title: TGF-beta1 overexpression: a mechanism of diastolic filling dysfunction in the aged population.
abstract: The prevalence of cardiovascular disease in the United States dramatically increases with age. A hallmark feature of the aged myocardium is increased fibrosis resulting in diastolic dysfunction. Moreover, the survival of patients subsequent to a myocardial infarction is inversely related to age because of a certain extent to maladaptive remodeling mediated by cardiac fibroblasts. Our hypothesis is that cardiac fibroblast (CF) dysfunction results in overexpressed TGF-beta1 leading to increased cardiac collagen content in the aged population. TGF-beta1 stimulates the synthesis of the extracellular matrix proteins, including collagen in the cardiac tissues. The RT-PCR analysis of mRNA expression of TGF-beta1 of the CF was increased by 43% in the aged mice as compared to the younger. The stiffness of the left ventricle is expressed with the slope of the end-diastolic pressure-volume relationship parameter, beta (mmHg/microL). In a mouse model, we demonstrated that beta was 0.30 +/- 0.05 in the young as compared to 0.52 +/- 0.10 in the aged (p < .05). The ventricular stiffness was associated with the myocardial collagen content; namely, young versus the aged was 9.5 +/- 4.0 as compared to 16.4 +/- 2.3% of total protein, respectively (p < .05). In conclusion, the gene structure-function relationships support our hypothesis that cardiac fibroblast disregulation contributes to diastolic filling dysfunction in elderly persons. These data provide a potential contributory mechanism for diastolic dysfunction that may be vital in caring for the aged open-heart surgical patient.
authors.affiliation: Circulatory Science Graduate Perfusion Program, Sarver Heart Center, The University of Arizona College of Medicine, Tucson, Arizona, USA. dflarson@u.arizona.edu
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Larson
authors.forename: Rene
authors.initials: R
authors.lastname: Ingham
authors.forename: Cory M
authors.initials: CM
authors.lastname: Alwardt
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D003971:Diastole / Q000502:physiology*; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000503:physiopathology*; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D003094:Collagen