Abstract 20722: The Insulin-Like Growth Factor Binding Protein 5 (IGFBP5) - A Potential Biomarker for Heart Failure Transition

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Introduction: Available pharmacological treatments for cardiovascular diseases (CVD) delay, but do not prevent the onset of heart failure (HF). To succeed with novel interventions preventing HF, it is essential to identify stage-specific mechanisms involved in the transition to maladaptive heart remodeling. Insulin-like growth factor binding proteins (IGFBPs) are increasingly recognized factors in understanding the pathogenesis and severity of CVD.

Hypothesis: IGFBP5 is a novel cardiac- and disease stage-specific biomarker reporting heart failure progression.

Results:Igfbp5 mRNA expression is high in early cardiac mesoderm (stage E9.5); becoming markedly decreased in the adult heart (E9.5 / adult; 0.82 ± 0.015, n=3 / 0.05 ± 0.003, n=3) and is significantly elevated in the adult heart upon transvers aortic constriction (TAC) during the transition to HF (TAC / Sham; 2.18 ± 0.23, n=8 / 1.4 ± 0.15, n=6). This upregulation was prevented in a mouse model with cardiomyocyte specific β-catenin loss of function, which showed preserved cardiac function post-TAC, indicating a high correlation of Igfbp5 expression with disease progression (TAC / Sham; 15.43 ± 4.88, n=9 / 9.49 ± 2.09, n=13). A significant upregulation of IGFBP5 was also observed in human aortic stenosis patients in comparison to healthy controls (CT); increasing from compensated hypertrophy (CH) to HF (CT / CH / HF; 8389 ± 555.5, n=4 / 13984 ± 1248, n=5 / 21936 ± 1115, n=5). Antagonistic to mRNA expression, IGFBP5 targeting microRNAs were found downregulated in patients with aortic stenosis Intracellular IGFBP5 protein levels were unchanged, whereas serum levels in mice with HF were found significantly increased (TAC / Sham; 11.45 ± 0.36, n=9 / 10.21 ± 0.27, n=11).

Conclusions:Igfbp5 is highly expressed in early cardiogenesis and is upregulated upon HF in mouse and human, but not elevated under preserved cardiac function post-TAC. We conclude that IGFBP5 participates in a conserved developmental gene program becoming reactivated in the diseased adult heart. Its secretion qualifies it as a possible biomarker indicating the transition to heart failure, predicting the functional outcome of CVD.

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