title: Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy.
abstract: Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction. A transgenic (TG) mouse model of FHC with a mutation in tropomyosin at position 180 was employed. Adenoviral-Serca2a (Ad.Ser) was injected into the left ventricle of 1-day-old non-transgenic (NTG) and TG mice. Ad.LacZ was injected as a control. Serca2a protein expression was significantly increased in NTG and TG hearts injected with Ad.Ser for up to 6 weeks. Compared to TG-Ad.LacZ hearts, the TG-Ad.Ser hearts showed improved whole heart morphology. Moreover, there was a significant decline in ANF and β-MHC expression. Developed force in isolated papillary muscle from 2- to 3-week-old TG-Ad.Ser hearts was higher and the response to isoproterenol (ISO) improved compared to TG-Ad.LacZ muscles. In situ hemodynamic measurements showed that by 3 months the TG-Ad.Ser hearts also had a significantly improved response to ISO compared to TG-Ad.LacZ hearts. The present study strongly suggests that Serca2a expression should be considered as a potential target for gene therapy in FHC. Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth.
authors.affiliation: Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Peña
authors.forename: Ariani C
authors.initials: AC
authors.lastname: Szkudlarek
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.forename: Lynley S
authors.initials: LS
authors.lastname: Heinrich
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gaffin
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Paul H
authors.initials: PH
authors.lastname: Goldspink
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000503:physiopathology* / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007267:Injections; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D018995:Myosin Heavy Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D018995:Myosin Heavy Chains; D020033:Protein Isoforms; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban