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F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy

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Abstract

Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.

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References

  • Benedetto U, Melina G, di Batolomeo R, Angeloni E, Sansone D, Falaschi G, Capuano F, Comito C, Roscitano A, Sinatra R (2011) N-polyunsaturated fatty acids after coronary artery bypass grafting. Ann Thorac Surg 91:1169–1175

    Article  PubMed  Google Scholar 

  • Billman GE, Nishijima Y, Belevych AE, Terentyev D, Xu Y, Haizlip KM, Monasky MM, Hiranandani N, Harris WS, Gyorke S, Carnes CA, Janssen PML (2010) Effects of dietary omega-3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies. Am J Physiol Heart Circ Physiol 298:H1219–H1228

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boland LM, Drzewiecki MM (2008) Polyunsaturated fatty acid modulation of voltage gated ion channels. Cell Biochem Biophys 52:59–84

    Article  CAS  PubMed  Google Scholar 

  • Brune F, Delhon A, Gardette J, Patoiseau JF, Marty A, Severac E, (2007) (2007/06/22) WO2007147899, DHA esters and use thereof in treatment and prevention of cardiovascular disease.

  • Den Ruijter HM, Berecki G, Verkerk AO, Bakker D, Baartscheer A, Schumacher CA, Belterman CN, De Jonge N, Fiolet JW, Brouwer IA, Coronel R (2008) Acute administration of fish oil inhibits triggered activity in isolated myocytes from rabbits and patients with heart failure. Circulation 117:536–544

    Article  Google Scholar 

  • Duda MK, O’Shea KM, Lei B, Barrows BR, Azimzadeh AM, McElfresh TE, Hoit BD, Kop WJ, Stanley WC (2007) Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res 76:303–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Duda MK, O’Shea KM, Stanley WC (2009a) N-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res 84:33–41

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Duda MK, O'Shea KM, Tintinu A, Xu W, Khairallah RJ, Barrows BR, Chess DJ, Azimzadeh AM, Harris WS, Sharov VG, Sabbah HN, Stanley WC (2009b) Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res 81:319–327

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fareh S, Benardeau A, Nattel S (2001) Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs. Cardiovasc Res 49:762–770

    Article  CAS  PubMed  Google Scholar 

  • Guizy M, David M, Arias C, Zhang L, Cofán M, Ruiz-Gutiérrez V, Ros E, Lillo MP, Martens JR, Valenzuela C (2008) Modulation of the atrial specific Kv1.5 channel by the n-3 polyunsaturated fatty acid, alpha-linolenic acid. J Mol Cell Cardiol 44:323–335

    Article  CAS  PubMed  Google Scholar 

  • Khairallah RJ, O’Shea K, Brown BH, Khanna N, Des Rosiers C, Stanley WC (2010) Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2 + -induced mitochondria permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther 335:155–162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kitamura K, Shibata R, Tsuji Y, Inden Y, Murohara T (2011) Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model. Am J Physiol Heart Circ Physiol 300:H1814–H1821

    Article  CAS  PubMed  Google Scholar 

  • Kourliouros A, Savelieva I, Kiotsekoglou A, Jahangiri M, Camm J (2009) Current concepts in the pathogenesis of atrial fibrillation. Am Heart J 157:243–252

    Article  PubMed  Google Scholar 

  • Kowey PR, Reiffel JA, Ellenbogen KA, Naccarelli GV, Pratt CM (2010) Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA 304:2363–2372

    Article  CAS  PubMed  Google Scholar 

  • Lau DH, Psaltis PJ, Carbone A, Kelly DJ, Mackenzie L, Worthington M, Metcalf RG, Kuklik P, Nelson AJ, Zhang Y, Wong CX, Brooks AG, Saint DA, James MJ, Edwards J, Young GD, Worthley SG, Sanders P (2011) Atrial protective effects of n-3 polyunsaturated fatty acids: a long-term study in ovine chronic heart failure. Heart Rhythm 8:575–582

    Article  PubMed  Google Scholar 

  • Lavie CJ, Milani RV, Mehra MR, Ventura HO (2009) Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol 54:585–594

    Article  CAS  PubMed  Google Scholar 

  • Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95

    Article  CAS  PubMed  Google Scholar 

  • McLennan PL, Abeywardena MY, Dallimore JA, Raederstorff D (2011) Dietary fish oil preserves cardiac function in the hypertrophied rat heart. Br J Nutr 9:1–10

    Google Scholar 

  • Metcalf RG, James MJ, Gibson RA, Edwards JRM, Stubberfield J, Stuklis R, Robert-Thomson K, Young GD, Cleland LG (2007) Effects of fish-oil supplementation on myocardial fatty acids in humans. Am J Clin Nutr 85:1222–1228

    CAS  PubMed  Google Scholar 

  • Milliez P, DeAngelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, Delcayre C, Hatem SN (2005) Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 26:2193–2199

    Article  CAS  PubMed  Google Scholar 

  • Mozaffarian D, Wu JH (2011) Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 58:2047–2067

    Article  CAS  PubMed  Google Scholar 

  • Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226

    Article  CAS  PubMed  Google Scholar 

  • Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, Gheorghiade M, Dei Cas L (2011a) Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. J Am Coll Cardiol 57:870–879

    Article  CAS  PubMed  Google Scholar 

  • Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, Gheorghiade M, Dei Cas L (2011b) N-3 polyunsaturated fatty acids in the prevention of atrial fibrillation recurrences after electrical cardioversion: a prospective, randomized study. Circulation 124:1100–1106

    Article  CAS  PubMed  Google Scholar 

  • Pignier C, Revenaz C, Rauly-Lestienne I, Cussac D, Delhon A, Gardette J, Le Grand B (2007) Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current: a mechanism for ischemia selectivity. Basic Res Cardiol 102:553–564

    Article  CAS  PubMed  Google Scholar 

  • Ramadeen A, Connelly KA, Leong-Poi H, Hu X, Fujii H, Laurent G, Domenichiello AF, Bazinet RP, Dorian P, 2012. Docosahexaenoic acid, but not eicosapentaenoic acid, supplementation reduces vulnerability to atrial fibrillation. Circulation Arrhythm Electrophysiol Aug 24 (Epub ahead of print)

  • Rucker-Martin C, Milliez P, Tan S, Decrouy X, Recouvreur M, Vranckx R, Delcayre C, Renaud JF, Dunia I, Segretain D, Hatem SN (2006) Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts. Cardiovasc Res 72:69–79

    Article  CAS  PubMed  Google Scholar 

  • Sakabe M, Shiroshita-Takeshita A, Maguy A, Dumesnil C, Nigam A, Leung TK, Nattel S (2007) Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling. Circulation 116:2101–2109

    Article  CAS  PubMed  Google Scholar 

  • Sandmann S, Claas R, Cleutjens JP (2001) Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats. J Cardiovasc Pharm 37:64–77

    Article  CAS  Google Scholar 

  • Savelieva I, Kakouros N, Kourliouros A, Camm AJ (2011) Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace 13:308–328

    Article  PubMed  Google Scholar 

  • Segretain D, Falk MM (2004) Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim Biophys Acta 1662:3–21

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN (2008) Systems approach with inflammatory exudates uncovers novel anti-inflammatory and pro-resolving mediators. Prostaglandins Leukot Essent Fatty Acids 79:157–163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tang WH, Samara MA (2011) Polyunsaturated fatty acids in heart failure: Should we give more and give earlier. J Am Coll Cardiol 57:880–883

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G (2008) Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 372:1223–1230

    Article  PubMed  Google Scholar 

  • Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D’agostino RB, Murabito JM, Kannel WB, Benjamin EJ (2003) Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 107:2920–2925

    Article  PubMed  Google Scholar 

  • Wu JH, Lemaitre RN, King IB, Song X, Sacks FM, Rimm EB, Heckbert SR, Siscovick DS, Mozaffarian D (2012) Association of plasma phospholipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. Circulation 125:1084–1093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xiao YF, Sigg DC, Ujhelyi MR, Wilhelm JJ, Richardson ES, Iaizzo PA (2008) Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias. Am J Physiol Heart Circ Physiol 294:H2212–H2218

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are indebted to our colleagues in the Division of Cardiovascular Diseases II and Medicinal Chemistry II for performing the experimentations described in the present manuscript. We thank M. Cabailh for the secretarial assistance.

Conflicts of interest

Bruno Le Grand, Robert Létienne, Elisabeth Dupont-Passelaigue, Frédérique Lantoine-Adam, and Frédéric Longo are employees of Institut de Recherche Pierre Fabre.

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Authors and Affiliations

  1. Institut de Recherche Pierre Fabre, Castres Cedex, France

    Bruno Le Grand, Robert Letienne, Elisabeth Dupont-Passelaigue, Frédérique Lantoine-Adam & Frédéric Longo

  2. INSERM (UMRS 956), Paris Cedex, France

    Monique David-Dufilho & Stéphane Hatem

  3. Institut de Cardiologie and Université de Montréal, Montréal, Canada

    Georghia Michael, Kunihiro Nishida & Stanley Nattel

  4. AGROCAMPUS-OUEST (INRA), Rennes Cedex, France

    Daniel Catheline & Philippe Legrand

  5. Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106, Castres Cedex, France

    Bruno Le Grand

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  1. Bruno Le Grand
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Correspondence to Bruno Le Grand.

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Le Grand, B., Letienne, R., Dupont-Passelaigue, E. et al. F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy. Naunyn-Schmiedeberg's Arch Pharmacol 387, 667–677 (2014). https://doi.org/10.1007/s00210-014-0975-3

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