ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
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 PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Adam E. Saltman
Irvin B. Krukenkamp
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horimoto, H.
Right arrow Articles by Krukenkamp, I. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horimoto, H.
Right arrow Articles by Krukenkamp, I. B.

Ann Thorac Surg 1999;68:844-849
© 1999 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Nitric oxide–generating ß-adrenergic blocker nipradilol preserves postischemic cardiac function

Hitoshi Horimoto, MDa, Adam E. Saltman, MD, PhDa, Glenn R. Gaudette, MSca, Irvin B. Krukenkamp, MDa

a Division of Cardiothoracic Surgery, University Hospital at Stony Brook, State University of New York, Stony Brook, New York, USA

Address reprint requests to Dr Krukenkamp, Division of Cardiothoracic Surgery, University Hospital at Stony Brook, T19-080 Health Sciences Center, Stony Brook, NY 11794-8191
e-mail: ibkmd{at}hotmail.com

Presented at the Poster Session of the Thirty-Fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by ß-adrenergic blockade. We hypothesize that because nitric oxide is known to precondition the heart, the nitric oxide–generating ß-blocker nipradilol may simultaneously precondition and provide clinically relevant ß-blockade.

Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery ischemia followed by 1 hour of reperfusion. Before ischemia, six hearts received nipradilol, six received the nitric oxide donor L-arginine, four hearts received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester before L-arginine, nine underwent ischemic preconditioning, and six received ß-blockade by esmolol before ischemic preconditioning. Seven hearts received no pretreatment (control). Action potential duration and ventricular pressure were measured. Infarct size was determined at the end of reperfusion.

Results. Both L-arginine and ischemic preconditioning prolonged action potential duration significantly at 60 minutes of reperfusion. Compared with control, infarct size was reduced by ischemic preconditioning (26% ± 4% versus 49% ± 3%, IPC versus control; p < 0.01), L-arginine (24% ± 2%; p < 0.01 versus control), and nipradilol (24% ± 2%; p < 0.01 versus control). Only nipradilol preserved peak developed pressure during reperfusion.

Conclusions. Despite its properties as a ß-adrenergic blocking agent, nipradilol was able to precondition the heart, probably as a result of its ability to produce nitric oxide.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Preconditioning renders the myocardium resistant to subsequent sustained ischemia [1, 2]. Preconditioning has classically been produced by repetitive cycles of transient global or regional ischemia and reperfusion, although it has also been shown to occur after rapid stimulation and the administration of drugs such as adenosine triphosphate-sensitive potassium-channel openers [3, 4], phorbol esters [5, 6], the {alpha}-adrenergic agent phenylephrine [5, 7], and adenosine [5, 6, 8]. Recently, nitric oxide (NO) has been implicated in the mechanism of preconditioning [9]. We have shown that NO is a requisite for cofactor in the preconditioning response generated by the administration of adenosine triphosphate-sensitive potassium-channel openers [10].

Because many patients who undergo coronary operations are prescribed ß-blockers, and because we have previously shown that ß-adrenergic blockade alone prevents preconditioning, we evaluated the NO-generating ß-blocker nipradilol as a sole preconditioning stimulus.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Animals received humane care in compliance with the "Principles of Laboratory Animal Care," formulated by the National Society for Medical Research, and the "Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Thirty-eight adult male New Zealand rabbits, weighing between 2.8 and 3.0 kg, were anesthetized with sodium pentobarbital (30 mg/kg) and anticoagulated with 1000 U sodium heparin by ear vein. Once the corneal reflex was abolished, the rabbits were placed in the supine position, and the chest was entered through a bilateral thoracotomy ("clam-shell" incision). The heart was rapidly excised and placed in an iced bath of Krebs-Henseleit solution. The aorta was cannulated with a stainless steel 8F cannula, and the heart was suspended from the cannula within a heated glass chamber (Radnotti, Monrovia, CA). The aorta was then perfused with oxygenated (95% O2/5% CO2) Krebs solution at 37°C and 75 mm Hg root pressure.

The heart was permitted to equilibrate for 30 minutes. During that period, both atria were excised, and a small balloon was placed through the mitral valve into the left ventricle. Balloon pressure was monitored continuously with an indwelling catheter probe (Millar, Houston, TX); the initial end-diastolic pressure (EDP) was set to approximately 5 mm Hg by water inflation, and the volume remained constant throughout the experiment. End-systolic pressure and EDP were measured directly from the balloon pressure tracings, and peak developed pressure was calculated as the difference between end-systolic pressure and EDP for each beat. The heart was paced at 150 beats per minute with an asynchronous pacemaker (Medtronics, Minneapolis, MN). Monophasic action potentials were recorded from the left ventricular epicardium within the distribution of the left anterior descending coronary artery (LAD) with an 8F spring-loaded probe (EP Technologies, Mountainview, CA). Coronary flow was measured directly by timed collection of Krebs effluent.

Ischemia was induced by encircling the LAD close to its origin with a 3-0 silk suture and snaring the suture. At the end of 1 hour of ischemia, reperfusion was achieved by releasing the ligature and briefly massaging the LAD with a moistened cotton swab. After 1 hour of reperfusion, the heart was removed from the perfusion apparatus, the ligature resnared, and 2 mL of monastryl blue was infused through the aortic cannula. The right ventricle was excised, and then the left ventricle was sectioned horizontally at 1- to 2-mm intervals into 5 to 7 slices. The unstained area was scanned (Sigma Scan, Jandel Scientific, San Rafael, CA) into an IBM-compatible computer (Dell, Austin, TX) and labeled the area at risk. The slices were then incubated in triphenyl tetrazolium chloride for 15 minutes, and the unstained (white) area was scanned and labeled the infarcted region. Infarct area was expressed as the percentage of area at risk. Overall infarct area was computed as a weighted average of the slices, by weight.

Seven hearts served as controls without treatment before LAD ischemia and reperfusion (Fig 1). Six hearts received the NO donor L-arginine [11] (1 mmol/L) before LAD ischemia, four hearts received NO synthetase inhibitor, NG-L-nitro-L-arginine methyl ester (L-NAME, 500 µmol/L) before infusion of L-arginine, and six hearts received nipradilol (5 µmol/L). Nine hearts underwent global ischemic preconditioning (IPC) before LAD ischemia and reperfusion. Ischemic preconditioning was accomplished with two episodes of 5 minutes of complete aortic occlusion followed by 5 minutes of reperfusion. Six hearts received ß-adrenergic blocker esmolol (100 µmol/L) before IPC.



View larger version (25K):
[in this window]
[in a new window]
  		Fig 1. Schematic diagram of experimental protocol. Hearts were subdivided into groups receiving one of the five preconditioning stimuli shown. Control hearts did not receive any stimulus before regional ischemia. (L-NAME = NG-nitro-L-arginine methyl ester; IPC = ischemic preconditioning; LAD = left anterior descending coronary artery.)

 
Comparisons between groups were made with analysis of variance (Systat v5.02, Systat, Evanston, IL). Comparisons within groups at different time points were made with the paired Student’s t test with the Bonferroni correction (Excel v5.0, Microsoft, Redmond, WA). When indicated, multiple comparisons were made with the Tukey post hoc test. Significant changes were taken at the p less than 0.05 level.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Left ventricular pressure
The effects of pretreatment, LAD ischemia, and reperfusion on developed pressures (EDP and peak developed pressure) are shown in Figures 2 and 3. Although there were no significant differences in EDP among all groups throughout the experiments, hearts treated with esmolol before IPC tended to have a higher EDP than other groups after reperfusion. All groups exhibited a significant decrease in peak developed pressure during ischemia (versus pretreatment value), that increased during reperfusion as compared with peak developed pressure at 60 minutes of ischemia. There were no significant differences between groups during pretreatment and regional ischemic periods. However, during reperfusion, nipradilol-treated hearts showed significantly higher peak developed pressure as compared with control hearts (p < 0.05).



View larger version (23K):
[in this window]
[in a new window]
  		Fig 2. Left ventricular end-diastolic pressure. Ischemic preconditioning (IPC) or drug infusion occurred before 0 on the time line. Regional ischemia occurred from 0 to 60 minutes, and reperfusion from 60 to 120 minutes. Data are shown as mean ± SEM. (L-NAME = NG-nitro-L-arginine methyl ester; LARG = L-arginine; ESM = esmolol; NIP = nipradilol.)

 


View larger version (22K):
[in this window]
[in a new window]
  		Fig 3. Left ventricular peak developed pressure. Peak developed pressure was defined as the difference between end-systolic pressure and end-diastolic pressure. Data are shown as mean ± SEM. * = p < 0.05 versus control. See Figure 2 for abbreviations and events time table.

 
Action potential duration
The effects of ischemia and reperfusion on the time course of 50% action potential repolarization (APD50) are shown in Figure 4 for all experiments. There were no significant differences among all groups during pretreatment and regional ischemic periods. During ischemia, all groups showed a decrease in APD50, which then increased with reperfusion. Both IPC- (93 ± 3 ms, p < 0.05 versus control) and L-arginine- (94 ± 6 ms, p < 0.05 versus control) treated hearts prolonged APD50 significantly as compared with control hearts (69 ± 2 ms) at 60 minutes of reperfusion. This increase in APD50 was blocked in the IPC group by esmolol (75 ± 6 ms) and in the L-arginine group by L-NAME (70 ± 2 ms). Nipradilol did not increase APD50 (75 ± 4 ms, not significantly different versus control).



View larger version (24K):
[in this window]
[in a new window]
  		Fig 4. Action potential duration at 50% repolarization (APD50). Data are shown as mean ± SEM. * = p < 0.05 versus control. See Figure 2 for abbreviations and events time table.

 
Infarct size
Infarct size for all experiments is shown as percentage of the area at risk (infarct size = infarct area (cm2)/area at risk (cm2) x 100%) in Figure 5. Control hearts had an infarct size of 49% ± 3%. L-Arginine infusion before ischemia significantly reduced infarct size to 24% ± 2% (p < 0.01 versus control). This reduction in infarct size was reversed by infusion of L-NAME before L-arginine, as the infarct size in this group was 53% ± 4%. Ischemic preconditioning reduced infarct size to 26% ± 4% (p < 0.01 versus control), and infusion of esmolol before IPC produced an infarct size of 33% ± 6%. Infusion of nipradilol resulted in a significant reduction in infarct as compared with control (24% ± 2%, p < 0.01). This reduction was not significantly different from IPC- or L-arginine-treated hearts, but was significantly lower than L-NAME + L-arginine-treated hearts (p < 0.01).



View larger version (13K):
[in this window]
[in a new window]
  		Fig 5. Infarct size for each heart is marked with an X. Bars indicate mean ± SEM for each group of hearts. Infarct sizes are based on the infarcted area as a percentage of the left ventricle at risk. * = p < 0.05 versus control and L-NAME + L-arginine. See Figure 2 for abbreviations.

 
Coronary flow
Figure 6 illustrates the change of coronary flow of control, L-arginine-, or nipradilol-treated hearts. There was no significant difference among the three groups during pretreatment or regional ischemic periods, and all groups showed a decrease in flow as a result of regional ischemia. The coronary flow increased in all groups (compared with ischemia) during reperfusion. However, during reperfusion, coronary flow in nipradilol-treated hearts increased significantly as compared with control or L-arginine-treated hearts after reperfusion (p < 0.01). L-Arginine infusion significantly increased coronary flow (54 ± 6 versus 63 ± 7 mL/min, p < 0.05; before versus after 5-minute infusion), whereas nipradilol infusion had no immediate effect on coronary flow (61 ± 6 versus 60 ± 8 mL/min; not significantly different before versus after 5-minute infusion).



View larger version (20K):
[in this window]
[in a new window]
  		Fig 6. Coronary flow throughout the experiments. Data are shown as mean ± SEM. * = p < 0.05 versus control and L-arginine. See Figure 2 for events time table.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Rationale for studying developed pressure and action potential duration
Most studies addressing the mechanism of preconditioning to date have used infarct size as their end point. Very few have been concerned with mechanical function, and none has addressed electrical function. We elected to emphasize the effect of preconditioning on mechanical and electrical function as these issues, as well as infarctsize, are especially important for the cardiac surgical patient. It is accepted that aortic cross-clamping and cardioplegic arrest constitute an ischemic insult, and that the immediate postoperative reperfusion period represents a critical time in the management of the patient. Pump failure and electrical derangement are common during this interval and directly affect patient care and outcome. With respect to electrical function, little is known about preconditioning except that the action potential duration shortens during and immediately after the preconditioning period, becoming very similar to the action potential recorded from a region of acute ischemia [12, 13]. This study not only quantified the changes in action potential duration during preconditioning, but also demonstrated that the action potential duration in preconditioned hearts was actually prolonged during reperfusion beyond those recorded from unconditioned hearts.

Role of nitric oxide in myocardial response to preconditioning
In the present study, infusion of both the NO donor L-arginine and the NO-generating ß-blocker nipradilol before prolonged ischemia offered myoprotective effects in terms of infarct size reduction and electrophysiologic preservation against ischemia–reperfusion insult. When the NO synthase inhibitor L-NAME was administered before L-arginine infusion, these protective effects were abolished. Although the concentration of NO was not measured in this study, these results imply that the generation of NO in some way contributes to the preconditioning seen with both L-arginine and nipradilol.

The specific mechanism underlying the protective effect of NO, however, remains unclear. Several energy-sparing actions have been proposed, including antagonizing ß-adrenergic activation [14], inhibiting calcium influx into myocytes [15], decreasing myocardial contractility, and decreasing mitochondrial respiration [14].

Effect of ß-adrenergic manipulation on ischemic preconditioning
Although many drugs have been shown to promote or block the infarct size-reducing effects of IPC [3–8], none has been studied from either the mechanical or electrophysiologic point of view. One subcellular mechanism of particular interest as regards this study proposes that ß-adrenergic stimulation increases the concentration of intracellular cyclic adenosine monophosphate by a G protein-dependent adenylate cyclase. The rise in cyclic adenosine monophosphate activates protein kinase C, which phosphorylates intracellular enzymes and transmembrane ion channels such as the adenosine triphosphate-sensitive potassium channel. Activation of the adenosine triphosphate-sensitive potassium channel increases transmembrane conductance during the repolarization phase and shortens the action potential. Therefore, ß-adrenergic blockade can be expected to interfere with IPC [16]. Because many patients who undergo coronary operations are already prescribed ß-blockers, it is not clear what effect this will have, if any, on attempts at pharmacologic preconditioning.

Effect of nipradilol on ischemic preconditioning
In this study, nipradilol, a NO-generating ß-blocker, preserved postischemic cardiac function and reduced infarct size. With regard to mechanical function, nipradilol may have its effect by increasing coronary flow after reperfusion. It remains unclear, however, why this change was not evident immediately after infusion of nipradilol, but rather apparent only during the reperfusion period. Perhaps this effect was contributed by either NO production alone, or by both NO and ß-adrenergic modulation.

Study limitations
We have demonstrated some myoprotective effects of the NO-generating ß-blocker nipradilol in the isolated, crystalloid-perfused rabbit heart. However, NO may have many more complex effects in vivo, as it has been shown to inhibit leukocyte adherence to vascular endothelium and to diminish neutrophil and platelet aggregation [17].

Although our findings suggest that NO may protect against ischemia–reperfusion injury, the peroxynitrate radical, derived from the reaction between NO and superoxide, may damage the myocardium [18]. In addition, hemoglobin is believed to be a potent inactivator of NO [17]; thus, NO might not be protective in the intact human. Furthermore, the effects of NO on other organs remain to be completely elucidated, and NO may even sometimes play a detrimental role [19]. Therefore, the effects of NO on other organs must be carefully investigated before the administration of nipradilol is considered in clinical practice.

Another limitation of this study is the short-term application of nipradilol. Clinically, this drug is likely to be given over much longer periods of time. This model of preconditioning, along with all other models, uses a short-term administration of the pharmacologic stimulus. Whether long-term administration of preconditioning stimuli reduces the protective response of the heart is unknown and will be addressed in future studies.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia. Circulation 1986;74:1124-1136.[Abstract/Free Full Text]
  2. Downey J.M. Ischemic preconditioning. Trends Cardiovasc Med 1992;2:170-176.
  3. Parratt J.R., Kane K.A. K-ATP channels in ischemic preconditioning. Cardiovasc Res 1994;28:783-787.[Free Full Text]
  4. Yao Z., Gross J.G. Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K+ channel in mediating the effects of acetylcholine to mimic preconditioning in dogs. Circ Res 1993;73:1193-1201.[Abstract/Free Full Text]
  5. Hu K., Nattel S. Mechanism of ischemic preconditioning in rat hearts. Involvement of alpha 1B-adrenoceptors, pertussis toxin-sensitive G proteins, and protein kinase C. Circulation 1995;92:2259-2265.[Abstract/Free Full Text]
  6. Khandoudi N., Moffat M.P., Karmazyn M. Adenosine-sensitive alpha 1-adrenoceptor effects on reperfused ischemic hearts. Br J Pharmacol 1994;112:1007-1016.[Medline]
  7. Banerjee A., Locke-Winter C., Rogers K.B., et al. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res 1993;73:656-670.[Abstract/Free Full Text]
  8. Yokota R., Fujiwara H., Miyamae M., et al. Transient adenosine infusion before ischemia and reperfusion protects against metabolic damage in pig hearts. Am J Physiol 1995;268:H1149-H1157.[Abstract/Free Full Text]
  9. Vegh A., Szekeres L., Parratt J. Preconditioning of the ischemic myocardium. Br J Pharmacol 1992;107:648-652.[Medline]
  10. Horimoto H., Gaudette G.R., Krukenkamp I.B. The nitric oxide is a requisite cofactor to generate ATP-sensitive potassium channel-mediated preconditioning. Surg Forum 1998;48:202-203.
  11. Amezcua J.L., Palmer R.M.J., Sonza B.M., Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol 1989;97:1119-1124.[Medline]
  12. Patterson E., Jackman W.N., Scherlag B.J., Lazzara R. The monophasic action potential in clinical cardiology. Clin Cardiol 1991;14:505-510.[Medline]
  13. Harris L., Kimura Y., Shaikh N. Phospholipase inhibition and electrophysiology of acute ischemia. J Mol Cell Cardiol 1993;25:1075-1090.[Medline]
  14. Balligand J.L., Kelly R.A., Marsden P.A., Smith T.W., Michael T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 1993;90:347-351.[Abstract/Free Full Text]
  15. Levi R.C., Alloatti G., Fischmeister R. Cyclic GMP regulates the Ca-channel current in guinea pig ventricular myocytes. Eur J Physiol 1989;413:685-687.[Medline]
  16. Xie Y.W., Shen W., Zhao G., Xu X., Wolin M.S., Hintze T.H. Role of endothelium-derived nitric oxide in the modulation of canine myocardial mitochondrial respiration in vivo. Implication for the development of heart failure. Circ Res 1996;79:381-387.[Abstract/Free Full Text]
  17. Moncada S., Higgd A. The L-arginine–nitric oxide pathway. N Engl J Med 1993;329:2002-2012.[Free Full Text]
  18. Maulik N., Engelman D.T., Watanabe M., et al. Nitric oxide/carbon monoxide. A molecular switch for myocardial preservation during ischemia. Circulation 1996;94(Suppl 2):II-398-II-406.
  19. Galaris D., Cadenas E., Hochstein P. Redox cycling of myoglobin and ascorbate. Arch Biochem Biophys 1989;273:497-504.[Medline]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
M. V. Cohen, X.-M. Yang, and J. M. Downey
Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies
Cardiovasc Res, May 1, 2006; 70(2): 231 - 239.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
Q. Qin, X.-M. Yang, L. Cui, S. D. Critz, M. V. Cohen, N. C. Browner, T. M. Lincoln, and J. M. Downey
Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H712 - H718.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
M. Zaugg, E. Lucchinetti, C. Garcia, T. Pasch, D. R. Spahn, and M. C. Schaub
Anaesthetics and cardiac preconditioning. Part II. Clinical implications
Br. J. Anaesth., October 1, 2003; 91(4): 566 - 576.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
S. Mieno, H. Horimoto, F. Watanabe, Y. Nakai, E. Furuya, and S. Sasaki
Potent adenylate cyclase agonist forskolin restores myoprotective effects of ischemic preconditioning in rat hearts after myocardial infarction
Ann. Thorac. Surg., October 1, 2002; 74(4): 1213 - 1218.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
A. E. Saltman, T. O. Aksehirli, V. Valiunas, G. R. Gaudette, N. Matsuyama, P. Brink, and I. B. Krukenkamp
Gap junction uncoupling protects the heart against ischemia
J. Thorac. Cardiovasc. Surg., August 1, 2002; 124(2): 371 - 376.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
Y. Suematsu, T. Ohtsuka, H. Horimoto, K. Maeda, Y. Nakai, S. Mieno, and S. Takamoto
Long-term treatment with nipradilol, a nitric oxide-releasing {beta}-adrenergic blocker, enhances postischemic recovery and limits infarct size
Ann. Thorac. Surg., January 1, 2002; 73(1): 173 - 179.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
M. Zaugg, M. C. Schaub, T. Pasch, and D. R. Spahn
Modulation of {beta}-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action
Br. J. Anaesth., January 1, 2002; 88(1): 101 - 123.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
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 PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Adam E. Saltman
Irvin B. Krukenkamp
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Horimoto, H.
Right arrow Articles by Krukenkamp, I. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Horimoto, H.
Right arrow Articles by Krukenkamp, I. B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS