Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts

Circulation Research

Volumn 113, Issue 3, 2013, Pages 313-321

  Parikh, Ashish ^a,b   Patel, Divyang ^b,c   McTiernan, Charles F ^b,c   Xiang, Wenyu ^b,c   Haney, Jamie ^a   Yang, Lei ^d   Lin, Bo ^d   Kaplan, Aaron D ^e   Bett, Glenna C L ^e,f,g   Rasmusson, Randall L ^e,f   Shroff, Sanjeev G ^a   Schwartzman, David ^b,c   Salama, Guy ^a,b,c,h  

^a Departments of Bioengineering   (United States)

^b VANDERBILT UNIVERSITY   (United States)

^c UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^d UNIVERSITY OF PITTSBURGH   (United States)

^e Center for Cellular and Systems Electrophysiology   (United States)

^f Departments of Physiology and Biophysics   (United States)

^g UNIVERSITY AT BUFFALO   (United States)

^h UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Action potential; Atrial fibrillation; Fibrosis; Hypertrophy; INa upregulation; Optical mapping; Relaxin; Spontaneously hypertensive rats

Indexed keywords

CALCIUM ION; COLLAGEN TYPE 1; COLLAGEN TYPE 3; CONNEXIN 43; GELATINASE A; GELATINASE B; RECOMBINANT RELAXIN; TRANSFORMING GROWTH FACTOR BETA;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD PRESSURE; CALCIUM CELL LEVEL; CONTROLLED STUDY; DISEASE PREDISPOSITION; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG EFFICACY; HEART ATRIUM ENLARGEMENT; HEART ATRIUM FIBRILLATION; HEART CONDUCTION; HEART HYPERTROPHY; HEART MUSCLE CELL; HEART MUSCLE FIBROSIS; HEART MUSCLE POTENTIAL; HEART RATE; HEART STIMULATION; HISTOLOGY; HUMAN; HUMAN CELL; MALE; NONHUMAN; OSMOTIC MINIPUMP; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; SODIUM CURRENT; SPONTANEOUSLY HYPERTENSIVE RAT; UPREGULATION; WISTAR KYOTO RAT;

ATRIAL FIBRILLATION; FIBROSIS; HYPERTROPHY; INA UPREGULATION; OPTICAL MAPPING, ACTION POTENTIAL; RELAXIN; SPONTANEOUSLY HYPERTENSIVE RATS;

ANIMALS; ATRIAL FIBRILLATION; CARDIOMYOPATHIES; FIBROSIS; HEART CONDUCTION SYSTEM; HUMANS; HYPERTROPHY; MALE; MYOCYTES, CARDIAC; RATS; RATS, INBRED SHR; RATS, INBRED WKY; RECOMBINANT PROTEINS; RELAXIN;

EID: 84880771641     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.113.301646     Document Type: Article

References (50)

1. Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest. 2012;142:1489-1498.
2. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
3. Lau YF, Yiu KH, Siu CW, Tse HF. Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications. J Hum Hypertens. 2012;26:563-569.
4. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512-525.
5. Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy PM, Nerbonne JM. Atrial L-type Ca2+ currents and human atrial fibrillation. Circ Res. 1999;85:428-436.
6. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802-809.
7. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87:425-456.
8. Anter E, Callans DJ, Wyse DG. Pharmacological and electrical conversion of atrial fibrillation to sinus rhythm is worth the effort. Circulation. 2009;120:1436-1443.
9. Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley SC Jr, Kasi VS, Hoit BD, Keshelava G, Zhao H, Capecchi MR, Bernstein KE. Mice with cardiacrestricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004;165:1019-1032.
10. Anné W, Willems R, Roskams T, Sergeant P, Herijgers P, Holemans P, Ector H, Heidbüchel H. Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation. Cardiovasc Res. 2005;67:655-666.
11. de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol. 2011;57:630-638.
12. Chiu YW, Lo MT, Tsai MR, Chang YC, Hsu RB, Yu HY, Sun CK, Ho YL. Applying harmonic optical microscopy for spatial alignment of atrial collagen fibers. PLoS One. 2010;5:e13917.
13. Aliot E, Ruskin JN. Controversies in ablation of atrial fibrillation. Eur Heart J Suppl. 2008;10:H32-H54
14. Chen SA, Tai CT, Yeh HI, Chen YJ, Lin CI. Controversies in the mechanisms and ablation of pulmonary vein atrial fibrillation. Pacing Clin Electrophysiol. 2003;26:1301-1307.
15. Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963;27:282-293.
16. Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res. 1998;39:89-105.
17. Choisy SC, Arberry LA, Hancox JC, James AF. Increased susceptibility to atrial tachyarrhythmia in spontaneously hypertensive rat hearts. Hypertension. 2007;49:498-505.
18. Bani D, Yue SK, Bigazzi M. Clinical profile of relaxin, a possible new drug for human use. Curr Drug Saf. 2009;4:238-249.
19. Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep. 2011;13:409-420.
20. Teichman SL, Unemori E, Dschietzig T, Conrad K, Voors AA, Teerlink JR, Felker GM, Metra M, Cotter G. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2009;14:321-329.
21. Conrad KP. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol. 2011;31:15-32.
22. Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res. 2003;57:395-404.
23. Lekgabe ED, Kiriazis H, Zhao C, Xu Q, Moore XL, Su Y, Bathgate RA, Du XJ, Samuel CS. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005;46:412-418.
24. Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, Tregear GW, Du XJ. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004;145:4125-4133.
25. Debrah DO, Debrah JE, Haney JL, McGuane JT, Sacks MS, Conrad KP, Shroff SG. Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. J Appl Physiol. 2011;111:260-271.
26. Debrah DO, Conrad KP, Danielson LA, Shroff SG. Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol. 2005;98:1013-1020.
27. Choi BR, Nho W, Liu T, Salama G. Life span of ventricular fibrillation frequencies. Circ Res. 2002;91:339-345.
28. Shorofsky SR, Aggarwal R, Corretti M, Baffa JM, Strum JM, Al-Seikhan BA, Kobayashi YM, Jones LR, Wier WG, Balke CW. Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks. Circ Res. 1999;84:424-434.
29. Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, Huser T, Keller G, Kong CW, Li RA. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol. 2013;6:191-201.
30. Lin B, Kim J, Li Y, Pan H, Carvajal-Vergara X, Salama G, Cheng T, Li Y, Lo CW, Yang L. High-purity enrichment of functional cardiovascular cells from human iPS cells. Cardiovasc Res. 2012;95:327-335.
31. Frustaci A, Caldarulo M, Buffon A, Bellocci F, Fenici R, Melina D. Cardiac biopsy in patients with "primary" atrial fibrillation. Histologic evidence of occult myocardial diseases. Chest. 1991;100:303-306.
32. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther. 1962;140:183-188.
33. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666.
34. Moe GK. Evidence for reentry as a mechanism of cardiac-arrhythmias. Rev Physiol Bioch P. 1975;72:55-81
35. Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ. Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol. 2010;7:48-58.
36. Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, Tregear GW, Du XJ. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004;145:4125-4133.
37. Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OH. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation. 1995;91:161-170.
38. Garber SL, Mirochnik Y, Brecklin CS, Unemori EN, Singh AK, Slobodskoy L, Grove BH, Arruda JA, Dunea G. Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int. 2001;59:876-882.
39. Heeg MH, Koziolek MJ, Vasko R, Schaefer L, Sharma K, Müller GA, Strutz F. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int. 2005;68:96-109.
40. Boixel C, Fontaine V, Rücker-Martin C, Milliez P, Louedec L, Michel JB, Jacob MP, Hatem SN. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol. 2003;42:336-344.
41. Moe GW, Laurent G, Doumanovskaia L, Konig A, Hu X, Dorian P. Matrix metalloproteinase inhibition attenuates atrial remodeling and vulnerability to atrial fibrillation in a canine model of heart failure. J Card Fail. 2008;14:768-776.
42. Lee KW, Everett TH 4th, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. 2006;114:1703-1712.
43. Weber KT, Sun Y, Katwa LC, Cleutjens JP, Zhou G. Connective tissue and repair in the heart. Potential regulatory mechanisms. Ann N Y Acad Sci. 1995;752:286-299.
44. Osheroff PL, Cronin MJ, Lofgren JA. Relaxin binding in the rat heart atrium. Proc Natl Acad Sci U S A. 1992;89:2384-2388.
45. Ward DG, Thomas GR, Cronin MJ. Relaxin increases rat heart rate by a direct action on the cardiac atrium. Biochem Biophys Res Commun. 1992;186:999-1005.
46. Piedras-Rentería ES, Sherwood OD, Best PM. Effects of relaxin on rat atrial myocytes. I. Inhibition of I(to) via PKA-dependent phosphorylation. Am J Physiol. 1997;272:H1791-H1797.
47. Piedras-Rentería ES, Sherwood OD, Best PM. Effects of relaxin on rat atrial myocytes. II. Increased calcium influx derived from action potential prolongation. Am J Physiol. 1997;272:H1798-H1803.
48. Ponikowski P, Metra M, Teerlink JR, Unemori E, Felker GM, Voors AA, Filippatos G, Greenberg B, Teichman SL, Severin T, Mueller-Velten G, Cotter G, Davison BA. Design of the RELAXin in acute heart failure study. Am Heart J. 2012;163:149-55.e1.
49. Voors AA, Davison BA, Felker GM, Ponikowski P, Unemori E, Cotter G, Teerlink JR, Greenberg BH, Filippatos G, Teichman SL, Metra M; Pre-RELAX-AHF Study Group. Early drop in systolic blood pressure and worsening renal function in acute heart failure: renal results of Pre-RELAX-AHF. Eur J Heart Fail. 2011;13:961-967.
50. Dickhout JG, Lee RM. Blood pressure and heart rate development in young spontaneously hypertensive rats. Am J Physiol. 1998;274:H794-H800.