Metrics of Left Ventricular Active Relaxation Reflect Proteomic Myocardial Remodelling and Reverse Remodelling

AIMS: Pressure overload (PO) induces adverse myocardial remodelling, whereas efficient pressure unloading interventions can promote reverse remodelling at structural and molecular levels. This study seeks to identify a metric of left ventricular (LV) performance that reflects the degree of myocardial remodelling and reverse remodelling. METHODS: Male and female rats underwent surgical aortic constriction/banding (AB) to generate pressure overload (PO) and subsequent debanding (DB) to induce pressure unloading. The architecture and function of the left ventricle were evaluated using echocardiography and pressure-volume analysis. Exploratory proteome profiling via LC-MS/MS on left ventricular samples was followed by LASSO-based feature selection on existing data to determine LV parameters linked to myocardial proteomic changes. RESULTS: Tau (τ), the time constant of LV isovolumic pressure decay and an index of active relaxation, and LV mass showed the strongest associations with proteome-wide abundance changes. With 842 associated proteins and 154 overrepresented gene ontology terms, Tau demonstrated a strong correlation with LV proteomic changes during myocardial remodelling, and reverse remodelling. 19 Tau-associated proteins had an AUC > 0.85 when discriminating remodelled proteomes of AB rats from non-banded counterparts. Network analysis reveals varied protein-protein correlations across circumstances and indicates transcription factors regulating Tau-associated proteome changes. Across sham (Co), 6- and 12-week banding (AB6/AB12), and debanding after 6 weeks followed by 6 weeks unloading (DB), τ showed the largest set of associated proteins (n=842) and enriched processes. CONCLUSIONS: LV active relaxation, quantified by Tau, most comprehensively reflects myocardial proteomic remodelling during pressure overload and unloading. Indices of diastolic relaxation may therefore represent integrative functional readouts of molecular remodelling and potential translational markers of reverse remodelling.