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(Circulation. 2006;113:e724-e725.)
© 2006 American Heart Association, Inc.

Correspondence

Letter Regarding Article by Ejiri et al, "Possible Role of Brain-Derived Neurotrophic Factor in the Pathogenesis of Coronary Artery Disease"

Marek Lommatzsch, MD; J. Christian Virchow, MD

University of Rostock, Rostock, Germany

To the Editor:

We have read with interest the article by Ejiri and colleagues¹ about the possible role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of coronary artery disease, which suggests that BDNF might contribute to plaque instability in coronary artery disease because of enhanced local nicotinamide adenine dinucleotide (phosphate) oxidase activity and superoxide production. On the basis of increased BDNF concentrations in EDTA-containing plasma in the coronary sinus (compared with concentrations measured in the aortic root) and several histological studies in patients with acute coronary syndrome, the authors assume that BDNF is derived mainly from diseased coronary arteries.¹ We would like to suggest an alternative interpretation. It has been well established that BDNF is one of the major mediators stored in human platelets. Human platelets contain large amounts of BDNF (&100 pg/10⁶ platelets) that is released rapidly by platelets in response to shear stress or agonist stimulation.^2,3 The fact that platelets in 1 mL human blood contain 200-fold more BDNF than 1 mL human plasma³ makes it very difficult to avoid a partial release of BDNF from activated platelets during plasma extraction. We have recently shown that heparinized human plasma contains <100 pg BDNF/mL,³ whereas EDTA plasma from the same individuals contained >700 pg BDNF/mL. These data strongly suggest that EDTA plasma, which has been examined by Ejiri and coworkers,¹ contains BDNF from activated platelets. Increased blood flow velocity and shear stress in the presence of significant narrowing of epicardial coronary arteries lead to platelet activation.⁴ Thus, elevated concentrations of BDNF in EDTA plasma taken from the coronary sinus in acute coronary syndrome might be explained by a release of BDNF from activated platelets, either in vivo or in vitro. Elevated concentrations of other platelet-derived mediators in EDTA plasma taken from the coronary sinus have previously been linked to platelet activation in coronary artery disease.⁵ It is therefore likely that the observations by Ejiri and coworkers are related to platelet activation. This interpretation reveals a hitherto unknown aspect of platelet activation in the acute coronary syndrome.

	Acknowledgments

 
Disclosures

None.

	References

Top References Acknowledgments  References

 

1. Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K, Honjo T, Takahashi M, Ohashi Y, Ichikawa S, Terashima M, Mori T, Awano K, Shinke T, Shite J, Hirata KI, Yokozaki H, Kawashima S, Yokoyama M. Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation. 2005; 112: 2114–2120.[Abstract/Free Full Text]
   
2. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, Sun B, Tandon NN. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002; 87: 728–734.[Medline] [Order article via Infotrieve]
   
3. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005; 26: 115–123.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Diodati JG, Cannon RO 3rd, Epstein SE, Quyyumi AA. Platelet hyperaggregability across the coronary bed in response to rapid atrial pacing in patients with stable coronary artery disease. Circulation. 1992; 86: 1186–1193.[Abstract/Free Full Text]
   
5. Golino P, Piscione F, Benedict CR, Anderson HV, Cappelli-Bigazzi M, Indolfi C, Condorelli M, Chiariello M, Willerson JT. Local effect of serotonin released during coronary angioplasty. N Engl J Med. 1994; 330: 523–528.[Abstract/Free Full Text]
   

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Nobutaka Inoue, MD, PhD; Junya Ejiri, MD, PhD; Seiichi Kobayashi, MD, PhD; Rio Shiraki, MD, PhD; Kazunori Otsui, MD; Tomoyuki Honjo, MD; Motonori Takahashi, MD; Toshiro Shinke, MD, PhD; Junya Shite, MD, PhD; Ken-ichi Hirata, MD, PhD; Seinosuke Kawashima, MD, PhD; Mitsuhiro Yokoyama, MD, PhD

Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

Hiroshi Yokozaki, MD, PhD

Division of Surgical Pathology, Department of Biological Informatics, Kobe University Graduate School of Medicine, Kobe, Japan

Takao Mori, MD, PhD; Yoshitaka Ohashi, MD, PhD; Shinobu Ichikawa, MD, PhD; Mitsuyasu Terashima, MD; Kojiro Awano, MD, PhD

Division of Cardiology, Miki City Hospital, Kobe, Japan

Response

We thank Drs Lommatzsch and Virchow for their interest in our article on the role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of coronary artery disease.¹ We found that the difference in the plasma BDNF concentrations between the coronary sinus and the aortic root was significantly greater in the unstable angina group than in the stable angina and control groups. Our observation suggests the possibility that the generation of BDNF in the coronary circulation was enhanced in patients with unstable angina. In fact, the precise origin of plasma BDNF remains to be elucidated. In our investigation, blood samples were obtained from patients during cardiac catheterization; therefore, heparin was administrated to all subjects before blood sampling. Because the samples were placed immediately in tubes containing EDTA, we measured the concentrations of BDNF in the EDTA plasma from heparinized blood in our study; however, we did not analyze the contribution of BDNF released by platelets. Because platelets are activated in acute coronary syndrome and contain BDNF, as Drs Lommatzsch and Virchow have pointed out, it is possible that platelet activation in the coronary circulation is responsible for the difference in BDNF concentrations between the coronary sinus and aortic root. Further investigation of the relationship between BDNF concentrations and the markers of platelet activation in the coronary circulation would provide a better understanding. However, immunohistochemical analysis revealed intense immunoreactivity of BDNF in the atherosclerotic plaques of patients with unstable angina. Furthermore, previous studies have reported that various nonneural cells, including endothelial cells, monocytes, and activated lymphocytes, have potent ability to produce BDNF.^2,3 These suggest that other cell types might contribute to the enhanced difference in BDNF concentrations between the coronary sinus and aortic root. Another possibility is that disrupted unstable plaque might release BDNF into the coronary circulation. Regardless of its origin, we speculate that BDNF in the coronary circulation plays an important role in the pathogenesis of acute coronary syndrome because it has potent ability to activate nicotinamide adenine dinucleotide (phosphate) oxidase and produce reactive oxygen species. Once again, we appreciate the comments of Drs Lommatzsch and Virchow, which brought up an important point.

	Acknowledgments

Top References Acknowledgments  References

 
Disclosures

None.

	References

Top References Acknowledgments  References

 

1. Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K, Honjo T, Takahashi M, Ohashi Y, Ichikawa S, Terashima M, Mori T, Awano K, Shinke T, Shite J, Hirata K, Yokozaki H, Kawashima S, Yokoyama M. Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation. 2005; 112: 2114–2120.[Abstract/Free Full Text]
   
2. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999; 189: 865–870.[Abstract/Free Full Text]
   
3. Nakahashi T, Fujimura H, Altar CA, Li J, Kambayashi J, Tandon NN, Sun B. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000; 470: 113–117.[CrossRef][Medline] [Order article via Infotrieve]
   

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