Existing users Log In New users Sign up


The mechanisms, diagnosis and management of MR in MVP and HCM

DISCOVERIES (ISSN 2359-7232), 2016, April-June issue

CITATION: 

Popa MO, Irimia AM, Papagheorghe MN, Vasile EM, Tircol SA, Negulescu RA et al. The mechanisms, diagnosis and management of mitral regurgitation in mitral valve prolapse and hypertrophic cardiomyopathy. Discoveries 2016, Apr-Jun; 4(2): e61. DOI: 10.15190/d.2016.8

Submitted: June 19, 2016; Revised: June 30, 2016; Accepted: June 30, 2016; Published: June 30, 2016;

 GO BACK to 2016, April-June issue

 GO BACK to DISCOVERIES

The mechanisms, diagnosis and management of mitral regurgitation in mitral valve prolapse and hypertrophic cardiomyopathy

Mihaela Octavia Popa (1,*), Ana Maria Irimia (1), Mihai Nicolae Papagheorghe(1), Elena Miruna Vasile (1), Simona Andreea Tircol (1), Raluca Andreea Negulescu (1), Catalina Toader (1), Robert Adam (1), Lucian Dorobantu (2), Cristina Caldararu (3), Maria Alexandrescu (4), Sebastian Onciul (5)

(1) Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 

(2) Department of Cardiovascular Surgery, Monza Hospital, Bucharest, Romania; 

(3) Department of Cardiology, Monza Hospital, Bucharest, Romania; 

(4) Department of Radiology and Imaging Sciences, Monza Hospital, Bucharest, Romania; 

(5) Department of Cardiology, Floreasca Clinical Emergency Hospital, Bucharest, Romania;

*Correspondence to: Mihaela Octavia Popa, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Phone: +4 0727754559; Email: mihaela.octavia@yahoo.com 

Abstract

     Valvular disease is a frequent cardiac pathology leading to heart failure and, ultimately, death. Mitral regurgitation, defined as the inability of the two mitral leaflets to coapt, is a common valvular disease and a self sustained pathology. A better understanding of the mitral valve histological layers provides a better understanding of the leaflet and chordae changes in mitral valve prolapse. 

Mitral valve prolapse may occur in myxomatous degenerative abnormalities, connective tissue disorders or in sporadic isolated cases. It is the most common mitral abnormality of non-ischemic cause leading to severe surgery-requiring mitral regurgitation. In addition to standard echocardiographic investigations, newly implemented three-dimensional techniques are being used and they permit a better visualisation, from the so-called ‘surgical view’, and an improved evaluation of the mitral valve. 

     Hypertrophic cardiomyopathy is the most frequent inherited myocardial disease caused by mutations in various genes encoding proteins of the cardiac sarcomere, leading to a marked left ventricular hypertrophy unexplained by other comorbidities. The pathological echocardiographic hallmarks of hypertrophic cardiomyopathy are left ventricular hypertrophy, left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. The systolic anterior motion of the mitral valve contributes to the development of mitral regurgitation and further narrows the left ventricular outflow tract, leading to more severe symptomatology. Cardiac magnetic resonance imaging accurately measures the left ventricular mass, the degree of diastolic function and it may also be used to distinguish phenotypic variants. The clinical outcome of patients with these pathologies is mostly determined by the selected option of treatment. 

     The purpose of surgical correction regarding mitral valve involvement is to restore valvular competence. Surgery has proven to be the only useful treatment in preventing heart failure, improving symptomatology and reducing mortality. Our approach wishes to enhance the understanding of the mitral valve’s involvement in hypertrophic cardiomyopathy and mitral valve prolapse from genetic, haemodynamic and clinical perspectives, as well as to present novelties in the grand field of treatment.

Access full text of the manuscript here: 

References

1. Enriquez-Sarano M, Akins C, Vahanian A. Mitral regurgitation. Lancet (London, England). 2009 Apr 10; 373(9672):1382–94. doi: 10.1016/S0140-6736(09)60692-9. 

2. Nkomo V, Gardin J, Skelton T, Gottdiener J, Scott C, Enriquez-Sarano M. Burden of valvular heart diseases: A population-based study. Lancet (London, England). 2006 Sep 19; 368(9540):1005–11. 

3. Iung B, Vahanian A. Epidemiology of acquired valvular heart disease. Can J Cardiol. 2014 Jul 6; 30(9):962–70. doi: 10.1016/j.cjca.2014.03.022. 

4. Zeng Y, Sun R, Li X, Liu M, Chen S, Zhang P. Pathophysiology of valvular heart disease. Exp Ther Med. 2016 Apr;11(4):1184-1188. DOI: 10.3892/etm.2016.3048

5. Levine R, Hagége A, Judge D, Padala M, Dal-Bianco J, Aikawa E, et. al. Mitral valve disease--morphology and mechanisms. Nat Rev Cardiol. 2015 Oct 21; 12(12):689–710.doi:10.1038/nrcardio.2015.161. 

6. Judge DP, Markwald RR, Hagège AA, Levine RA. Translational research on the mitral valve: From developmental mechanisms to new therapies. J. of Cardiovasc. Trans. Res. 2011 Sep 7;4(6):699–701. DOI 10.1007/s12265-011-9320-0.

7. Henein M, Arvidsson S, Pilebro B, Backman C, Mörner S, Lindqvist P. Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy. Int J Cardiol. 2016 Apr 1; 212:47–53. doi: 10.1016/j.ijcard.2016.03.041. 

8. Delling FN, Vasan RS. Epidemiology and Pathophysiology of mitral valve Prolapse. Circulation. 2014; 129(21):2158–70. doi: 10.1161/CIRCULATIONAHA.113.006702.

9. Dorobanţu LF, Iliescu VA. Plastia mitrală în insuficienţa mitrală degenerativă; 2014 Oct 1.

10. Minardi G, Pino P, Manzara C, Pulignano G, Stefanini G, Viceconte G, et al. Preoperative scallop-by-scallop assessment of mitral prolapse using 2D-transthoracic echocardiography. Cardiovasc Ultrasound. 2010 Jan 5; 8. doi: 10.1186/1476-7120-8-1. 

11. Akhter N, Zhao Q, Andrei A, Kane B, McCarthy P, Rigolin V. Identification of prolapsing mitral valve scallops by a three-dimensional multiplanar reconstruction method. Echocardiography (Mount Kisco, N.Y.). 2014 Apr 8; 32(1):106–13. doi: 10.1111/echo.12608. 

12. Nordrum IS, Skallerud B. Smooth muscle in the human mitral valve: Extent and implications for dynamic modelling. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2012 May 16; 120(6):484–94

13. Grande-Allen K, Calabro A, Gupta V, Wight T, Hascall V, Vesely I. Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: Association with regions of tensile and compressive loading. Glycobiology. 2004 Mar 27; 14(7):621–33.

14. Timek TA, Lai DT, Dagum P, Tibayan F, Daughters GT, Liang D et al. Ablation of mitral annular and leaflet muscle: Effects on annular and leaflet dynamics. Am J Physiol Heart Circ Physiol. - Heart Circ Physiol. 2003 Sep 11;285(4):H1668–74.

15. Greenhouse DG, Murphy A, Mignatti P, Zavadil J, Galloway AC, Balsam LB. Mitral valve prolapse is associated with altered extracellular matrix gene expression patterns. Gene. 2016 Apr 12; 586(1):56–61. doi: 10.1016/j.gene.2016.04.004.  

16. Shapero K, Wylie-Sears J, Levine R, Mayer J, Bischoff J. Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. J Mol Cell Cardiol. 2015 Jan 31; 80:175–85. doi: 10.1016/j.yjmcc.2015.01.006.  

17. Pham T, Sun W. Material properties of aged human mitral valve leaflets. J Biomed Mater Res A. Part A. 2013 Sep 17; 102(8):2692–703. doi: 10.1002/jbm.a.34939. 

18. Sell S, Scully RE. Aging changes in the Aortic and mitral valves. Am J Pathol. 1965 Mar 1; 46(3): 345–365. 

19. Barlow JB, Bosman CK. Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome. Am Heart J. 1966 Feb 1; 71(2):166–78. 

20. Nesta F, Leyne M, Yosefy C, Simpson C, Dai D, Marshall J et al. New locus for autosomal dominant mitral valve prolapse on chromosome 13: Clinical insights from genetic studies. Circulation. 2005 Sep 21; 112(13):2022–30. 

21. Disse S, Abergel E, Berrebi A, Houot A, Heuzey L, Diebold B et al. Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2-p12.1. Am J Hum Genet. 1999 Oct 16; 65(5):1242–51. 

22. Freed LA, Acierno JS, Dai D, Leyne M, Marshall JE, Nesta F et al. A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. Am J Hum Genet. 2003 Apr 23; 72(6):1551–9.

23. Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004 Jul 6; 36(8):855–60.

24. Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D et al. TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004 Dec 1; 114(11):1586-1592. 

25. Kyndt F, Schott JJ, Trochu JN, Baranger F, Herbert O, Scott V et al. Mapping of x-linked myxomatous valvular dystrophy to chromosome Xq28. Am  J Hum Genet .1998 Mar 1; 62(3): 627–632. 

26. Durst R, Sauls K, Peal D, de Vlaming A, Toomer K, Leyne M et al. Mutations in DCHS1 cause mitral valve prolapse. Nature. 2015 Aug 11; 525(7567):109–13. 

27. Brenner B, Seebohm B, Tripathi S, Montag J, Kraft T. Familial hypertrophic cardiomyopathy: Functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development. Front Physiol. 2014 Oct 28; 5:392. doi:  10.3389/fphys.2014.00392. 

28. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H et al. Prevalence of idiopathic hypertrophic cardiomyopathy in china: A population-based echocardiographic analysis of 8080 adults Am J Med. 2004 Jan 7; 116(1):14–8. 

29. Maron B, Gardin J, Flack J, Gidding S, Kurosaki T, Bild D. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary artery risk development in (Young) adults. Circulation. 1995 Aug 15; 92(4):785–9. 

30. Xu J, Li Z, Ren X, Dong M, Shi X, Zhang Y et al. Investigation of pathogenic genes in Chinese sporadic Hypertrophic Cardiomyopathy patients by whole Exome Sequencing. Sci Rep. 2015 Nov 18; 5:16609. doi:  10.1038/srep16609. 

31. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk P, Costa D et al. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet. 2010 Jul 14; 53(5):261–7.

32. Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophiccardiomyopathy.  Nat RevCardiol. 2011 Oct 27; 9(2):91-100 doi: 10.1038/nrcardio.2011.159. 

33. Wilder T, Ryba DM, Wieczorek DF, Wolska BM, Solaro RJ. N-acetylcysteinereverses diastolic dysfunctionandhypertrophy in familial hypertrophiccardiomyopathy. Am J Physiol Heart Circ Physiol. 2015 Nov 15;309(10):H1720-30. doi: 10.1152/ajpheart.00339.2015. 

34. Gan X, Rajapurohitam V, Xue J, Huang C, Bairwa S, Tang X et al. Myocardial Hypertrophic remodeling and impaired left ventricular function in mice with a cardiac-specific deletion of Janus Kinase 2. Am J Pathol. 2015 Oct 18; 185(12):3202–10. doi: 10.1016/j.ajpath.2015.08.007. 

35. Foster E. Clinical practice. Mitral regurgitation due to degenerative mitral-valve disease N Engl J Med. 2010 Jul 22; 63(2):156–65. doi: 10.1056/ NEJMcp0906782. 

36. Fornes P, Heudes D, Fuzellier JF, Tixier D, Bruneval P, Carpentier A. Correlation between clinical and histologic patterns of degenerative mitral valve insufficiency: a histomorphometric study of 130 excised segments. Cardiovasc Pathol: Off J Soc Cardiovasc Pathol. 1999;8:81–92.

37. Delling FN, Vasan RS. Epidemiology and pathophysiology of mitral valve prolapse: New insights into disease progression, genetics, and molecular basis. Circulation. 2014 May 29; 129(21):2158–70. doi: 10.1161/CIRCULATIONAHA.113.006702. 

38. Bischoff J,  Aikawa E. Progenitor cells confer plasticity to cardiac valve endothelium. J Cardiovasc Transl Res. 2011;4:710–719

39. Brown CB, Boyer AS,  Runyan RB,  Barnett JV. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science.1999;283:2080–2082.

40. Disatian S, Ehrhart EJ, Zimmerman S, Orton EC. Interstitial cells from dogs with naturally occurring myxomatous mitral valve disease undergo phenotype transformation. J Heart Valve Dis. 2008 Aug 30; 17(4):402–11. 

41. Geirsson A, Singh M, Ali R, Abbas H, Li W, Sanchez JA et al. Modulation of transforming growth factor-beta signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers. Circulation. 2012; 126:S189–S197.

42. Hulin A, Deroanne CF, Lambert CA, Dumont B, Castronovo V, Defraigne JO et al. Metallothionein-dependent up-regulation of TGF-β2 participates in the remodelling of the myxomatous mitral valve. Cardiovasc Res. 2012;93:480–489. doi: 10.1093/cvr/cvr337. 

43. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104:2525–2532.

44. Rabkin-Aikawa E, Farber M, Aikawa M, Schoen F. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J. Heart Valve Dis. 2004 Oct 12; 13(5):841–7. 

45. Salhiyyah K, Yacoub MH, Chester AH. Cellular mechanisms in mitral valve disease. J Cardiovasc Transl Res. 2011; 4:702–9 doi: 10.1007/s12265-011-9318-7.

46. Dainese L, Polvani G, Barili F, Maccari F, Guarino A, Alamanni F et al. Fine characterization of mitral valve glycosaminoglycans and their modification with degenerative disease. Clin Chem Lab Med. 2007; 45(3): 361-366.

47. Gupta V, Barzilla JE, Mendez JS, Stephens EH, Lee EL, Collard CD et al. Abundance and location of proteoglycans and hyaluronan within normal an  myxomatous mitral valves. Cardiovasc Pathol. 2009 Jul-Aug; 18(4):191-7. doi:10.1016/j.carpath.2008.05.001. 

48. Tamura K, Fukuda Y, Ishizaki M, Masuda Y, Yamanaka N, Ferrans VJ.Abnormalities in elastic fibers and other connective-tissue components of floppy mitral valve. Am Heart J. 1995;129:1149–1158.

49. Grande-Allen KJ, Griffin BP, Calabro A, Ratliff NB, Cosgrove DM, Vesely I. Myxomatous mitral valve chordae, II: selective elevation of glycosaminoglycan content. J Heart Valve Dis. 2001;10:325–32. 

50. Barber JE, Ratliff NB, Cosgrove DM, Griffin BP, Vesely I. Myxomatous mitral valve chordae, I: mechanical properties. J Heart Valve Dis. 2001;10:320–324.

51. Ali G, Fusini L, Tamborini G, Muratori M, Gripari P, Mapelli M et al. Detailed Transthoracic and Transesophageal Echocardiographic analysis of mitral leaflets in patients undergoing mitral valve repair. Am J Cardiol. 2016 May 18; 118(1):113–20. doi: 10.1016/j.amjcard.2016.04.020. 

52. Roberts W, Vowels T, Ko J, Hebeler R. Gross and histological features of excised portions of posterior mitral leaflet in patients having operative repair of mitral valve prolapse and comments on the concept of missing (= ruptured) chordae tendineae. J Am Coll Cardiol. 2013 Dec 10; 63(16):1667–74. doi: 10.1016/j.jacc.2013.11.017. 

53. Luckie M, Khattar R. Systolic anterior motion of the mitral valve--beyond hypertrophic cardiomyopathy. Heart (British Cardiac Society). 2008 Oct 22; 94(11):1383–5. doi: 10.1136/hrt.2007.122069. 

54. Patel P, Dhillon A, Popovic ZB, Smedira NG, Rizzo J, Thamilarasan M et al. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients without severe septal hypertrophy: implications of mitral valve and papillary muscle abnormalities assessed using cardiac magnetic resonance and echocardiography. Circ Cardiovasc Imaging 2015 Jul; 8(7):e003132. doi: 10.1161/CIRCIMAGING.115.003132

55. Klues HG, Maron BJ, Dollar AL, Roberts WC.  Diversity of structural mitral valve alterations in hypertrophic cardiomyopathy. Circulation. 1992 May; 85(5):1651-60.

56. He S, Hopmeyer J, Lefebvre XP, Schwammenthal E, Yoganathan AP, Levine RA. Importance of leaflet elongation in causing systolic anterior motion of the mitral valve. J Heart Valve Dis. 1997 Mar; 6(2):149-59.

57. Hagège A, Bruneval P, Levine R, Desnos M, Neamatalla H, Judge D. The mitral valve in hypertrophic cardiomyopathy: Old versus new concepts. J Cardiovasc Transl Res. 2011 Sep 13; 4(6):757–66.  doi: 10.1007/s12265-011-9319-6. 

58. Tarkiainen M, Sipola P, Jalanko M, Heliö T, Laine M, Järvinen V et al. Cardiovascular magnetic resonance of mitral valve length in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2016 Jun 4;18(1):33. doi: 10.1186/s12968-016-0250-5.

59. Schantz D, Benson L, Windram J, Wong D, Dragulescu A, Yoo SJ et al. Abnormal Mitral Valve Dimensions in Pediatric Patients with Hypertrophic Cardiomyopathy. Pediatr Cardiol. 2016 Apr;37(4):784-8. doi: 10.1007/s00246-016-1351-5.

60. Maron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011 Jul 5;124(1):40-7. doi: 10.1161/CIRCULATIONAHA.110.985812. 

61. Hagège AA, Dubourg O, Desnos M, Mirochnik R, Isnard G, Bonne G et al. Familial hypertrophic cardiomyopathy. Cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy. Eur Heart J. 1998 Mar; 19(3):490-499.

62. Judge DP, Neamatalla H, Norris RA, Levine RA, Butcher JT, Vignier N, et al. Targeted Mybpc3 knock-out mice with non-obstructive hypertrophic cardiomyopathy exhibit structural mitral valve abnormalities. J Cardiovasc Dev Dis. 2015;2(2):48-65. 

63. Dal-Bianco J, Aikawa E, Bischoff  J, Guerrero J, Handschumacher M, Sullivan S et al. Active adaptation of the tethered mitral valve: Insights into a compensatory mechanism for functional mitral regurgitation. Circulation. 2009 Jul; 120(4):334–42. doi: 10.1161/CIRCULATIONAHA.108.846782. 

64. Germans T, Wilde AA, Dijkmans PA, Chai W, Kamp O, Pinto YM et al. Structural abnormalities of the inferoseptal left ventricular wall detected by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am Coll Cardiol. 2006, 48: 2518-2523. doi: 10.1016/j.jacc.2006.08.036.

65. Maron BJ, Lindberg J, Lesser JR. Ventricular septal crypt in hypertrophic cardiomyopathy. Eur Heart J. 2010 May 25;31(15):1923.

66. Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K et al. A myocardial lineage derives from Tbx18 epicardial cells. Nature. 2008 Jul 3;454(7200):104-8. doi: 10.1038/nature06969. 

67. Hoersch S, Andrade-Navarro MA. Periostin shows increased evolutionary plasticity in its alternatively spliced region. BMC Evol Biol. 2010;10(1):30. doi: 10.1186/1471-2148-10-30.

68. Rajan S, Pena J, Jegga A, Aronow B, Wolska B, Wieczorek D. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics. 2013 Jun 27; 45(17):764–73. 

69. Niu Z, Iyer D, Conway S, Martin J, Ivey K, Srivastava D et al. Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart. Proc Natl Acad Sci U S A. 2008 Nov 14; 105(46):17824–9. doi: 10.1073/pnas.0805491105.

70. Hakuno D, Kimura N, Yoshioka M, Mukai M, Kimura T, Okada Y et al. Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents. J Clin Invest. 2010 Jul;120(7):2292-306. doi: 10.1172/JCI40973.

71. Norris RA, Moreno-Rodriguez RA, Sugi Y, Hoffman S, Amos J, Hart MM,  et al. Periostin regulates atrioventricular valve maturation. Dev Biol. 2008 Apr 15;316(2):200-13. doi: 10.1016/j.ydbio.2008.01.003. 

72. Nishimura RA, Vahanian A, Eleid MF, Mack MJ. Mitral valve disease--current management and future challenges. Lancet (London, England). 2016 Mar 31; 387(10025):1324–34. doi: 10.1016/S0140-6736(16)00558-4. 

73. Faletra FF, Pedrazzini G, Pasotti E, Pandian NG. Echocardiography in Mitral Valve Disease. Springer Science + Business Media; 2013. Mitral valve Insufficiency; p. 23–47. ISBN: 9788847054349. 

74. Hayek E, Gring C, Griffin B. Mitral valve prolapse. Lancet (London, England). 2005 Feb 12 ; 365(9458):507–18.

75. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Lehman B et al . Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med. 1999;341:1-7.

76. Devereux RB, Kramer-Fox R, Brown WT, Shear MK, Hartman N, Kligfield P et al. Relation between clinical features of the mitral prolapse syndrome and echocardiographically documented mitralvalve prolapse. J Am Coll Cardiol 1986;8:763-72.

77. Delling FN, Rong J, Larson MG, Lehman B, Fuller D, Osypiuk E et al., Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study. Circulation. 2016 Apr 26;133(17):1688-95. doi: 10.1161/CIRCULATIONAHA.115.020621.

78. Savage DD, Devereux RB, Garrison RJ, Castelli W, Anderson S, Levy D et al. Mitral valve prolapse in the general population. 2. Clinical features: The Framingham study. Am Heart J. 1983 Sep 1; 106(3):577–81.

79. Avierinos JF, Gersh BJ, Melton LJ, Bailey KR, Shub C, Nishimura RA et al. Natural history of asymptomatic mitral valve prolapse in the community. Circulation. 2002 Sep 10;106(11):1355-61.

80. Weis AJ, Salcedo EE, Stewart WJ, Lever HM, Klein AL, Thomas JD. Anatomic explanation of mobile systolic clicks: implications for the clinical andechocardiographic diagnosis of mitral valve prolapse. Am Heart J. 1995 Feb;129(2):314-20.

81. Motiwala SR, Delling FN. Assessment of mitral valve disease: a review of imaging modalities. Curr Treat Options Cardiovasc Med. 2015 Jul; 17(7):390. doi: 10.1007/s11936-015-0390-1.

82. ESC, EACTS, Vahanian A, Alfieri O, Andreotti F, Antunes M et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Aug 28; 33(19):2451–96.

83. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(22):e57-e185. doi:10.1016/j.jacc.2014.02.536.

84. Addetia K, Mor-Avi V, Weinert L, Salgo I, Lang R. A new definition for an old entity: Improved definition of mitral valve prolapse using three-dimensional echocardiography and color-coded parametric models. J Am Soc Echocardiogr. 2013 Oct 8; 27(1):8–16. doi: 10.1016/j.echo.2013.08.

85. Levine RA, Stathogiannis E, Newell JB, Harrigan P, Weyman AE. Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol. 1988 May;11(5):1010-9.

86. Enriquez-Sarano M, Tribouilloy C. Quantitation of mitral regurgitation: Rationale, approach, and interpretation in clinical practice. Heart. 2002 Nov 1;88(Supplement 4):1iv–3.

87. Groot-de Laat LE, Ren B, McGhie J, Oei F, Strachinaru M, Kirschbaum S et al. The role of experience in echocardiographic identification of location and extent of mitral valve prolapse with 2D and 3D echocardiography. Int J Cardiovasc Imaging. 2016 May 12. 

88. Freeman W, Schaff H, Khandheria B, Oh J, Orszulak T, Abel M et al. Intraoperative evaluation of mitral valve regurgitation and repair by transesophageal echocardiography: Incidence and significance of systolic anterior motion. J Am Coll Cardiol. 1992 Sep 1; 20(3):599–609.

89. Beraud AS, Schnittger I, Miller DC, Liang DH. Multiplanar reconstruction of three-dimensional transthoracic echocardiography improves the presurgical assessment of mitral prolapse. J Am Soc Echocardiogr. 2009 Aug;22(8):907-13. doi: 10.1016/j.echo.2009.05.007.

90. Hien MD, Großgasteiger M, Weymann A, Rauch H, Rosendal C. Reproducibility in echocardiographic two- and three-dimensional mitral valve assessment Echocardiography. 2014 Mar; 31(3):311-7. doi: 10.1111/echo.12365. 

91. Le Goffic C, Toledano M, Ennezat PV, Binda C, Castel AL, Delelis F. Quantitative Evaluation of Mitral Regurgitation Secondary to Mitral Valve Prolapse by Magnetic Resonance Imaging and Echocardiography. Am J Cardiol. 2015 Nov 1;116(9):1405-10. doi: 10.1016/j.amjcard.2015.07.064. 

92. Gabriel RS, Kerr AJ, Raffel OC, Stewart RA, Cowan BR, Occleshaw CJ. Mapping of mitral regurgitant defects by cardiovascular magnetic resonance in moderate or severe mitral regurgitation secondary to mitral valve prolapse. J Cardiovasc Magn Reson. 2008 Apr 9;10:16. doi: 10.1186/1532-429X-10-16.

93. Stork A, Franzen O, Ruschewski H, Detter C, Müllerleile K, Bansmann PM et al. Assessment of functional anatomy of the mitral valve in patients with mitral regurgitation with cine magnetic resonance imaging: comparison with transoesophageal echocardiography and surgical results.Eur Radiol. 2007 Dec;17(12):3189-98. 

94. Han Y, Peters DC, Salton CJ, Bzymek D, Nezafat R, Goddu B et al.  Cardiovascular magnetic resonance characterization of mitral valve prolapse. JACC Cardiovasc Imaging. 2008 May;1(3):294-303. doi: 10.1016/j.jcmg.2008.01.013.

95. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. The New England journal of medicine. 2011 Apr 29; 364(17):1643–56. 

96. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015 Mar;65(12):1249-54.

97. Maron S. Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation [Internet]. [Place unknown]: 2016 [updated 2016 Mar 1]. 

98. Gilligan DM, Chan WL, Ang EL, Oakley CM. Effects of a meal on hemodynamic function at rest and during exercise in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1991; 18:429–436.

99. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003 Sep 12; 349(11):1064–75.

100. Cirino AL, Ho C. Hypertrophic Cardiomyopathy Overview. [Internet] 2008 Aug 5. Seattle (WA):1993-2016. 

101. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003 Jan 23;348(4):295-303.

102. Sherrid MV, Balaram S, Kim B, Axel L, Swistel DG. The Mitral Valve in Obstructive Hypertrophic Cardiomyopathy: A Test in Context. J Am Coll Cardiol. 2016;67(15):1846-1858. doi:10.1016/j.jacc.2016.01.071.

103. Newman DB, Miranda WR, Geske JB, Nishimura RA. Dynamic auscultation in hypertrophic obstructive cardiomyopathy: What can we learn from a murmur? Eur Heart J. 2015 Mar 22;37(5):498. doi:10.1093/eurheartj/ehv067.

104. McKenna WJ. Types and pathophysiology of obstructive hypertrophic cardiomyopathy. [Internet]. [Place unknown]: 2016 [updated 2012 Mar 1]. 

105. Goldberger AL. Electrocardiographic diagnosis of left ventricular hypertrophy. [Internet]. [Place unknown]: 2016 [updated 2014 Iun 23]. 

106. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761.

107. Teo EP, Teoh JG, Hung J. Mitral valve and papillary muscle abnormalities in hypertrophic obstructive cardiomyopathy. Current Opinion in Cardiology. 2015 Sep;30(5):475–82. doi:10.1097/HCO.0000000000000200.

108. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M et al. The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Jun 16;43(12):2260-4.

109. Elliott P, McKenna W. Hypertrophic cardiomyopathy. Lancet (London, England). 2004 Jun 9; 363(9424):1881–91.

110. Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopathology. 2004 May 14; 44(5):412–27.

111. Walker CM, Reddy GP, Mohammed T-LH, Chung JH. Systolic anterior motion of the mitral valve. J Thorac Imaging. 2012 Jul;27(4):W87. doi: 10.1097/RTI.0b013e31825412dd.

112. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy. Recent observations regarding the specificity of three hallmarks of the disease: asymmetric septal hypertrophy, septal disorganization and systolic anterior motion of the anterior mitral leaflet.Am J Cardiol. 1980 Jan; 45(1):141-54.

113. Maslow AD, Regan MM, Haering JM, Johnson RG, Levine RA. Echocardiographic predictors of left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve after mitral valve reconstruction for myxomatous valve disease. J Am Coll Cardiol. 1999;34:2096–2104.

114. Levine RA, Schwammenthal E, Song JK. Diastolic leading to systolic anterior motion: new technology reveals physiology. J Am Coll Cardiol. 2014;64:1996–1999.

115. Kim DH, Handschumacher MD, Levine RA, Choi YS, Kim YJ, Yun SC, Song JM, Kang DH, Song JK. In vivo measurement of mitral leaflet surface area and subvalvular geometry in patients with asymmetrical septal hypertrophy: insights into the mechanism of outflow tract obstruction. Circulation.2010;1222:1298–1307.

116. Nagueh SF, Bierig SM, Budoff MJ, Desai M,et al. American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with hypertrophic cardiomyopathy. Endorsed by the American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. J Am Soc Echocardiogr. 2011; 24:473–498.

117. Spirito P, Maron B. Patterns of systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy: Assessment by two-dimensional echocardiography.  Am J Cardiol. 1984 Nov 1; 54(8):1039–46.

118. Woo A, Jedrzkiewicz S. The mitral valve in Hypertrophic Cardiomyopathy: It’s a Long Story. Circulation. 2011 Jul 5;124(1):9–12.

119. Maron BJ, Gottdiener JS, Arce J, Rosing DR, Wesley YE, Epstein SE. Dynamic subaortic obstruction in hypertrophic cardiomyopathy: analysis by pulsed Doppler echocardiography. J Am Coll Cardiol. 1985;6(1):1.

120. Schwammenthal E, Nakatani S, He S, Hopmeyer J, Sagie A, Weyman AE et al. Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: mismatch of posterior to anterior leaflet length and mobility. Circulation. 1998;98(9):856.

121. Grigg LE, Wigle E, Williams WG, Daniel LB, Rakowski H. Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: Clarification of pathophysiology and importance in intraoperative decision making. J Am Coll Cardiol. 1992;20(1):42-52. doi:10.1016/0735-1097(92)90135-A.

122. Bottini PB, Carr AA, Prisant LM, Flickinger FW, Allison JD, Gottdiener JS. Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient Am J Hypertens. 1995 Mar; 8(3):221-8.

123. White RD, Obuchowski NA, Gunawardena S, Lipchik EO, Lever HM, Van Dyke CW et al. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: presurgical and postsurgical evaluation by computed tomography magnetic resonance imaging. Am J Card Imaging. 1996 Jan; 10(1):1-13.

124. Hoey ET, Elassaly M, Ganeshan A, Watkin RW, Simpson H. The role of magnetic resonance imaging in hypertrophic cardiomyopathy. Quant Imaging Med Surg. 2014 Oct; 4(5):397-406. doi: 10.3978/j.issn.2223-4292.2014.09.04.

125. Suzuki J, Shimamoto R, Nishikawa J, Yamazaki T, Tsuji T, Nakamura F et al.  Morphological onset and early diagnosis in apical hypertrophic cardiomyopathy: a long term analysis with nuclear magnetic resonance imaging. J Am Coll Cardiol. 1999 Jan;33(1):146-51.

126. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography Heart. 2004 Jun; 90(6):645-9.

127. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ. Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol. 2003 May 7; 41(9):1561-7.

128. Thakkar VB. Mitral valve Prolapse treatment & management: Medical care, surgical care; 2016 Apr 10. 

129. Hanson I. Mitral Regurgitation treatment & management: Medical care, surgical care, consultations. [Internet] 2016 Apr 10. 

130. Verma S, Mesana TG.  Mitral-Valve Repair for Mitral-Valve Prolapse N Engl J Med. 2009 Dec 3;361(23):2261-9. doi: 10.1056/NEJMct0806111.

131. Yun-Dan D, Wen-Jing D, Xi-Jun X. Comparison of outcomes following mitral valve repair versus replacement for chronic Ischemic mitral Regurgitation: A Meta-Analysis. Thorac Cardiovasc Surg. 2016 Apr 9.

132. Gao C, Chitwood WR. Atlas of Robotic Cardiac Surgery. [place unknown]: Springer Science + Business Media; 2014. Robotic mitral valve replacement: Techniques and results; p. 261–4. ISBN: 9781447163312.

133. Dreyfus GD, Bahrami T, Alayle N, Mihealainu S, Dubois C, De Lentdecker P. Papillary muscle repositioning: the gold standard technique to repair anterior mitral leaflet prolapse Ann Thorac Surg. 2001 May;71(5):1464-70

134. Holubec T, Sündermann SH, Jacobs S, Falk V. Chordae replacement versus leaflet resection in minimally invasive mitral valve repair. Ann Cardiothorac Surg. 2013 Nov;2(6):809-13. doi: 10.3978/j.issn.2225-319X.2013.10.08.

135. Seeburger J, Borger MA, Tschernich H, Leontjev S, Holzhey D, Noack T, et al. Transapical Beating Heart Mitral Valve Repair Circ Cardiovasc Interv. 2010 Dec;3(6):611-2. doi: 10.1161/CIRCINTERVENTIONS.110.957944.

136. Elliott P, Anastasakis A, Borger M, Borggrefe M, Cecchi F, Charron P et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: The task force for the diagnosis and management of Hypertrophic Cardiomyopathy of the European society of Cardiology (ESC). European heart journal. 2014 Sep 1; 35(39):2733–79.

137. Ommen S, Maron B, Olivotto I, Maron, Cecchi F, Betocchi S et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005 Aug 2; 46(3):470–6. 

138. Dulguerov F, Marcacci C, Alexandrescu C, Chan K, Dreyfus G. Hypertrophic obstructive cardiomyopathy: The mitral valve could be the key. Eur J Cardiothorac Surg. 2016 Jan 23. 

139. Moss TJ, Zipse MM, Krantz MJ, Sauer WH, Salcedo EE, Schuller JL .Incidence of Atrial Fibrillation following Alcohol Septal Ablation for Hypertrophic Cardiomyopathy. Ann Noninvasive Electrocardiol. 2016 Mar 11. doi: 10.1111/anec.12335. 

140. Heric B, Lytle B, Miller D, Rosenkranz E, Lever H, Cosgrove D. Surgical management of hypertrophic obstructive cardiomyopathy. Early and late results. J Thorac Cardiovasc Surg. 1995 Jul 1; 110(1):195–206.

141. Kato TS, Takayama H, Yoshizawa S, Marboe C, Schulze PC et al. Cardiac transplantation in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2012 Aug 15;110(4):568-74. doi: 10.1016/j.amjcard.2012.04.030. 

142. Yu EH, Omran AS, Wigle ED, Williams WG, Siu SC, Rakowski H. Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstructon and relief with myectomy. J Am Coll Cardiol. 2000 Dec; 36(7):2219-25.

143. Wang S, Cui H, Yu Q, Chen H, Zhu C, Wang J et al. Excision of anomalous muscle bundles as an important addition to extended septalmyectomy for treatment of left ventricular outflow tract obstruction.  J Thorac Cardiovasc Surg. 2016 Feb 17. doi: 10.1016/j.jtcvs.2016.01.051.

144. Pagani F. Surgical septal myectomy: An enduring but evolving treatment for obstructive hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg. 2016 Apr 18. doi: 10.1016/j.jtcvs.2016.03.025. 

145. Maron BJ, Rowin EJ, Casey SA, Maron MS. How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality: Shaped by 50 Years of Clinical Research and Practice. JAMA Cardiol. 2016;1(1):98-105. doi:10.1001/jamacardio.2015.0354.

146. Stassano P, Di Tommaso L, Triggiani D, Contaldo A, Gagliardi C, Spampinato N. Mitral valve replacement and limited myectomy for hypertrophic obstructive cardiomyopathy: a 25-year follow-up. Tex Heart Inst J. 2004;31(2):137-42.

147. Kofflard M, Herwerden van LA, Waldstein D, Ruygrok P, Boersma E, Taams M et al. Initial results of combined anterior mitral leaflet extension and myectomy in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 1996 Jul 1; 28(1):197–202. 

148. Kwon DH, Smedira NG, Thamilarasan M, Lytle BW, Lever H, Desai MY. Characteristics and surgical outcomes of symptomatic patients with hypertrophic cardiomyopathy with abnormal papillary muscle morphology undergoing papillarymuscle reorientation. J Thorac Cardiovasc Surg. 2010 Aug;140(2):317-24. doi: 10.1016/j.jtcvs.2009.10.045.

149. Patel R, Rajamanickam A, Kini A. Practical Manual of Interventional Cardiology. [place unknown]: Springer Science + Business Media; 2014. Alcohol Septal ablation; p. 287–91. ISBN: 9781447165804.

150. Ueda A, Oginosawa Y, Soejima K, Abe H, Kohno R, Ohe H et al. Outcomes of single- or dual-chamber implantable cardioverter defibrillator systems inJapanese patients. J Arrhythm. 2016 Apr;32(2):89-94. doi: 10.1016/j.joa.2015.09.007. Epub 2015 Dec 10.

151. Konstantinio Y, Haim M, Boxer J, Goldenberg I, Feldman A, Michowitz Y et al. Clinical outcomes of single- versus dual-chamber implantable Cardioverter Defibrillators: Lessons from the Israeli ICD registry. J Cardiovasc Electrophysiol. 2016 Mar 18;27(6):718–23.

152. Wilke I, Witzel K, Münch J, Pecha S, Blankenberg S, Reichenspurner H et al. High Incidence of De Novo and Subclinical Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy and Cardiac Rhythm Management Device. J Cardiovasc Electrophysiol. 2016 Apr 6. doi: 10.1111/jce.12982. 

153. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death inpatients with hypertrophic cardiomyopathy. N Engl J Med. 2000 Feb 10;342(6):365-73.

154. Maron MS, Kalsmith BM, Udelson JE, Li W, DeNofrio D. Survival after cardiac transplantation in patients with Hypertrophic Cardiomyopathy. Circulation: Heart Failure. 2010 Aug 24;3(5):574–9.

155. Ribeiro AH, Wender OC, Almeida AS, Soares LE, Picon PD. Comparison of clinical outcomes in patients undergoing mitral valve replacement with mechanical or biological substitutes: a 20 years cohort. BMC Cardiovasc Disord. 2014 Oct 18;14:146. doi: 10.1186/1471-2261-14-146.

156. Shuhaiber J, Anderson R J. Meta-analysis of clinical outcomes following surgical mitral valve repair or replacement. Eur J Cardiothorac Surg. 2007 Feb;31(2):267-75. 

157. Sorajja P, Valeti U, Nishimura RA, Ommen SR, Rihal CS, Gersh BJ et al. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation. 2008 Jul 8;118(2):131-9. doi: 10.1161/ CIRCULATIONAHA.107.738740.

158. McIntosh CL,Maron BJ, Cannon RO, Klues HG. Initial results of combined anterior mitral leaflet plication and ventricular septal myotomy-myectomy for relief of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Circulation. 1992 Nov;86(5 Suppl):II60-7.

159. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet (London, England). 1995 Jul 22; 346(8969):211–4. 

160. Nishimura RA, Ommen SR. Septal reduction therapy for obstructive hypertrophic cardiomyopathy and sudden death: what statistics cannot tell you. Circ Cardiovasc Interv. 2010 Apr;3(2):91-3. doi: 10.1161/CIRCINTERVENTIONS.110.952085.

161. Agarwal S, Tuzcu EM, Desai MY, Smedira N, Lever HM, Lytle BW et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010 Feb 23;55(8):823-34. doi: 10.1016/j.jacc.2009.09.047.

162. Maron BJ, Dearani JA, Ommen SR, Maron MS, Schaff HV, Gersh BJ, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2044-53.

163. Maron BJ, Rastegar H, Udelson JE, Dearani JA, Maron MS. Contemporary surgical management of hypertrophic cardiomyopathy, the need for more myectomy surgeons and disease-specific centers, and the Tufts initiative. Am J Cardiol. 2013 Nov 1;112(9):1512-5. doi: 10.1016/j.amjcard.2013.06.040. 

164. Maron BJ, Nishimura RA. Surgical Septal Myectomy versus alcohol Septal ablation. Circulation. 2014; 130(18):1617–24. doi: 10.1161/CIRCULATIONAHA.114.011580.

165. Khan SS, Trento A, DeRobertis M, Kass RM, Sandhu M, Czer LS et al. Twenty-year comparison of tissue and mechanical valve replacement. J Thorac Cardiovasc Surg. 2001 Aug;122(2):257-69.

166. Umezu K, Saito S, Yamazaki K, Kawai A, Kurosawa H. Cardiac valvular surgery in dialysis patients: comparison of surgical outcome for mechanical versus bioprosthetic valves. Gen Thorac Cardiovasc Surg. 2009 Apr;57(4):197-202. doi: 10.1007/s11748-008-0365-1.

167. Bush B, Nifong LW, Alwair H, Chitwood WR Jr. Robotic mitral valve surgery-current status and future directions. Ann Cardiothorac Surg. 2013 Nov;2(6):814-7. doi: 10.3978/j.issn.2225-319X.2013.10.04

168. Rim Y, Choi A, McPherson DD, Kim H Personalized Computational Modeling of Mitral Valve Prolapse: Virtual Leaflet Resection PLoS One. 2015 Jun 23;10(6):e0130906. doi: 10.1371/journal.pone.0130906. eCollection 2015

169. Namiri M, Ashtiani MK, Mashinchian O, Hasani-Sadrabadi MM, Mahmoudi M, Aghdami N, et al. Engineering natural heart valves: possibilities and challenges. J Tissue Eng Regen Med. 2016 Jan 22. doi: 10.1002/term.2127

170. Suckau L, Fechner H, Chemaly E, Krohn S, Hadri L, Kockskamper J et al. Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation. 2009;119:1241–1252.

171. Ashrafian H, McKenna WJ, Watkins H. Disease pathways and novel therapeutic targets in Hypertrophic Cardiomyopathy. Circulation Research. 2011 Jun 23;109(1):86–96.

172. Werfel S, Jungmann A, Lehmann L, Ksienzyk J, Bekeredjian R, Kaya Z et al. Rapid and highly efficient inducible cardiac gene knockout in adult mice using AAV-mediated expression of Cre recombinase. Cardiovasc Res. 2014;104:15–23.

173. Tardiff JC, Carrier L, Bers DM, Poggesi C, Ferrantini C, Coppini R et al. Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res. 2015;105(4):457-470. doi:10.1093/cvr/cvv023.

174. Wally V, Murauer EM, Bauer JW. Spliceosome-mediated trans-splicing: the therapeutic cut and paste. J Invest Dermatol. 2012;132:1959–1966.

175. Hammond SM, Wood MJ. Genetic therapies for RNA mis-splicing diseases. Trends Genet. 2011; 27: 196–205.

176. Gedicke-Hornung C, Behrens-Gawlik V, Reischmann S, Geertz B, Stimpel D, Weinberger F et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO Mol Med. 2013;5:1128–1145.

177. Mearini G, Stimpel D, Geertz B, Weinberger F, Krämer E, Schlossarek S, et al. Mybpc3 gene therapy for neonatal cardiomyopathy enables longterm disease prevention in mice. Nat Commun. 2014;5:5515.

178. Basille C., Frydman R., El Aly A. Preimplantation genetic diagnosis:state of the art. Eur J Obstet Gynecol Reprod Biol. 2009; 145:9-13.

179. Maron BJ, Maron MS, Semsarian C. Genetics of Hypertrophic Cardiomyopathy After 20 Years: Clinical Perspectives. J Am Coll Cardiol. 2012;60(8):705-715. doi:10.1016/j.jacc.2012.02.068.

News & Events Latest news from Discoveries

  • 2020, April | For Authors!

    WE DO NOT TOLERATE ANY MISCONDUCT! Please be aware that we are testing all received articles with specialized software for PLAGIARISM and WE WILL TAKE MEASURES if your article is already published or in consideration for publication by other journals! This may result in serious professional consequences for the authors. The latest striking case is the following article which is already published and was re-submitted here.  

  • 2020, April | For Authors!

    We are happy to let you know that all articles published in Discoveries are now included in PubMedCentral (PMC). New accepted articles will be included in PMC and PubMed within 1-2 weeks after their publication.

  • 2020, January | For Authors!

    Starting in January 2020, Discoveries will also consider articles submitted by Discoveries' Editorial Board members. However, only a small number of such articles (maximum 4 articles/year) will be considered for publication after the peer-review process, and the authors who are also our editors will be clearly disclosed.  

  • 2019, September | Indexed by PMC

    Discoveries is now indexed by PubMedCentral and Pubmed. The agreement with US National Library of Medicine was signed on September 10, 2019. Our next step is ISI Web of Knowledge indexing. NOTE: previously published articles will be included on PubMed in early 2020.

  • 2019, September | PubMed inclusion!

    We are happy to let you know that Discoveries successfuly passed the last step (Technical Review) required for PubMedCentral and PubMed inclusion!

  • 2019, July | PubMed inclusion News!

    We are happy to receive positive comments from PMC/NLM-NIH regarding Discoveries' last step (Technical Review) required for PubMedCentral and PubMed inclusion. We will let you know once whole indexing process is completed. 

  • 2019| Sharing and Distribution!

    All articles published in Discoveries are Open Access articles distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited and it is not used for commercial purposes.

  • 2018-2019 | For Authors!

    From now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our editors will be immediately rejected until further notice (one accepted article was already rejected). 

  • 2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • 2016, April | Faster Peer-Review

    Starting on April 13th 2016, all articles selected for a peer-review will receive the post peer-review decision within ~10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • 2016, February | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • 2016, January | Main Objective

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles before Discoveries is indexed.

  • 2015, August | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded authors) are now processed for being included.

    Discoveries articles now on PubMed
  • 2015, April | Special Issue

    DISCOVERIES published the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • 2014, September | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • 2014, April | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! First citations to Discoveries articles are included! Search for the article's title (recommended) or the authors:

    Google Scholar Search
  • 2014 | DISCOVERIES

    DOIs (Digital Object Identifiers) are now assigned to all our published manuscripts in Discoveries. DOI uniquely identifies an article and is provided by CrossRef.

    CrossRef
  • 2013, July | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)! There are NO fees for the manuscript submission or publishing of the accepted manuscripts.
    read more

  • 2013, July | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim publishing a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    read more
Member Login
Free Registration Click here to sign up
Copyright © 2013 Applied Systems. All Rights Reserved.