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Journal of Interventional Cardiac Electrophysiology
Published in: Journal of Interventional Cardiac Electrophysiology 1/2015

01-06-2015

The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation assessed using beat-to-beat pacemaker Holter follow-up

Authors: Conn Sugihara, Nick Freemantle, Steven G. Hughes, Steve Furniss, Neil Sulke

Published in: Journal of Interventional Cardiac Electrophysiology | Issue 1/2015

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Abstract

Purpose

C-reactive protein (CRP) is known to be strongly associated with atrial fibrillation (AF). However, it is not clear if CRP is a causal factor for AF. ISIS-CRPRx is a novel antisense oligonucleotide that reduces CRP production by specifically inhibiting mRNA translation. The effect of ISIS-CRPRx on AF was evaluated.

Methods

A double-blind phase II trial of ISIS-CRPRx in patients with paroxysmal AF and DDDRP permanent pacemakers (PPMs) with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up.

Results

Twenty six patients were screened and seven patients dosed with ISIS-CRPRx. After 4 weeks of baseline assessment, patients were randomly assigned to two treatment periods of either placebo then ISIS-CRPRx or ISIS-CRPRx then placebo. All patients were followed up for 8 weeks after the active treatment period. There was a 63.7 % (95 % CI 38.4 to 78.6 %, p = 0.003) relative reduction in CRP on treatment with ISIS-CRPRx versus baseline. Sensitivity analyses demonstrated a consistent treatment effect. The primary end-point was change in AF burden assessed by PPM. There was no significant difference in AF burden on treatment with ISIS-CRPRx versus baseline (OR 1.6, 95 % CI −2.42 to 5.62, p = 0.37). ISIS CRPRx was safe and well tolerated and there were no serious adverse events.

Conclusions

Treatment with ISIS-CRPRx did not reduce AF burden in patients with paroxysmal AF and PPMs, despite a large relative reduction in CRP. In this population, highly specific CRP reduction had no clinically discernable effect upon paroxysmal AF. However, average levels of CRP at baseline were relatively low, so it remains possible that AF patients with higher levels of CRP may benefit from CRP-directed therapy.
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Literature
1.
Pena, J. M., MacFadyen, J., Glynn, R. J., & Ridker, P. M. (2012). High-sensitivity C-reactive protein, statin therapy, and risks of atrial fibrillation: an exploratory analysis of the JUPITER trial. European Heart Journal, 33(4), 531–537.CrossRefPubMedCentralPubMed
2.
Dernellis, J. (2004). Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. European Heart Journal, 25(13), 1100–1107.CrossRefPubMed
3.
Liu, J., Fang, P.-H., Dibs, S., Hou, Y., Li, X.-F., & Zhang, S. (2011). High-sensitivity C-reactive protein as a predictor of atrial fibrillation recurrence after primary circumferential pulmonary vein isolation. Pacing and Clinical Electrophysiology, 34(4), 398–406.CrossRefPubMed
4.
Marcus, G. M., Smith, L. M., Ordovas, K., Scheinman, M. M., Kim, A. M., Badhwar, N., & Olgin, J. E. (2010). Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm, 7(2), 149–154.CrossRefPubMedCentralPubMed
5.
Pellegrino, P. L., Brunetti, N. D., Gennaro, L., Ziccardi, L., Grimaldi, M., & Biase, M. D. (2013). Inflammatory activation in an unselected population of subjects with atrial fibrillation: links with structural heart disease, atrial remodeling and recent onset. Internal and Emergency Medicine, 8(2), 123–128.CrossRefPubMed
6.
Bisoendial, R. J., Kastelein, J. J. P., Peters, S. L. M., Levels, J. H. M., Birjmohun, R., Rotmans, J. I., & Stroes, E. S. G. (2007). Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects. The Journal of Lipid Research, 48(4), 952–960.CrossRef
7.
Fauchier, L., Pierre, B., de Labriolle, A., Grimard, C., Zannad, N., & Babuty, D. (2008). Antiarrhythmic effect of statin therapy and atrial fibrillation. Journal of the American College of Cardiology, 51(8), 828–835.CrossRefPubMed
8.
Frendl, G., Sodickson, A. C., Chung, M. K., Waldo, A. L., Gersh, B. J., Tisdale, J. E., & Adler, D. (2014). 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. The Journal of Thoracic and Cardiovascular Surgery, 148(3), e153–e193.CrossRefPubMed
9.
Marik, P. E., & Fromm, R. (2009). The efficacy and dosage effect of corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a systematic review. Journal of Critical Care, 24(3), 458–463.CrossRefPubMed
10.
Healey, J. S., Baranchuk, A., Crystal, E., Morillo, C. A., Garfinkle, M., Yusuf, S., & Connolly, S. J. (2005). Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. Journal of the American College of Cardiology, 45(11), 1832–1839.CrossRefPubMed
11.
Deftereos, S., Giannopoulos, G., Kossyvakis, C., Efremidis, M., Panagopoulou, V., Kaoukis, A., & Stefanadis, C. (2012). Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation. Journal of the American College of Cardiology, 60(18), 1790–1796.CrossRefPubMed
12.
Altmann, K.-H., Dean, N. M., Fabbro, D., Freier, S. M., Geiger, T., Hanera, R., & Miiller, M. (1996). Second generation of antisense oligonucleotides: from nuclease resistance to biological efficacy in animals. CHIMIA International Journal for Chemistry, 50(4), 168–176.
13.
Brignole, M., Vardas, P., Hoffman, E., Huikuri, H., Moya, A., Ricci, R., & Wieling, W. (2009). Indications for the use of diagnostic implantable and external ECG loop recorders. Europace, 11(5), 671–687.CrossRefPubMed
14.
Henry, S. P., Novotny, W., Leeds, J., Auletta, C., & Kornbrust, D. J. (1997). Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense and Nucleic Acid Drug Development, 7(5), 503–510.CrossRefPubMed
15.
Arya, A., Silberbauer, J., Teichman, S. L., Milner, P., Sulke, N., & Camm, A. J. (2009). A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology. Europace, 11(4), 458–464.CrossRefPubMedCentralPubMed
16.
Noveck, R., Stroes, E. S. G., Flaim, J. D., Baker, B. F., Hughes, S., Graham, M. J., & Ridker, P. M. (2014). Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers. Journal of the American Heart Association, 3(4), e001084–e001084.CrossRefPubMedCentralPubMed
17.
Warren, M., Hughes, S., Flaim, J., Singleton, W., Yamashita, M., & Genovese, M. (2014). Isis-Crp Rx: pharmacokinetics, pharmacodynamics, safety and tolerability of an antisense oligonucleotide specific for inhibition of CRP in inflammation. Annals of the Rheumatic Diseases, 73(Suppl 2), 369–369.CrossRef
18.
Jones, N. R., Pegues, M. A., McCrory, M. A., Singleton, W., Bethune, C., Baker, B. F., & Szalai, A. J. (2012). A selective inhibitor of human C-reactive protein translation is efficacious in vitro and in C-reactive protein transgenic mice and humans. Molecular Therapy—Nucleic Acids, 1(11), e52.CrossRefPubMedCentralPubMed
19.
Visser, M. E., Wagener, G., Baker, B. F., Geary, R. S., Donovan, J. M., Beuers, U. H. W., & Stroes, E. S. G. (2012). Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. European Heart Journal, 33(9), 1142–1149.CrossRefPubMedCentralPubMed
Metadata
Title
The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation assessed using beat-to-beat pacemaker Holter follow-up
Authors
Conn Sugihara
Nick Freemantle
Steven G. Hughes
Steve Furniss
Neil Sulke
Publication date
01-06-2015
Publisher
Springer US
Published in
Journal of Interventional Cardiac Electrophysiology / Issue 1/2015
Print ISSN: 1383-875X
Electronic ISSN: 1572-8595
DOI
https://doi.org/10.1007/s10840-015-9986-3

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