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(Circulation. 2008;118:e691.)
© 2008 American Heart Association, Inc.

Correspondence

Response to Letter Regarding Article, "Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis"

Andreas J. Flammer, MD; Isabella Sudano, MD, PhD; Frank Hermann, MD; Frank Enseleit, MD; Daniel Périat, MD; Matthias Hermann, MD; Thomas F. Lüscher, MD; Roberto Corti, MD; Georg Noll, MD; Frank Ruschitzka, MD

Cardiovascular Centre, Cardiology, University Hospital Zurich, Zurich, Switzerland

Steffen Gay, MD; Adrian Forster, MD; Michael Neidhart, PhD; Peter Künzler, MSc

Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland

Juerg Nussberger, MD

Department of Internal Medicine, Division of Angiology and Hypertension, University Hospital Lausanne, Lausanne, Switzerland

We would like to thank Drs Popa and Netea for their interest in our study¹ and their comments.

It is a prerequisite of clinical studies investigating endothelial function that patients remain clinically stable throughout the course of the study to allow the assessment of the potential impact of the study drug. Clinically stable patients, however, present with low disease activity and demonstrate low markers of inflammation, thus explaining the relatively low levels of interleukin-1, interleukin-6, CD40, myeloperoxidase, and tumor necrosis factor (TNF)- in our study. The average serum concentration of TNF- in the present study was 1.74±1.82 pg/mL. The manufacturer gives a minimal detection limit of 0.03 pg/mL for the high-sensitivity assay kit, which is 15-fold more sensitive than the older Quantikine kit and allows measurement further down into the physiological range of plasma TNF- levels.

Although we concur with Drs Popa and Netea that "therapeutic TNF neutralization on its own also is able to improve endothelial function," it is somewhat surprising that they cite an article published in 2004 because the first evidence was provided by our group in 2002 in this journal.² Importantly, the effects of angiotensin-converting enzyme inhibition on endothelial function were observed in patients on stable background therapy, including TNF- antagonists. Hence, it is unlikely that the concomitant therapy, which remained unchanged throughout the study, affected the study results. It is of note that the improvement in endothelial function in the present study showed a moderate inverse correlation with TNF- levels even after the 3 patients treated with TNF antagonists were excluded (r=–0.46, P=0.02).

Finally, although we appreciate that Drs Popa and Netea agree with our conclusion that further exploration of angiotensin-converting enzyme inhibitory strategies in rheumatoid arthritis is extremely important, only large-scale prospective randomized clinical trials will provide evidence that the improvements in vascular function with angiotensin-converting enzyme inhibitors,¹ antiinflammatory strategies,² and statins³ translate into a reduction in the cardiovascular burden of our patients with rheumatoid arthritis.

	Acknowledgments

 
Disclosures

Dr Ruschitzka received an unrestricted research grant from Sanofi-Aventis. Dr Nussberger received a research grant from Sanofi-Aventis and was co-winner of the Sanofi-Aventis Heart Prize 2007. The other authors report no conflicts.

	References

Top References

 
1. Flammer AJ, Sudano I, Hermann F, Gay S, Forster A, Neidhart M, Kunzler P, Enseleit F, Periat D, Hermann M, Nussberger J, Lüscher TF, Corti R, Noll G, Ruschitzka F. Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis. Circulation. 2008; 117: 2262–2269.[Abstract/Free Full Text]

2. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, Bechir M, Spieker LE, Neidhart M, Michel BA, Gay RE, Lüscher TF, Gay S, Ruschitzka F. Anti–tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002; 106: 2184–2187.[Abstract/Free Full Text]

3. Hermann F, Forster A, Chenevard R, Enseleit F, Hurlimann D, Corti R, Spieker LE, Frey D, Hermann M, Riesen W, Neidhart M, Michel BA, Hellermann JP, Gay RE, Lüscher TF, Gay S, Noll G, Ruschitzka F. Simvastatin improves endothelial function in patients with rheumatoid arthritis. J Am Coll Cardiol. 2005; 45: 461–464.[Free Full Text]

This Article Extract 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 Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Flammer, A. J. Articles by Nussberger, J. Search for Related Content PubMed Articles by Flammer, A. J. Articles by Nussberger, J. Related Collections Pathophysiology Endothelium/vascular type/nitric oxide