1044
Circulation Vol 86, No 3 September 1992
incorrectly interpreted to be irreversible if only stress-reinjection images were acquired. Dr. Freedman's finding of low differential uptake in 11% of their patients after reinjection appears to confirm our results. We agree with Dr. Freedman that similar information might be obtained if an analysis of thallium activity after a resting injection of 20`T1 were used. Preliminary data in our laboratory suggest a high concordance between the results of stress-redistributionreinjection imaging and rest-redistribution imaging.5 We caution that a resting image alone may be insufficient and that a subsequent redistribution image after the injection at rest is often necessary. Vasken Dilsizian, MD Nanette M.T. Freedman, PhD Stephen L. Bacharach, PhD Pasquale Perrone-Filardi, MD Robert 0. Bonow, MD Cardiology Branch National Heart, Lung, and Blood Institute Bethesda, Md.
References 1. Dilsizian V, Freedman NMT, Bacharach SL, Perrone-Filardi P, Bonow RO: Regional thallium uptake in irreversible defects: Magnitude of change in thallium activity after reinjection distinguishes viable from nonviable myocardium. Circulation 1992;85:627-634 2. Bonow RO, Dilsizian V, Cuocolo A, Bacharach SL: Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction: Comparison of thallium scintigraphy with reinjection and PET imaging with '8F-fluorodeoxyglucose. Circulation 1991;83:26-37 3. Dilsizian V, Rocco TP, Freedman NM, Leon MB, Bonow RO: Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N Engl J Med 1990;323:141-146 4. Dilsizian V, Bonow RO: Differential uptake and apparent 2OITI washout after thallium reinjection: Options regarding early redistribution imaging before reinjection or late redistribution imaging after reinjection. Circulation 1992;85:1032-1038 5. Dilsizian V, Bacharach SL, Perrone-Filardi P, Arrighi JA, Maurea S, Bonow RO: Concordance and discordance between restredistribution thallium imaging and thallium reinjection after stressredistribution imaging for assessing viable myocardium: Comparison with metabolic activity by PET. (abstract) Circulation 1991;84:89
Intracellular [Ca 2+] in Normal and Diseased Human Myocardium Letter To the Editor Beuckelmann et al recently published a report in Circulation' showing that peak systolic intracellular calcium measured by fura-2 was diminished in single ventricular cells from patients with heart failure. Although the experimental findings were interesting, the suggestion by the authors that the major defect in contractile failure is a diminished intracellular calcium concentration was distressing. The authors propose that diminished calcium availability might explain impaired contractile performance in human heart failure because calcium concentration is intimately related to force production; it is important to note, however, that this conclusion is weakened by the fact that Beuckelmann et al did not measure force or cell shortening during excitation in their cells. These results are in contrast to those obtained by other investigators who used different experimental techniques and reported similar systolic calcium concentrations in myopathic and control human myocardium.2-6 More importantly, we and others have found similar force production in control and myopathic hearts, and it has been clearly demonstrated that in failing human myocardium, there is a significant increase in resting intracellular calcium concentration. The clinical extrapolation of the data proposed by the authors was especially alarming because they suggest that agents that increase intracellular calcium would be beneficial in patients
with failure. Recently, however, the PROMISE trials7 have indicated that such agents may not be useful or may even be harmful to patients with failure. We feel that it is very important to alert the reader that the issue of whether intracellular calcium release is reduced during excitation-contraction coupling in heart failure is still controversial and that therapeutic decisions should not be based on this one report.
James P. Morgan, MD, PhD Judith K. Gwathmey, VMD, PhD Department of Medicine Cardiovascular Division Beth Israel Hospital Harvard University Boston, Mass.
References 1. Beuckelmann DJ, Nabauer DJ, Erdmann E: Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 1992;85:1046-1055 2. Gwathmey JK, Slawsky MT, Habar RJ, Briggs GM, Morgan JP: The role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest 1990;85:1599-1613 3. Lederer WJ, Berlin JR, Cohen NM, Hadley RW, Bers DM, Cannell MB: Excitation-contraction coupling in heart cells: Roles of the sodium-calcium exchange, the calcium current, and the sarcoplasmic reticulum. Ann N YAcad Sci 1990;588:190-206 4. Movsesian MA, Bristow MR, Krall J: Ca2' uptake by cardiac sarcoplasmic reticulum from patients with idiopathic dilated cardiomyopathy. Circ Res 1989;65:1141-1144 5. Movsesian MA, Colyer J, Wang JH, Krall J: Phospholambanmediated stimulation of Ca2` uptake in sarcoplasmic reticulum from normal and failing hearts. J Clin Invest 1990;85:1698-1702 6. D'Agnolo A, Luciani GB, Mazzucco A, Gallucci V, Salviati G: Contractile properties and Ca2` release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 1992;85:518-525 7. Packer M, Carver JR, Rodenheffer RS: Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1990;325: 1468-1475
Reply We appreciate the comments by Dr. Morgan and Dr. Gwathmey concerning the interpretation of our data. There may have been some misunderstanding, however, as our results do not indicate a generally diminished intracellular [Ca21], concentration. In fact, we have shown that resting [Ca2+]J levels are increased but that peak systolic [Ca21]1 transients are diminished in heart cells from patients with heart failure. Therefore, we completely agree that pharmacological agents that would simply increase resting [Ca2+]1 might be harmful. An increase in resting [Ca 2+I1 might further reduce Ca2' release from the sarcoplasmic reticulum through Ca2+-dependent inactivation of the Ca2' release channel as shown by Fabiato.1 Therefore, in our paper we have put forward the idea that pharmacological agents that enhance Ca21 uptake by the sarcoplasmic reticulum would be expected to be beneficial, which agrees with suggestions in earlier papers from Drs. Morgan and Gwathmey. Whether such a pharmacological intervention is beneficial in heart failure, of course, has to await a clinical trial. Our data concerning the systolic [Ca2+]1 transient disagree with results from Dr. Gwathmey and her colleagues, and we have discussed possible reasons in our paper. [Ca2+], transients have not been measured in the papers by Movsesian et al2.3 and by D'Agnolo et al.4 On the contrary, in their paper D'Agnolo et al showed an abnormal Ca 2+ release from the sarcoplasmic reticulum, which they proposed could lead to a diminished [Ca2+]1 transient. In the general review article on excitation-contraction coupling by Lederer et al,5 a single [Ca 21Ji record in a myocyte from a patient with heart failure is shown. In that paper, however, no quantitative comparison between diseased and undiseased myocardium has been attempted. Therefore, we think that the
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Intracellular [Ca2+] in normal and diseased human myocardium. J P Morgan and J K Gwathmey Circulation. 1992;86:1044-1045 doi: 10.1161/01.CIR.86.3.1044 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/86/3/1044.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
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Circulation Vol 86, No 3 September 1992
incorrectly interpreted to be irreversible if only stress-reinjection images were acquired. Dr. Freedman's finding of low differential uptake in 11% of their patients after reinjection appears to confirm our results. We agree with Dr. Freedman that similar information might be obtained if an analysis of thallium activity after a resting injection of 20`T1 were used. Preliminary data in our laboratory suggest a high concordance between the results of stress-redistributionreinjection imaging and rest-redistribution imaging.5 We caution that a resting image alone may be insufficient and that a subsequent redistribution image after the injection at rest is often necessary. Vasken Dilsizian, MD Nanette M.T. Freedman, PhD Stephen L. Bacharach, PhD Pasquale Perrone-Filardi, MD Robert 0. Bonow, MD Cardiology Branch National Heart, Lung, and Blood Institute Bethesda, Md.
References 1. Dilsizian V, Freedman NMT, Bacharach SL, Perrone-Filardi P, Bonow RO: Regional thallium uptake in irreversible defects: Magnitude of change in thallium activity after reinjection distinguishes viable from nonviable myocardium. Circulation 1992;85:627-634 2. Bonow RO, Dilsizian V, Cuocolo A, Bacharach SL: Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction: Comparison of thallium scintigraphy with reinjection and PET imaging with '8F-fluorodeoxyglucose. Circulation 1991;83:26-37 3. Dilsizian V, Rocco TP, Freedman NM, Leon MB, Bonow RO: Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N Engl J Med 1990;323:141-146 4. Dilsizian V, Bonow RO: Differential uptake and apparent 2OITI washout after thallium reinjection: Options regarding early redistribution imaging before reinjection or late redistribution imaging after reinjection. Circulation 1992;85:1032-1038 5. Dilsizian V, Bacharach SL, Perrone-Filardi P, Arrighi JA, Maurea S, Bonow RO: Concordance and discordance between restredistribution thallium imaging and thallium reinjection after stressredistribution imaging for assessing viable myocardium: Comparison with metabolic activity by PET. (abstract) Circulation 1991;84:89
Intracellular [Ca 2+] in Normal and Diseased Human Myocardium Letter To the Editor Beuckelmann et al recently published a report in Circulation' showing that peak systolic intracellular calcium measured by fura-2 was diminished in single ventricular cells from patients with heart failure. Although the experimental findings were interesting, the suggestion by the authors that the major defect in contractile failure is a diminished intracellular calcium concentration was distressing. The authors propose that diminished calcium availability might explain impaired contractile performance in human heart failure because calcium concentration is intimately related to force production; it is important to note, however, that this conclusion is weakened by the fact that Beuckelmann et al did not measure force or cell shortening during excitation in their cells. These results are in contrast to those obtained by other investigators who used different experimental techniques and reported similar systolic calcium concentrations in myopathic and control human myocardium.2-6 More importantly, we and others have found similar force production in control and myopathic hearts, and it has been clearly demonstrated that in failing human myocardium, there is a significant increase in resting intracellular calcium concentration. The clinical extrapolation of the data proposed by the authors was especially alarming because they suggest that agents that increase intracellular calcium would be beneficial in patients
with failure. Recently, however, the PROMISE trials7 have indicated that such agents may not be useful or may even be harmful to patients with failure. We feel that it is very important to alert the reader that the issue of whether intracellular calcium release is reduced during excitation-contraction coupling in heart failure is still controversial and that therapeutic decisions should not be based on this one report.
James P. Morgan, MD, PhD Judith K. Gwathmey, VMD, PhD Department of Medicine Cardiovascular Division Beth Israel Hospital Harvard University Boston, Mass.
References 1. Beuckelmann DJ, Nabauer DJ, Erdmann E: Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 1992;85:1046-1055 2. Gwathmey JK, Slawsky MT, Habar RJ, Briggs GM, Morgan JP: The role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest 1990;85:1599-1613 3. Lederer WJ, Berlin JR, Cohen NM, Hadley RW, Bers DM, Cannell MB: Excitation-contraction coupling in heart cells: Roles of the sodium-calcium exchange, the calcium current, and the sarcoplasmic reticulum. Ann N YAcad Sci 1990;588:190-206 4. Movsesian MA, Bristow MR, Krall J: Ca2' uptake by cardiac sarcoplasmic reticulum from patients with idiopathic dilated cardiomyopathy. Circ Res 1989;65:1141-1144 5. Movsesian MA, Colyer J, Wang JH, Krall J: Phospholambanmediated stimulation of Ca2` uptake in sarcoplasmic reticulum from normal and failing hearts. J Clin Invest 1990;85:1698-1702 6. D'Agnolo A, Luciani GB, Mazzucco A, Gallucci V, Salviati G: Contractile properties and Ca2` release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 1992;85:518-525 7. Packer M, Carver JR, Rodenheffer RS: Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1990;325: 1468-1475
Reply We appreciate the comments by Dr. Morgan and Dr. Gwathmey concerning the interpretation of our data. There may have been some misunderstanding, however, as our results do not indicate a generally diminished intracellular [Ca21], concentration. In fact, we have shown that resting [Ca2+]J levels are increased but that peak systolic [Ca21]1 transients are diminished in heart cells from patients with heart failure. Therefore, we completely agree that pharmacological agents that would simply increase resting [Ca2+]1 might be harmful. An increase in resting [Ca 2+I1 might further reduce Ca2' release from the sarcoplasmic reticulum through Ca2+-dependent inactivation of the Ca2' release channel as shown by Fabiato.1 Therefore, in our paper we have put forward the idea that pharmacological agents that enhance Ca21 uptake by the sarcoplasmic reticulum would be expected to be beneficial, which agrees with suggestions in earlier papers from Drs. Morgan and Gwathmey. Whether such a pharmacological intervention is beneficial in heart failure, of course, has to await a clinical trial. Our data concerning the systolic [Ca2+]1 transient disagree with results from Dr. Gwathmey and her colleagues, and we have discussed possible reasons in our paper. [Ca2+], transients have not been measured in the papers by Movsesian et al2.3 and by D'Agnolo et al.4 On the contrary, in their paper D'Agnolo et al showed an abnormal Ca 2+ release from the sarcoplasmic reticulum, which they proposed could lead to a diminished [Ca2+]1 transient. In the general review article on excitation-contraction coupling by Lederer et al,5 a single [Ca 21Ji record in a myocyte from a patient with heart failure is shown. In that paper, however, no quantitative comparison between diseased and undiseased myocardium has been attempted. Therefore, we think that the
Downloaded from http://circ.ahajournals.org/ by guest on March 20, 2015
Intracellular [Ca2+] in normal and diseased human myocardium. J P Morgan and J K Gwathmey Circulation. 1992;86:1044-1045 doi: 10.1161/01.CIR.86.3.1044 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/86/3/1044.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
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