TGF-β₁ Overexpression: A Mechanism of Diastolic Filling Dysfunction in the Aged Population

Circulatory Science Graduate Perfusion Program, Sarver Heart Center, The University of Arizona College of Medicine, Tucson, Arizona

^* Address correspondence to: Douglas F. Larson, PhD, CCP, Department of Surgery, Room 4402, College of Medicine, 1501 N. Campbell Avenue, Tucson, AZ 85724. E-mail: dflarson@u.arizona.edu

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-β₁ leading to increased cardiac collagen content in the aged population. TGF-β₁ stimulates the synthesis of the extracellular matrix proteins, including collagen in the cardiac tissues. The RT–PCR analysis of mRNA expression of TGF-β₁ 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, (mmHg/L). In a mouse model, we demonstrated that 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.