Application of 4-D ultrasound-derived regional strain and proteomics analysis in Nkx2-5-deficient male mice

The comprehensive characterization of cardiac structure and function is critical to better understanding various murine models of cardiac disease. We demonstrate here a multimodal analysis approach using high-frequency four-dimensional ultrasound (4DUS) imaging and proteomics to explore the relationship between regional function and tissue composition in a murine model of metabolic cardiomyopathy (Nkx2-5(183P/+)). The presented 4DUS analysis outlines a novel approach to mapping both circumferential and longitudinal strain profiles through a standardized framework. We then demonstrate how this approach allows for spatiotemporal comparisons of cardiac function and improved localization of regional left ventricular dysfunction. Guided by observed trends in regional dysfunction, our targeted Ingenuity Pathway Analysis (IPA) results highlight metabolic dysregulation in the Nkx2-5(183P/+) model, including altered mitochondrial function and energy metabolism (i.e., oxidative phosphorylation and fatty acid/lipid handling). Finally, we present a combined 4DUS-proteomics z-score-based analysis that highlights IPA canonical pathways showing strong linear relationships with 4DUS biomarkers of regional cardiac dysfunction. The presented multimodal analysis methods aim to help future studies more comprehensively assess regional structure-function relationships in other preclinical models of cardiomyopathy.

Automated summary

In this study, a multimodal analysis approach combining high-frequency four-dimensional ultrasound (4DUS) imaging and proteomics was used to comprehensively characterize cardiac structure and function in a murine model of metabolic cardiomyopathy. The presented 4DUS analysis provided a novel method for mapping circumferential and longitudinal strain profiles, enabling spatiotemporal comparisons of cardiac function and improved localization of regional dysfunction. The results of targeted Ingenuity Pathway Analysis (IPA) and combined 4DUS-proteomics analysis highlighted metabolic dysregulation and potential pathways associated with regional cardiac dysfunction.