, 2006.[Abstract/Free Full Text]
  57. Gross ER, Hsu AK, Gross GJ. GSK3beta inhibition and K(ATP) channel opening mediate acute opioid-induced cardioprotection at reperfusion. Basic Res Cardiol 102: 341–349, 2007.[CrossRef][Web of Science][Medline]
  58. Gross GJ, Auchampach JA. Reperfusion injury: does it exist? J Mol Cell Cardiol 42: 12–18, 2007.[CrossRef][Web of Science][Medline]
  59. Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol 285: H921–H930, 2003.[Abstract/Free Full Text]
  60. Gumina RJ, El Schultz J, Moore J, Beier N, Schelling P, Gross GJ. Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning. Cardiovasc Drugs Ther 19: 315–322, 2005.[CrossRef][Web of Science][Medline]
  61. Gumina RJ, Jahangir A, Gross GJ, Terzic A. Cardioprotection: emerging pharmacotherapy. Expert Opin Pharmacother 2: 739–752, 2001.[CrossRef][Medline]
  62. Gumina RJ, Pucar D, Bast P, Hodgson DM, Kurtz CE, Dzeja PP, Miki T, Seino S, Terzic A. Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics. Am J Physiol Heart Circ Physiol 284: H2106–H2113, 2003.[Abstract/Free Full Text]
  63. Hagen TM. Oxidative stress, redox imbalance, and the aging process. Antioxid Redox Signal 5: 503–506, 2003.[CrossRef][Web of Science][Medline]
  64. Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34: 232–237, 2006.[CrossRef][Web of Science][Medline]
  65. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res 61: 372–385, 2004.[Abstract/Free Full Text]
  66. Halestrap AP, Doran E, Gillespie JP, O'Toole A. Mitochondria and cell death. Biochem Soc Trans 28: 170–177, 2000.[Web of Science][Medline]
  67. Hanley PJ, Daut J. K(ATP) channels and preconditioning: a re-examination of the role of mitochondrial K(ATP) channels and an overview of alternative mechanisms. J Mol Cell Cardiol 39: 17–50, 2005.[CrossRef][Web of Science][Medline]
  68. Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70: 240–253, 2006.[Abstract/Free Full Text]
  69. Holmuhamedov E, Jovanovic S, Dzeja P, Jovanovic A, Terzic A. Mitochondrial ATP-sensitive K+ channels modulate cardiac mitochondrial function. Am J Physiol Heart Circ Physiol 275: H1567–H1576, 1998.[Abstract/Free Full Text]
  70. Holmuhamedov E, Lewis L, Bienengraeber M, Holmuhamedova M, Jahangir A, Terzic A. Suppression of human tumor cell proliferation through mitochondrial targeting. FASEB J 16: 1010–1016, 2002.[Abstract/Free Full Text]
  71. Holmuhamedov E, Ozcan C, Jahangir A, Terzic A. Restoration of Ca2+-inhibited oxidative phosphorylation in cardiac mitochondria by mitochondrial Ca2+ unloading. Mol Cell Biochem 220: 135–140, 2001.[CrossRef][Web of Science][Medline]
  72. Holmuhamedov E, Wang L, Terzic A. ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol 519: 347–360, 1999.[Abstract/Free Full Text]
  73. Holmuhamedov EL, Jahangir A, Oberlin A, Komarov A, Colombini M, Terzic A. Potassium channel openers are uncoupling protonophores: implication in cardioprotection. FEBS Lett 568: 167–170, 2004.[CrossRef][Web of Science][Medline]
  74. Ishihara M, Sato H, Tateishi H, Kawagoe T, Shimatani Y, Ueda K, Noma K, Yumoto A, Nishioka K. Beneficial effect of prodromal angina pectoris is lost in elderly patients with acute myocardial infarction. Am Heart J 139: 881–888, 2000.[Web of Science][Medline]
  75. Jahangir A, Holmuhamedov E, Ozcan C, Terzic A. Aging impairs cardiac mitochondrial functions: Protective effect of diazoxide on Ca2+ mediated injury. Cardiovasc Drugs Ther 15: 46, 2001.
  76. Jahangir A, Ozcan C, Holmuhamedov E, Terzic A. Increased calcium vulnerability of senescent cardiac mitochondria: Protective role for a mitochondrial potassium channel opener. Mech Ageing Devel 122: 1073–1086, 2001.[CrossRef][Web of Science][Medline]
  77. Jahangir A, Terzic A. K(ATP) channel therapeutics at the bedside. J Mol Cell Cardiol 39: 99–112, 2005.[CrossRef][Web of Science][Medline]
  78. Jneid H, Leessar M, Bolli R. Cardiac preconditioning during percutaneous coronary interventions. Cardiovasc Drugs Ther 19: 211–217, 2005.[CrossRef][Web of Science][Medline]
  79. Jovanovic A. Ageing, gender and cardiac sarcolemmal K(ATP) channels. J Pharm Pharmacol 58: 1585–1589, 2006.[CrossRef][Web of Science][Medline]
  80. Judge S, Leeuwenburgh C. Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol Cell Physiol 292: C1983–C1992, 2007.[Abstract/Free Full Text]
  81. Juhaszova M, Rabuel C, Zorov DB, Lakatta EG, Sollott SJ. Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res 66: 233–244, 2005.[Abstract/Free Full Text]
  82. Kane GC, Behfar A, Dyer RB, O'Cochlain DF, Liu XK, Hodgson DM, Reyes S, Miki T, Seino S, Terzic A. KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension. Hum Mol Genet 15: 2285–2297, 2006.[Abstract/Free Full Text]
  83. Kane GC, Behfar A, Yamada S, Perez-Terzic C, O'Cochlain F, Reyes S, Dzeja PP, Miki T, Seino S, Terzic A. ATP-sensitive K+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits. Diabetes 53, Suppl 3: S169–S175, 2004.[Abstract/Free Full Text]
  84. Kane GC, Liu XK, Yamada S, Olson TM, Terzic A. Cardiac KATP channels in health and disease. J Mol Cell Cardiol 38: 937–943, 2005.[CrossRef][Web of Science][Medline]
  85. Kanski J, Behring A, Pelling J, Schoneich C. Proteomic identification of 3-nitrotyrosine-containing rat cardiac proteins: effects of biological aging. Am J Physiol Heart Circ Physiol 288: H371–H381, 2005.[Abstract/Free Full Text]
  86. Kaplan P, Jurkovicova D, Babusikova E, Hudecova S, Racay P, Sirova M, Lehotsky J, Drgova A, Dobrota D, Krizanova O. Effect of aging on the expression of intracellular Ca(2+) transport proteins in a rat heart. Mol Cell Biochem 301: 219–226, 2007.[CrossRef][Web of Science][Medline]
  87. Kaufman TM, Horton JW, White DJ, Mahony L. Age-related changes in myocardial relaxation and sarcoplasmic reticulum function. Am J Physiol Heart Circ Physiol 259: H309–H316, 1990.[Abstract/Free Full Text]
  88. Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarction: where do we stand in 2004? J Am Coll Cardiol 44: 276–286, 2004.[Abstract/Free Full Text]
  89. Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 70: 297–307, 2006.[Abstract/Free Full Text]
  90. Kristal BS, Park BK, Yu BP. 4-Hydroxyhexenal is a potent inducer of the mitochondrial permeability transition. J Biol Chem 271: 6033–6038, 1996.[Abstract/Free Full Text]
  91. Krolikowski JG, Bienengraeber M, Weihrauch D, Warltier DC, Kersten JR, Pagel PS. Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion: the role of mitochondrial KATP channels. Anesth Analg 101: 1590–1596, 2005.[Abstract/Free Full Text]
  92. Kudo M, Wang Y, Xu M, Ayub A, Ashraf M. Adenosine A1 receptor mediates late preconditioning via activation of PKC-{delta} signaling pathway. Am J Physiol Heart Circ Physiol 283: H296–H301, 2002.[Abstract/Free Full Text]
  93. Kukreja RC. Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. Br J Pharmacol 150: 538–540, 2007.[CrossRef][Web of Science][Medline]
  94. Kukreja RC. Mechanism of reactive oxygen species generation following opening of mitochondrial KATP channels. Am J Physiol Heart Circ Physiol 291: H2041–H2043, 2006.[Free Full Text]
  95. Lakatta EG, Schulman S. Age-associated cardiovascular changes are the substrate for poor prognosis with myocardial infarction. J Am Coll Cardiol 44: 35–37, 2004.[Free Full Text]
  96. Lakatta EG, Sollott SJ. Perspectives on mammalian cardiovascular aging: humans to molecules. Comp Biochem Physiol A Mol Integr Physiol 132: 699–721, 2002.[CrossRef][Medline]
  97. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients GUSTO-I Investigators. Circulation 91: 1659–1668, 1995.[Abstract/Free Full Text]
  98. Lee TM, Su SF, Chou TF, Lee YT, Tsai CH. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 105: 334–340, 2002.[Abstract/Free Full Text]
  99. Lenaz G, Fato R, Formiggini G, Genova ML. The role of Coenzyme Q in mitochondrial electron transport. Mitochondrion 7, Suppl 1: S8–S33, 2007.[CrossRef][Web of Science][Medline]
  100. Lesnefsky E, Gudz T, Migita C, Ikeda-Saito M, Hassan M, Turkaly P, Hoppel C. Ischemic injury to mitochondrial electron transport in the aging heart: Damage to the iron-sulfur protein subunit of electron transport complex III. Arch Biochem Biophys 385: 117–128, 2001.[CrossRef][Web of Science][Medline]
  101. Lesnefsky EJ, Gallo DS, Ye J, Whittingham TS, Lust WD. Aging increases ischemia-reperfusion injury in the isolated, buffer-perfused heart. J Lab Clin Med 124: 843–851, 1994.[Web of Science][Medline]
  102. Lesnefsky EJ, He D, Moghaddas S, Hoppel CL. Reversal of mitochondrial defects before ischemia protects the aged heart. FASEB J 20: 1543–1545, 2006.[Abstract/Free Full Text]
  103. Lesnefsky EJ, Lundergan CF, Hodgson JM, Nair R, Reiner JS, Greenhouse SW, Califf RM, Ross AM. Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience. J Am Coll Cardiol 28: 331–337, 1996.[Abstract]
  104. Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore. Cardiovasc Res 75: 530–535, 2007.[Abstract/Free Full Text]
  105. Lisa FD, Canton M, Menabo R, Kaludercic N, Bernardi P. Mitochondria and cardioprotection. Heart Fail Rev 12: 249–260, 2007.[CrossRef][Web of Science][Medline]
  106. Liu XK, Yamada S, Kane GC, Alekseev AE, Hodgson DM, O'Cochlain F, Jahangir A, Miki T, Seino S, Terzic A. Genetic disruption of Kir6.2,the pore-forming subunit of ATP-sensitive K+ channel, predisposes to catecholamine-induced ventricular dysrhythmia. Diabetes 53, Suppl 3: S165–S168, 2004.[Abstract/Free Full Text]
  107. Loubani M, Ghosh S, Galinanes M. The aging human myocardium: tolerance to ischemia and responsiveness to ischemic preconditioning. J Thorac Cardiovasc Surg 126: 143–147, 2003.[Abstract/Free Full Text]
  108. Maggioni A, Maseri A, Fresco C, Francosi M, Mauri F, Santoro E, Tognoni G. Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. N Engl J Med 329: 1442–1448, 1993.[Abstract/Free Full Text]
  109. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88: 1264–1272, 1993.[Abstract/Free Full Text]
  110. Mather M, Rottenberg H. Aging enhances the activation of the permeability transition pore in mitochondria. Biochem Biophys Res Commun 273: 603–608, 2000.[CrossRef][Web of Science][Medline]
  111. McCormack JG, Denton RM. Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ in the regulation of energy metabolism. Dev Neurosci 15: 165–173, 1993.[Web of Science][Medline]
  112. McCully JD, Levitsky S. The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg 75: S667–S673, 2003.[Abstract/Free Full Text]
  113. Mehta RH, Rathore SS, Radford MJ, Wang Y, Krumholz HM. Acute myocardial infarction in the elderly: differences by age. J Am Coll Cardiol 38: 736–741, 2001.[Abstract/Free Full Text]
  114. Meng Q, Wong YT, Chen J, Ruan R. Age-related changes in mitochondrial function and antioxidative enzyme activity in fischer 344 rats. Mech Ageing Dev 128: 286–292, 2007.[CrossRef][Web of Science][Medline]
  115. Menon V, Webb JG, Hillis LD, Sleeper LA, Abboud R, Dzavik V, Slater JN, Forman R, Monrad ES, Talley JD, Hochman JS. Outcome and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries in cardiogenic shocK? J Am Coll Cardiol 36: 1110–1116, 2000.[Abstract/Free Full Text]
  116. Minami K, Miki T, Kadowaki T, Seino S. Roles of ATP-sensitive K+ channels as metabolic sensors: studies of Kir6. xnull mice. Diabetes 53, Suppl 3: S176–S180, 2004.[Abstract/Free Full Text]
  117. Morten KJ, Ackrell BA, Melov S. Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2: attenuation via antioxidant treatment. J Biol Chem 281: 3354–3359, 2006.[Abstract/Free Full Text]
  118. Murphy E, Steenbergen C. Preconditioning: the mitochondrial connection. Annu Rev Physiol 69: 51–67, 2007.[CrossRef][Web of Science][Medline]
  119. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124–1136, 1986.[Abstract/Free Full Text]
  120. Napoli C, Liguori A, Cacciatore F, Rengo F, Ambrosio G, Abete P. "Warm-up" phenomenon detected by electrocardiographic ambulatory monitoring in adult and older patients. J Am Geriatr Soc 47: 1114–1117, 1999.[Web of Science][Medline]
  121. Narula J, Haider N, Arbustini E, Chandrashekhar Y. Mechanisms of disease: apoptosis in heart failure–seeing hope in death. Nat Clin Pract Cardiovasc Med 3: 681–688, 2006.[CrossRef][Web of Science][Medline]
  122. Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292: C670–C686, 2007.[Abstract/Free Full Text]
  123. Nichols CG. KATP channels as molecular sensors of cellular metabolism. Nature 440: 470–476, 2006.[CrossRef][Medline]
  124. Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S, Asirvatham SJ, Jahangir A, Terzic A. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med 4: 110–116, 2007.[CrossRef][Web of Science][Medline]
  125. Ornato JP, Peberdy MA, Tadler SC, Strobos NC. Factors associated with the occurrence of cardiac arrest during hospitalization for acute myocardial infarction in the second national registry of myocardial infarction in the US. Resuscitation 48: 117–123, 2001.[CrossRef][Web of Science][Medline]
  126. Pepe S. Dysfunctional ischemic preconditioning mechanisms in aging. Cardiovasc Res 49: 11–14, 2001.[Free Full Text]
  127. Pepe S. Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. Exp Gerontol 40: 751–758, 2005.[CrossRef][Medline]
  128. Pepe S. Mitochondrial function in ischaemia and reperfusion of the ageing heart. Clin Exp Pharmacol Physiol 27: 745–750, 2000.[CrossRef][Web of Science][Medline]
  129. Powers SK, Quindry J, Hamilton K. Aging, exercise, cardioprotection. Ann NY Acad Sci 1019: 462–470, 2004.[CrossRef][Web of Science][Medline]
  130. Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25: 502–508, 2000.[CrossRef][Web of Science][Medline]
  131. Rezkalla SH, Kloner RA. Ischemic preconditioning and preinfarction angina in the clinical arena. Nat Clin Pract Cardiovasc Med 1: 96–102, 2004.[CrossRef][Web of Science][Medline]
  132. Roger V, Weston S, Killian J, Pfeifer E, Belau P, Kottke T, Frye R, Bailey K, Jacobsen S. Time trends in the prevalence of atherosclerosis: A population-based autopsy study. Am J Med 110: 267–273, 2001.[CrossRef][Web of Science][Medline]
  133. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115: e69–e171, 2007.[Free Full Text]
  134. Rottenberg H, Wu S. Mitochondrial dysfunction in lymphocytes from old mice: enhanced activation of the permeability transition. Biochem Biophys Res Commun 240: 68–74, 1997.[CrossRef][Web of Science][Medline]
  135. Saraste M. Oxidative phosphorylation at the fin de siecle. Science 283: 1488–1493, 1999.[Abstract/Free Full Text]
  136. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 27: 2775–2783, 2006.[Abstract/Free Full Text]
  137. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 281: H1630–H1636, 2001.[Abstract/Free Full Text]
  138. Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol 289: H237–H242, 2005.[Abstract/Free Full Text]
  139. Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 39: 285–296, 2005.[CrossRef][Web of Science][Medline]
  140. Sivaraman V, Mudalgiri NR, Di Salvo C, Kolvekar S, Hayward M, Yap J, Keogh B, Hausenloy DJ, Yellon DM. Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic Res Cardiol 102: 453–459, 2007.[CrossRef][Web of Science][Medline]
  141. Sonnenschein E, Brody JA. Effect of population aging on proportionate mortality from heart disease and cancer, U.S. 2000–2050. J Gerontol B Psychol Sci Soc Sci 60: S110–S112, 2005.[Abstract/Free Full Text]
  142. Tanaka K, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology 100: 707–721, 2004.[CrossRef][Web of Science][Medline]
  143. Tani M, Suganuma Y, Hasegawa H, Shinmura K, Hayashi Y, Guo X, Nakamura Y. Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation 95: 2559–2566, 1997.[Abstract/Free Full Text]
  144. Tani MSY, Hasegawa H, Shinmura K, Hayashi Y, Guo X, Nakamura Y. Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation 95: 2559–2566, 1997.[Abstract/Free Full Text]
  145. Terzic A, Jahangir A, Kurachi Y. Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs. Am J Physiol Cell Physiol 269: C525–C545, 1995.[Abstract/Free Full Text]
  146. Torella D, Ellison GM, Karakikes I, Nadal-Ginard B. Growth-factor-mediated cardiac stem cell activation in myocardial regeneration. Nat Clin Pract Cardiovasc Med 4, Suppl 1: S46–51, 2007.[CrossRef][Medline]
  147. Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94: 514–524, 2004.[Abstract/Free Full Text]
  148. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423, 2004.[CrossRef][Medline]
  149. Tsutsui H, Ide T, Kinugawa S. Mitochondrial oxidative stress, DNA damage, and heart failure. Antioxid Redox Signal 8: 1737–1744, 2006.[CrossRef][Web of Science][Medline]
  150. Vanden Hoek T, Becker LB, Shao ZH, Li CQ, Schumacker PT. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 86: 541–548, 2000.[Abstract/Free Full Text]
  151. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-2 Data Base. Circulation 88: 416–429, 1993.[Abstract/Free Full Text]
  152. Voss P, Siems W. Clinical oxidation parameters of aging. Free Radic Res 40: 1339–1349, 2006.[CrossRef][Web of Science][Medline]
  153. Wang Y, Haider HK, Ahmad N, Ashraf M. Mechanisms by which K(ATP) channel openers produce acute and delayed cardioprotection. Vascul Pharmacol 42: 253–264, 2005.[CrossRef][Web of Science][Medline]
  154. White HD, Barbash GI, Califf RM, Simes RJ, Granger CB, Weaver WD, Kleiman NS, Aylward PE, Gore JM, Vahanian A, Lee KL, Ross AM, Topol EJ. Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial Global Utilization of Streptokinase and TPA for Occluded coronary arteries trial. Circulation 94: 1826–1833, 1996.[Abstract/Free Full Text]
  155. Willems L, Zatta A, Holmgren K, Ashton KJ, Headrick JP. Age-related changes in ischemic tolerance in male and female mouse hearts. J Mol Cell Cardiol 38: 245–256, 2005.[CrossRef][Medline]
  156. Yamamura K, Steenbergen C, Murphy E. Protein kinase C and preconditioning: role of the sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 289: H2484–H2490, 2005.[Abstract/Free Full Text]
  157. Yan LJ, Sohal RS. Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA 95: 12896–12901, 1998.[Abstract/Free Full Text]
  158. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83: 1113–1151, 2003.[Abstract/Free Full Text]
  159. Yellon DM, Hausenloy DJ. Realizing the clinical potential of ischemic preconditioning and postconditioning. Nat Clin Pract Cardiovasc Med 2: 568–575, 2005.[CrossRef][Web of Science][Medline]
  160. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285: H579–H588, 2003.[Abstract/Free Full Text]
  161. Zingman LV, Hodgson DM, Alekseev AE, Terzic A. Stress without distress: homeostatic role for K(ATP) channels. Mol Psychiatry 8: 253–254, 2003.[CrossRef][Web of Science][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum
Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice
Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2436 - H2446.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
N. J. Palpant, S. M. Day, T. J. Herron, K. L. Converso, and J. M. Metzger
Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction
Cardiovasc Res, November 1, 2008; 80(2): 209 - 218.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. D. O'Brien and S. E. Howlett
Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H768 - H777.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
P. R. Crisostomo, Y. Wang, T. A. Markel, M. Wang, T. Lahm, and D. R. Meldrum
Human mesenchymal stem cells stimulated by TNF-{alpha}, LPS, or hypoxia produce growth factors by an NF{kappa}B- but not JNK-dependent mechanism
Am J Physiol Cell Physiol, March 1, 2008; 294(3): C675 - C682.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
103/6/2120    most recent
00647.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jahangir, A.
Right arrow Articles by Terzic, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jahangir, A.
Right arrow Articles by Terzic, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.