title: Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load.
  
  
  RESULTS
  Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (alphaMHC403/+) produced similarly elevated LV pressures (120+/-30 versus 112+/-14 mm Hg; P=NS). No mice developed heart failure, and mortality (26% alphaMHC403/+, 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv alphaMHC403/+ mice (LV anterior wall [LVAW]=1.28+/-0.11) and 129SvEv wild-type mice (LVAW=1.29+/-0.11 mm; P=NS). Genetically outbred Black Swiss (BS) alphaMHC403/+ mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS alphaMHC403/+ LVAW=1.30+/-0.13 mm; BS wild-type LVAW=1.17+/-0.15 mm; P=0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded alphaMHC403/+ mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy.
  
  
  CONCLUSIONS
  The uniform hypertrophic response to increased ventricular load in wild-type and alphaMHC403/+ mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.
authors.affiliation: Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Mass 02115, USA.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Schmitt
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.forename: Joseph
authors.initials: J
authors.lastname: Gannon
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Catherine
authors.initials: C
authors.lastname: Duffy
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D003250:Constriction; D016572:Cyclosporine / Q000494:pharmacology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging; D008297:Male; D051379:Mice; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D011312:Pressure; D012313:RNA / Q000378:metabolism; D012518:Sarcomeres / Q000737:chemistry; D016019:Survival Analysis; D014463:Ultrasonography
chemical_list: D012313:RNA; D016572:Cyclosporine; D018995:Myosin Heavy Chains