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Abstract: PO1838

Phenotyping CKD-Associated Cardiac Fibrosis

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Narayanan, Gayatri, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Halim, Arvin, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Lu, Tzongshi, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Lim, Kenneth, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Myocardial fibrosis is a pervasive and progressive complication in CKD patients. Mechanistically, increased collagen cross-linking has been shown to be a critical determinant of tensile strength, stiffness of collagen fibers, and resistance to degradation in ischemic cardiomyopathy, as opposed to increased collagen deposition alone. Whether similar metabolic processes and physiochemical alterations occur in CKD is largely unknown. Herein, we investigated the fibrotic phenotype in CKD-associated cardiomyopathy and the role of disordered mineral stressors.

Methods

Human left ventricular (LV) tissues were collected from hemodialysis (HD; n=13), hypertensive (HTN; n=8), and healthy control (n=12) donors to compare matrix proteins. Mechanistic in vitro studies involving treatment of human ventricular cardiac fibroblasts (HCFs) with either 1.8-3.8mM β-glycerophosphate (BGP) or 2.4-5.0mM CaCl2 in media were conducted. Protein expression was assessed by immunoblotting.

Results

We report increased trimeric (400 kDa) collagen I (COL1) in LV tissues from HD and HTN (p<0.05) compared to healthy control. Uniquely, monomeric (150 kDa) COL3 was decreased in HD hearts (p<0.05) compared to HTN and healthy control. Dimeric (250 kDa) or monomeric COL1 (139 kDa) and other COL3 multimers were not found in any groups. HD and HTN hearts exhibited increased periostin (p<0.05) compared to healthy control. There was no significant difference in fibronectin or α-smooth muscle actin (α-SMA) between groups. We next performed dose-dependent studies in HCFs treated with either BGP or CaCl2. 3.8 mM BGP stimulated increased trimeric but not dimeric COL1 (p<0.05), and reduced monomeric COL3 (p<0.01) synthesis leading to increased total COL1:3 ratio (p<0.05), in vitro. No other forms of COL1 or COL3 were observed. Additionally, 3.8mM BGP decreased fibronectin expression (p<0.01), but did not significantly change periostin or α-SMA expression. At 5 mM CaCl2 treatment, this decreased COL3 (p<0.01), fibronectin (p<0.05), and periostin (p<0.05) expression.

Conclusion

Cardiac fibrosis in hearts from HD patients is characterized by increased trimeric COL1 expression and increased COL1:3 ratio that can be driven by disordered mineral stressors. These changes suggest pathologic cross-linking that can lead to altered mechanical properties and further studies are warranted.

Funding

  • Other NIH Support