HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abete, P. Articles by Rengo, F. Search for Related Content PubMed PubMed Citation Articles by Abete, P. Articles by Rengo, F.

EXPERIMENTAL STUDIES

Exercise training restores ischemic preconditioning in the aging heart

^a Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche—Cattedra di Geriatria, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
^b Fondazione "Salvatore Maugeri"—IRCCS—Centro Medico di Telese Terme, Benevento, Italy
^c Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Napoli Federico II, Naples, Italy
^d Department of Medicine, University of California, San Diego, California, USA

Manuscript received September 27, 1999; revised manuscript received January 20, 2000, accepted March 28, 2000.

Reprint requests and correspondence: Dr. Pasquale Abete, Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Cattedra di Geriatria, Università degli Studi di Napoli "Federico II", Via S. Pansini, 5, 80131 Napoli, Italy
p.abete{at}cds.unina.it

	Abstract

Top Abstract Materials and methods Results Discussion References

 
OBJECTIVES

To investigate the effects of ischemic preconditioning in hearts from adult and both sedentary and trained senescent rats.

BACKGROUND

Ischemic preconditioning does not prevent postischemic dysfunction in the aging heart, probably because of reduction of cardiac norepinephrine release. Exercise training can reverse the age-related decrease of norepinephrine production.

METHODS

We investigated the effects on mechanical parameters of ischemic preconditioning against 20 min of global ischemia followed by 40 min of reperfusion in isolated perfused hearts from adult (six months) and sedentary or trained (six weeks of graduated swim training) senescent (24 months) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid cromatography.

RESULTS

Final recovery of percent-developed pressure was significantly improved after preconditioning in adult hearts (91.6 ± 9.6%) versus unconditioned controls (54.2 ± 5.1%, p < 0.01). The effect of preconditioning on developed pressure recovery was absent in sedentary but present in trained senescent hearts (39.6 ± 4.1% vs. 64.3 ± 7.1%, p < 0.05). Norepinephrine release significantly increased after preconditioning in adult and in trained but not in sedentary senescent hearts. The depletion of myocardial norepinephrine stores by reserpine abolished preconditioning effects in adult and trained senescent hearts.

CONCLUSIONS

In adult and trained but not in sedentary senescent hearts, preconditioning reduces postischemic dysfunction and is associated with an increase in norepinephrine release. Preconditioning was blocked by reserpine in both adult and trained senescent hearts. Thus, exercise training may restore preconditioning in the senescent heart through an increase of norepinephrine release.

Abbreviations and Acronyms   ANOVA = analysis of variance   CFR = coronary flow rate   DP = developed pressure   +dP/dt = first derivative of DP   EDP = end-diastolic pressure

Brief episodes of ischemia and reperfusion that protect the heart against a more prolonged episode of ischemia have been called "ischemic preconditioning" (11). In experimental models, it has been demonstrated that preconditioning is reduced with aging (12–15). Clinical equivalents of ischemic preconditioning, such as preinfarction angina (16) and the "warm-up phenomenon" (17,18), appear to protect the heart less effectively against myocardial ischemia in elderly patients.

Several mediators are implicated in preconditioning and appear to be species-related (19–25). In the adrenergic pathway, ischemic preconditioning seems to be partially mediated by norepinephrine release by intramyocardial adrenergic nerves in the rat (19). Norepinephrine release in response to preconditioning is reduced in the isolated senescent rat heart, and exogenous administration of norepinephrine is able to restore ischemic preconditioning in the aged heart (12). The capacity of cardiac sympathetic nerves to release norepinephrine is known to decline progressively with age in the rat (26–28).

Exercise training has been widely considered a means of offsetting age-induced physiological and anatomical changes in the heart (29–32). In the rat heart, aerobic exercise has been shown to improve ventricular mechanical performance (33,34) and pump function (35,36), and to reduce age-related alterations in collagen characteristics (37). Exercise training has also been shown to reverse some of the neuroendocrine consequences of aging, including the stimulation of catecholamine biosynthesis in the rat (38,39). Thus, if ischemic preconditioning is reduced in senescent animals as a result of the decline of norepinephrine release, exercise may be useful in restoring this protective mechanism in the aging heart.

The aim of the present study was to evaluate the early effect of preconditioning on ischemia-reperfusion injury in isolated hearts from adult and both sedentary and trained senescent rats. In order to investigate the pathophysiological role of norepinephrine release, further experiments were performed in animals depleted of norepinephrine stores by reserpine.

	Materials and methods

Top Abstract Materials and methods Results Discussion References

 
Experimental procedure.   Langendorff-perfused isolated hearts from male Wistar rats aged 6 (adult) and 24 (senescent) months were studied as previously described (9,12,40). Animal care was performed according to the "Position of the American Heart Association on Research Animal Use." The animals were anesthetized with diethyl ether, and sodium heparin (200 U) was injected intravenously. Hearts then were rapidly excised and attached via the aorta to a modified Langendorff perfusion apparatus. The basal perfusion medium (37°C, pH 7.4, perfusion pressure 66 mm Hg) contained in mM: NaCl 117, KCl 4.6, NaH₂PO₄ 0.8, NaHCO₃ 25, MgCl₂, CaCl₂ 2 and glucose 5. The perfusion liquid was oxygenated by a mixture of 5% CO₂ and 95% O₂. Left ventricular pressure was measured using an intraventricular balloon attached to a 1-mm-diameter cannula and connected to a Statham P23 pressure amplifier and to a low-level pre-amplifier and direct differentiator (OTE Biomedica model 2080 pressure meter; Florence, Italy) to obtain first derivative of diastolic pressure (±dP/dt). Isovolumic loading conditions were established by setting left ventricular end-diastolic pressure (EDP) at approximately 5 mm Hg. Heart electrogram was obtained by an atraumatic epicardial electrode (0.8 mm diameter, silver wire) attached to the free wall of the right ventricle (to avoid affecting left ventricular function). The electrical signal was obtained from a bioelectric amplifier (OTE Biomedica model 2077 ECG amplifier). Pacing wires were fixed to the pulmonary outflow tract and the hearts were paced at 6 Hz (pacer off during ischemia and drug infusion). Pacing was resumed 3 min after the start of reperfusion, and the hearts were defibrillated when necessary. Coronary flow rate (CFR) was measured in graduated cylinders at intervals of 5 min before, during, and after infusion and during reperfusion. Coronary flow rate was related to wet ventricular weight (ml/min/g) in both age groups. During the ischemic period, perfusion pressure was 0 mm Hg and the hearts were maintained at 37°C in a thermostated chamber. Diastolic pressure (mm Hg), EDP (mm Hg), +dP/dt, and CFR (ml/min/g) were monitored and recorded at intervals of 5 min on a Harvard oscillograph at a paper speed of 0.1 mm/s.

Exercise protocol in senescent rats.   Exercise training was induced in senescent rats as proposed by Orenstein et al. (41). The swimming protocol initially started for 5 min/day and increased by an additional 5 min/day until the senescent rats were swimming continuously for 40 min/day. Swim frequency was five days/week for a total duration of six weeks. The rats swam in groups of four animals in a 60-cm-deep tub with water temperature maintained at 35°C, and were toweled dry after each session. The senescent rats randomized to sedentary conditions were dipped in the water for 30 min for five days/week for a total duration of six weeks and toweled dry after each session. In the exercise group, nine rats did not complete the studies because of injuries (four rats) or death unrelated to swimming (five rats). However, we reached the final number of 21 for each group at the end of the study. All sedentary rats completed the study.

Experimental design.   After 20 min in which electrical and mechanical parameters were stabilized, the hearts were divided into four protocol groups of 21, comprising 7 each from adult, senescent sedentary and senescent trained rats:

1. Hearts perfused for 80 min to demonstrate the preparation stability, not counted in the present study;
   
2. Control hearts in which ischemic perfusion was performed for 20 min and reperfusion for 40 min (standard ischemia-reperfusion insult, control group);
   
3. Hearts treated with preconditioning transient ischemic stimulus for 2 min followed by 10 min of reperfusion (window) and then a standard ischemia-reperfusion insult (preconditioning group);
   
4. Hearts treated with preconditioning transient ischemic stimulus for 2 min followed by 10 min of reperfusion (window) and then a standard ischemia-reperfusion insult from reserpinized rat (0.15 mg/kg IP 24 h beforehand) (reserpinized preconditioning group).
   

Norepinephrine assay.   Norepinephrine levels were determined as described (42,43) by collecting coronary effluent after 2 min of transient global ischemia accumulated over the preconditioning window, corrected to the wet ventricular weight in both age groups (pmol/ml/g). The effluent was collected in chilled tubes containing 3% perchloric acid (final concentration) and frozen at –80°C. The assay was performed by high-performance liquid chromatography (HPLC, Beckman, Fullerton, California). Briefly, 50 ml of each sample (Beckman Model 210 injector) was separated on an ultrasphere ODS (3 mm particles) reverse-phase column (Beckman, Altex Division, San Ramon, California), and detected by dual electrode (ox-redox, +0.25; –0.25 V) colormetry (ESA 5100A Coulochem System, Bedford, Massachusetts) and finally matched to a standard control.

Statistical analysis.   Results are expressed as mean ± standard deviation. A one-way analysis of variance (ANOVA) was performed to separately test the main effects of age and exercise training in adult and sedentary and trained senescent rats. A one-way ANOVA was also done to compare the functional parameters (DP, EDP, +dP/dt, CFR) at specific time points and in the different protocol groups in adult and sedentary or trained senescent rats. The same analysis was performed to compare norepinephrine release at baseline and after ischemia in adult and sedentary or trained senescent rats in the presence and in the absence of reserpine. If the F ratios were significant, Scheffé’s test was applied post hoc. Comparison between two groups was performed by using paired samples t-test. Values less than 0.05 (p < 0.05) were considered significant.

	Results

Top Abstract Materials and methods Results Discussion References

 
Effect of age and training on body weight and left ventricle weight.   Body and left ventricle weight and the ratio of left ventricle weight to body weight of adult and both sedentary and trained senescent rats are shown in Table 1. Sedentary senescent rats were significantly heavier, and their left ventricular weight and ratio of left ventricular weight to body weight were significantly greater than in adult rats (p < 0.01). Age effect was also significant between trained senescent and adult rats in terms of body weight and left ventricular weight (p < 0.01). A significant training effect on both body weight and the ratio of left ventricular weight to body weight was also observed between sedentary and trained senescent rats (p < 0.05).

View larger version (21K): [in this window] [in a new window]   Figure 1 Bar graphs showing final recovery of percent DP (%) at 40 min of reperfusion in adult (open bars) and sedentary (solid bars) or trained (striped bars) senescent hearts subjected to ischemia for 20 min and reperfused for 40 min (standard ischemia-reperfusion insult, Control), treated with preconditioning transient ischemic stimulus for 2 min followed by 10 min of reperfusion and then a standard ischemia-reperfusion insult (PC) and treated with preconditioning transient ischemic stimulus for 2 min followed by 10 min of reperfusion and then a standard ischemia-reperfusion insult after pretreatment with reserpine (Res-PC). (*p < 0.05 vs. sedentary and trained senescent hearts; p < 0.01 vs. Control and Res-PC; p < 0.05 vs. sedentary senescent hearts; p < 0.05 vs. Control and Res-PC trained senescent hearts).

	Discussion

Top Abstract Materials and methods Results Discussion References

 
We showed that exercise training restored preconditioning in the senescent heart. Ischemic preconditioning improved both mechanical and electrical parameters in adult hearts but not in hearts from sedentary senescent animals. Restoration of ischemic preconditioning in trained senescent hearts appeared to be related to increased norepinephrine release in response to ischemic preconditioning.

Ischemic myocardial tolerance and aging.   The risk of death after acute myocardial infarction increases dramatically with age (1–7). There is as yet no certain explanation for this phenomenon. In the prethrombolytic era, the elevated prevalence of associated diseases in elderly patients was considered the principal cause of age-related increase of mortality for myocardial infarction (1,2). However, several adverse baseline and additional in-hospital characteristics did not explain the poor prognosis of infarction in elderly patients (4). Older patients who have had acute myocardial infarction are less likely to receive a thrombolytic agent because of the higher risk of iatrogenic hemorrhagic stroke and/or atypical electrocardiographic and clinical presentation (6). Nevertheless, Maggioni et al. (5) demonstrated that mortality in elderly patients with first myocardial infarction receiving thrombolytic therapy (GISSI-2 trial) is still higher than in younger patients, despite a similar degree of coronary stenosis at in-hospital autopsy. Moreover, animal studies have clearly demonstrated an age-related decrease in myocardial ischemic tolerance (7–10). Aging reduces contractile recovery from ischemia, and this is unrelated to an altered aerobic or anaerobic metabolism (9,10). For these reasons, our interest has been focused on a hypothetical age-related reduction of some endogenous protective mechanism such as ischemic preconditioning, which has been defined as one of the most powerful mechanisms of myocardial protection (11,45,46). Recently it has been proposed that preconditioning has both early and late effects that are afforded by different mechanisms (47,48). During transient ischemic preconditioning stimulus, numerous pathophysiological mechanisms are involved, including adenosine receptors (19), norepinephrine (20,21), bradykinin (22), sarcolemmal and mitochondrial KATP channels (23), opioid receptors (24) and several others. Protein kinase C and other components of the kinase cascade may serve as intracellular mediators of ischemic preconditioning (25). However, little is known about the nuclear end-effectors of the phenomenon.

Ischemic preconditioning and aging.   In the rat experimental model most commonly utilized in aging studies, norepinephrine release has been identified as one of the mediators of preconditioning to reduce postischemic electrical and mechanical dysfunction by a₁-adrenoreceptor stimulation (20,49). It has recently been demonstrated that the protective effect of preconditioning on electrical and mechanical function following ischemia-reperfusion injury was reduced in senescent hearts (12–15), for which the decline in norepinephrine release in response to preconditioning might be responsible (12). In fact, preconditioning achieved by a-adrenergic agonist in both adult and senescent hearts disappeared after administration of an a-adrenergic antagonist. Tani et al. (13) showed a reduction of preconditioning in middle-aged rat hearts, suggesting an impairment of ryanodine-sensitive sarcoplasmic reticulum Ca²⁺.

Exercise training and aging.   It is generally accepted that exercise training can reverse the morphologic, metabolic and functional modifications of the aging heart (29–32). It can also reverse the age-related prolongation of isometric contraction (34) and action potential duration (50), and the decrease of Ca-ATPase of the sarcoplasmic reticulum (51). Exercise training may also increase cardiac output (35) and modify age-induced alterations in collagen characteristics (37). Exercise training reverses the age-related adenylate cyclase depression and G_1a increase (51) and improves lusitropy by isoproterenol in papillary muscles from aged rats (52). Mazzeo et al. (39) demonstrated that cardiac norepinephrine release in response to stress declines with age but can be restored by exercise training. The age-related decline of tissue catecholamines (due either to a related diminished ability for catecholamine synthesis or to significant sympathetic axonal degeneration observed with aging) (26–28) could explain the reduction of preconditioning in the aging heart. In our experiments, the reduction of norepinephrine release in sedentary senescent hearts in response to preconditioning and its restoration by exercise training, together with the increase of norepinephrine release in trained senescent hearts and the abolition of this phenomenon by reserpine, suggest that exercise training may restore ischemic preconditioning in senescent hearts through increased norepinephrine release.

However, we cannot exclude that exercise may promote other protective mechanisms. In fact, a very recent study demonstrates that exercise provides direct biphasic cardioprotection via the activation of the oxygen radical scavenger manganese superoxide dismutase (53). Therefore, exercise training might reduce the generation of oxygen radicals during ischemia-reperfusion injury (40,47).

Clinical implications.   It is well known that maintained or improved physical activity reduces the risk of mortality from cardiovascular disease, especially in older patients (54–56). Further, it has been recently demonstrated that exercise training significantly increases functional capacity, with a lower incidence of cardiac events during follow-up, in patients with myocardial infarction (57–59). Although exercise training can improve myocardial perfusion by both structural and functional coronary artery adaptations, the reason for its protective effect on coronary heart disease is not yet fully understood (60,61). One hypothesis is that exercise training might increase and/or reestablish some endogenous protective mechanisms against coronary heart disease that decline with advancing age. In this regard, the sympathetic nervous system plays a major role in maintaining homeostasis in response to stressful conditions such as myocardial ischemia.

If the age-related higher mortality for coronary heart disease is in part due to the reduction of preconditioning stemming from the decrease of norepinephrine release, exercise training may represent a simple tool to restore preconditioning in the aging heart by reestablishing norepinephrine release. Restoration of preconditioning in the aging heart by exercise training may also explain the reduction of this protective phenomenon seen in elderly patients (12,15,16). In fact, some modifications of the aging heart might be due to the physical inactivity typical of elderly patients. This suggests that although the age-related decline of ischemic preconditioning may be related to the aging process per se, other factors such as sedentary lifestyle can contribute to such deleterious change.

Conclusions.   In senescent hearts from trained animals, exercise training appears to be capable of restoring preconditioning by increasing norepinephrine release in response to transient ischemic stimulus. The absence of the protection in adult and trained senescent hearts after norepinephrine depletion by reserpine administration seems to support this hypothesis. Furthermore, larger prospective studies are necessary to verify whether exercise training can restore the protective effect of preconditioning in elderly patients.

	Footnotes

 
This study was supported by a grant from Consiglio Nazionale delle Ricerche (CNR) n. 97.04358.CT14.

	References

Top Abstract Materials and methods Results Discussion References

 

1. Harris R, Piracha AR. Acute myocardial infarction in the aged: prognosis and management. J Am Geriatr Soc. 1970;18:893–904[Medline]
2. Latting CA, Silverman ME. Acute myocardial infarction in hospitalized patients over age 70. Am Heart J. 1980;100:311–318[CrossRef][Medline]
3. Udvarhelyi IS, Gatsonis C, Epstein AM, Pashos CL, Newhouse JP, McNeil BJ. Acute myocardial infarction in the Medicare population. Process of care and clinical outcome. JAMA. 1992;268:2350–2356
4. Tofler GH, Muller JE, Stone PH, et al. Factors leading to shorter survival after acute myocardial infarction in patients ages 65 to 75 years compared to younger patients. Am J Cardiol. 1988;62:860–867[CrossRef][Medline]
5. Maggioni AP, Maseri A, Fresco C, et al. Age-related increase in mortality among patients with first myocardial infarction treated with thrombolysis. N Engl J Med. 1993;329:1442–1448[Abstract/Free Full Text]
6. Participants in the National Registry of Myocardial InfarctionGurwitz JH, Gore JM, Goldberg RJ, Rubison M, Chandra N, Rogers WJ. Recent age-related trends in the use of thrombolytic therapy in patients who have had acute myocardial infarction. Ann Intern Med. 1996;124:283–291[Abstract/Free Full Text]
7. Frolkis VV, Frolkis RA, Mkhitarian LS, Fraifeld VE. Age-dependent effects of ischemia and reperfusion on cardiac function and Ca²⁺ transport in myocardium. Gerontology. 1991;37:233–239[Medline]
8. Ataka K, Chen D, Levitsky S, Jimenez E, Feinberg H. Effect of aging on intracellular Ca²⁺, pHi, and contractility during ischemia and reperfusion. Circulation 1992;86 Suppl. II:II-371–6.
9. Abete P, Cioppa A, Ferrara P, Caccese P, Ferrara N, Rengo F. Reduced aerobic metabolic efficiency in postischemic myocardium dysfunction in rats: role of aging. Gerontology. 1995;41:187–194[Medline]
10. Headrick JP. Aging impairs functional, metabolic and ionic recovery from ischemia-reperfusion and hypoxia-reoxygenation. J Mol Cell Cardiol. 1988;30:1415–1430
11. Murry CE, Sennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136[Abstract/Free Full Text]
12. Abete P, Ferrara N, Cioppa A, et al. Preconditioning does not prevent post-ischemic dysfunction in aging heart. J Am Coll Cardiol. 1996;27:1777–1786[Abstract]
13. Tani M, Suganuma Y, Hasegawa H, et al. Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation. 1997;95:2559–2566[Abstract/Free Full Text]
14. Uematsu M, Okada M. Ischemic preconditioning in the aged-heart-myocardial protective effects as compared with the mature heart. Jpn Thorac Cardiovasc Surg. 1998;46:833–845[Medline]
15. McCully JD, Uematsu M, Parker RA, Levitsky S. Adenosine-enhanced ischemic preconditioning provides enhanced cardioprotection in the aged heart. Ann Thorac Surg. 1998;66:2037–2043[Abstract/Free Full Text]
16. Abete P, Ferrara N, Cacciatore F, et al. Angina-induced protection against myocardial infarction in adult and senescent patients. A loss of preconditioning mechanism in aging heart? J Am Coll Cardiol. 1997;30:947–954[Abstract]
17. Napoli C, Liguori A, Cacciatore F, Rengo F, Ambrosio G, Abete P. "Warm-up" phenomenon detected by electrocardiographic ambulatory monitoring in adult and elderly patients. J Am Geriatr Soc. 1999;47:1–4[Medline]
18. Longobardi G, Abete P, Ferrara N, et al. "Warm-up" phenomenon in adult and elderly patients with coronary artery disease. Further evidence of the loss of "ischemic preconditioning" in the aging heart. J Gerontol 2000;55:M124–M129.
19. Liu GS, Thornton J, Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A₁-adenosine receptors in rabbit heart. Circulation. 1991;84:350–356[Abstract/Free Full Text]
20. Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an a₁-adrenergic mechanism. Circ Res. 1993;73:656–670[Abstract/Free Full Text]
21. Toombs CF, Wiltse AL, Shebuski RJ. Ischemic preconditioning fails to limit infarct size in reserpinized rabbit myocardium: implication of norepinephrine release in the preconditioning effect. Circulation. 1993;88:2351–2358[Abstract/Free Full Text]
22. Goto M, Liu Y, Yang X-M, Ardelle JL, Cohen MV, Downey JM. The role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res. 1995;77:611–621[Abstract/Free Full Text]
23. Gross GJ, Fryer RM. Sarcolemmal versus mitochondrial ATP sensitive K+ channels and myocardial preconditioning. Circ Res. 1999;84:973–979[Abstract/Free Full Text]
24. Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement for opioid receptor in ischemic preconditioning in rat heart. Am J Physiol. 1995;268:H2157–H2161
25. Simkhovich BZ, Przylenk K, Kloner RA. Role of protein kinase C as a cellular mediator of ischemic preconditioning: a critical review. Cardiovasc Res. 1998;40:9–22[Abstract/Free Full Text]
26. Mazzeo RS, Horvarth SM. A decline in myocardial and hepatic norepinephrine turnover with age in Fischer 344 rats. Am J Physiol. 1987;252:E762–E764
27. Dawson R Jr, Meldrum MJ. Norepinephrine content in cardiovascular tissue from the aged Fisher 344 rat. Gerontology. 1992;38:185–191[Medline]
28. McLean MR, Goldberg PB, Roberts J. An ultrastructural study of the effects of age on sympathetic innervation and atrial tissue in the rat. J Mol Cell Cardiol. 1983;15:75–92[Medline]
29. Blumenthal JA, Emery CF, Madden DJ, et al. Cardiovascular and behavioral effects of aerobic exercise training in healthy older men and women. J Gerontol. 1989;44:M147–M157[Medline]
30. Hagberg JM, Graves JE, Limacher M, et al. Cardiovascular responses of 70- to 79-yr-old men and women to exercise training. J Appl Physiol. 1989;66:2589–2594[Abstract/Free Full Text]
31. Posner JD, Gorman KM, Gitlin LN, et al. Effects of exercise training in the elderly on the occurrence and time to onset of cardiovascular diagnoses. J Am Geriatr Soc. 1990;38:205–210[Medline]
32. De Angelis KLD, Oliveira AR, Werner A, et al. Exercise training in aging. Hemodynamic, metabolic, and oxidative stress evaluations. Hypertension. 1997;30:767–771[Abstract/Free Full Text]
33. Lakatta EG, Spurgeon HA. Effect of exercise on cardiac muscle performance in aged rats. Fed Proc. 1987;46:1844–1849[Medline]
34. Li YX, Lincoln D, Mendelowitz D, Grossman W, Wei JY. Age-related differences in effect of exercise training on cardiac muscle function in rats. Am J Physiol. 1986;251:H12–H18
35. Starnes JW, Rumsey WL. Cardiac energetics and performance of exercise and food-restricted rats during aging. Am J Physiol. 1988;254:H599–H608
36. Starnes JW, Beyer R, Edington DW. Myocardial adaptations to endurance exercise in aged rats. Am J Physiol. 1983;245:H560–H566
37. Thomas DP, McCormick RJ, Zimmerman SD, Vadlamudi RK, Gosselin LE. Aging- and training-induced alterations in collagen characteristics of rat left ventricle and papillary muscle. Am J Physiol. 1992;263:H778–H783
38. Tumer N, LaRochelle JS, Yurekli M. Exercise training reverses the age-related decline in tyrosine hydroxylase expression in rat hypothalamus. J Gerontol. 1997;52:B255–B259
39. Mazzeo RS, Colburn RW, Horvath SM. Effect of aging and endurance training on tissue catecholamine response to strenuous exercise in Fischer 344 rats. Metabolism. 1986;35:602–607[CrossRef][Medline]
40. Abete P, Napoli C, Santoro G, et al. Age-related decrease in cardiac tolerance to oxidative stress. J Mol Cell Cardiol. 1999;31:227–236[CrossRef][Medline]
41. Orenstein TL, Parker TG, Butany JW, et al. Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression. J Clin Invest. 1995;96:858–866[Medline]
42. Hjemdhal P. Catecholamine measurements by high-performance liquid chromatography. Am J Physiol. 1984;247:E13–E20
43. Hall ME, Hoffer BJ, Gerhardt GA. Rapid and sensitive determination of catecholamines in small tissue sample by HPLC coupled with dual electrode coulometric electrochemical detection. LCGC. 1989;7:258–265
44. Metz V, Bernauer W. The effect of reserpine and guanethidine on carbohydrate metabolism in ischaemic rat myocardium. Cardiovasc Res. 1989;23:385–389[Medline]
45. Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E. Medical and cellular implications of stunning, hibernation and preconditioning. An NHLBI workshop. Circulation. 1988;97:1848–1867
46. Yellon DM, Baxter GF. A second window protection or delayed preconditioning phenomenon: future horizons for myocardial protection? J Mol Cell Cardiol. 1995;27:1023–1024[CrossRef][Medline]
47. Bolli R. The early and late phase of preconditioning against myocardial stunning and the essential role of oxyradicals in the late phase: an overview. Basic Res Cardiol. 1996;91:57–63[CrossRef][Medline]
48. Musters RJ, van der Meulen ET, Zuidwijk M, et al. PKC-dependent preconditioning with norepinephrine protects sarcoplasmic reticulum function in rat trabeculae following metabolic inhibition. J Mol Cell Cardiol. 1999;31:1083–1094[CrossRef][Medline]
49. Gwathmey JK, Slawsky MT, Perreault CL, Briggs GM, Morgan JM, Wei JY. Effect of exercise conditioning on excitation-contraction coupling in aged rats. J Appl Physiol. 1990;69:1366–1371[Abstract/Free Full Text]
50. Tate CA, Helgason T, Hyek MF, et al. SERCA2a and mitochondrial cytochrome oxidase expression are increased in hearts of exercise-trained old rats. Am J Physiol. 1996;27:H68–H72
51. Bohm M, Dorner H, Htun P, Lensche H, Platt D, Erdmann E. Effects of exercise on myocardial adenylate cyclase and G₁ alpha expression in senescence. Am J Physiol. 1993;264:H805–H814
52. Taffet GE, Michael LA, Tate CA. Exercise training improves lusitropy by isoproterenol in papillary muscles from aged rats. J Appl Physiol. 1996;81:1488–1494[Abstract/Free Full Text]
53. Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med. 1999;189:1699–1706[Abstract/Free Full Text]
54. Smith SC Jr, Blair SN, Criqui MH, et al. American Heart Association Consensus Panel Statement. Preventing heart attack and death in patients with coronary disease. J Am Coll Cardiol. 1995;26:292–294[CrossRef][Medline]
55. Blair SN, Kohl HW 3rd, Barlow CE, Paffenbarger RS Jr, Gibbons LW, Macera CA. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA. 1995;273:1093–1098[Abstract]
56. Brechue WF, Pollock ML. Exercise training for coronary artery disease in the elderly. Clin Geriatr Med. 1996;12:207–229[Medline]
57. Cobb FR, Williams RS, McEwan P, Jones RH, Colema RE, Wallace AG. Effects of exercise training on ventricular function in patients with recent myocardial infarction. Circulation. 1982;66:100–108[Abstract/Free Full Text]
58. O’Connor GT, Buring JE, Yusuf S, et al. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation. 1989;80:234–244[Abstract/Free Full Text]
59. Belardinelli R, Georgiou D, Purcaro A. Low dose dobutamine echocardiography predicts improvement in functional capacity after exercise training in patients with ischemic cardiomyopathy: prognostic implication. J Am Coll Cardiol. 1998;31:1027–1034[Abstract/Free Full Text]
60. Ehsani AA, Martin WH, Heath GW, Coyle EF. Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease. Am J Cardiol. 1982;50:246–254[CrossRef][Medline]
61. Sullivan MJ, Higgnbotham MB, Cobb FR. Exercise training in patients with severe left ventricular dysfunction: hemodynamic and metabolic effects. Circulation. 1988;78:506–515[Abstract/Free Full Text]

This article has been cited by other articles:

				J. Dow, A. Bhandari, and R. A. Kloner Ischemic Postconditioning's Benefit on Reperfusion Ventricular Arrhythmias Is Maintained in the Senescent Heart Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 141 - 148. [Abstract] [PDF]

				A. Jahangir, S. Sagar, and A. Terzic Aging and cardioprotection J Appl Physiol, December 1, 2007; 103(6): 2120 - 2128. [Abstract] [Full Text] [PDF]

				P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]

				D. H. Korzick, J. C. Kostyak, J. C. Hunter, and K. W. Saupe Local delivery of PKC{varepsilon}-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3beta but not F1-ATPase inactivation Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2056 - H2063. [Abstract] [Full Text] [PDF]

				M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]

				R. A. Kloner and B. Z. Simkhovich Benefit of an exercise program before myocardial infarction J. Am. Coll. Cardiol., March 15, 2005; 45(6): 939 - 940. [Full Text] [PDF]

				D. A. Liem, M. te Lintel Hekkert, O. C. Manintveld, F. Boomsma, P. D. Verdouw, and D. J. Duncker Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1165 - H1172. [Abstract] [Full Text] [PDF]

				M. Iemitsu, T. Miyauchi, S. Maeda, T. Tanabe, M. Takanashi, M. Matsuda, and I. Yamaguchi Exercise training improves cardiac function-related gene levels through thyroid hormone receptor signaling in aged rats Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1696 - H1705. [Abstract] [Full Text] [PDF]

				P. Abete, F. Cacciatore, N. Ferrara, C. Calabrese, D. de Santis, G. Testa, G. Galizia, S. Del Vecchio, D. Leosco, M. Condorelli, et al. Body mass index and preinfarction angina in elderly patients with acute myocardial infarction Am. J. Clinical Nutrition, October 1, 2003; 78(4): 796 - 801. [Abstract] [Full Text] [PDF]

				H. A. Demirel, K. L. Hamilton, R. A. Shanely, N. Tumer, M. J. Koroly, and S. K. Powers Age and attenuation of exercise-induced myocardial HSP72 accumulation Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1609 - H1615. [Abstract] [Full Text] [PDF]

				J. W. Starnes, R. P. Taylor, and Y. Park Exercise improves postischemic function in aging hearts Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H347 - H351. [Abstract] [Full Text] [PDF]

				E. G. Lakatta and S. J. Sollott The "Heartbreak" of Older Age Mol. Interv., November 1, 2002; 2(7): 431 - 446. [Abstract] [Full Text] [PDF]

				K. J. Stewart Exercise Training and the Cardiovascular Consequences of Type 2 Diabetes and Hypertension: Plausible Mechanisms for Improving Cardiovascular Health JAMA, October 2, 2002; 288(13): 1622 - 1631. [Abstract] [Full Text] [PDF]

				P. Abete, G. Testa, N. Ferrara, D. De Santis, P. Capaccio, L. Viati, C. Calabrese, F. Cacciatore, G. Longobardi, M. Condorelli, et al. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1978 - H1987. [Abstract] [Full Text] [PDF]

				C. Napoli, F. De Nigris, C. Cicala, J. L. Wallace, G. Caliendo, M. Condorelli, V. Santagada, and G. Cirino Protease-activated receptor-2 activation improves efficiency of experimental ischemic preconditioning Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2004 - H2010. [Abstract] [Full Text] [PDF]

				P. Abete, D. de Santis, M. Condorelli, C. Napoli, and F. Rengo A four-year-old rabbit cannot be considered the right model for investigating cardiac senescence J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1701 - 1701. [Full Text] [PDF]

				K. Przyklenk, G. Li, and P. Whittaker No loss in the in vivo efficacy of ischemic preconditioning in middle-aged and old rabbits J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1741 - 1747. [Abstract] [Full Text] [PDF]

				P. Abete, N. Ferrara, F. Cacciatore, E. Sagnelli, M. Manzi, V. Carnovale, C. Calabrese, D. de Santis, G. Testa, G. Longobardi, et al. High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1357 - 1365. [Abstract] [Full Text] [PDF]

				R. A. Kloner Preinfarct angina and exercise: yet another reason to stay physically active J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1366 - 1368. [Full Text] [PDF]

				S. Pepe Dysfunctional ischemic preconditioning mechanisms in aging Cardiovasc Res, January 1, 2001; 49(1): 11 - 14. [Full Text] [PDF]

				C. Napoli, F. De Nigris, C. Cicala, J. L. Wallace, G. Caliendo, M. Condorelli, V. Santagada, and G. Cirino Protease-activated receptor-2 activation improves efficiency of experimental ischemic preconditioning Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2004 - H2010. [Abstract] [Full Text] [PDF]

				P. Abete, G. Testa, N. Ferrara, D. De Santis, P. Capaccio, L. Viati, C. Calabrese, F. Cacciatore, G. Longobardi, M. Condorelli, et al. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1978 - H1987. [Abstract] [Full Text] [PDF]

This Article Abstract Figures Only