Amyloid-beta metabolism, cardiac remodeling and myocardial recovery in advanced heart failure

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Abstract Background A subgroup of left ventricular assist device (LVAD) patients may present reverse remodeling and myocardial recovery, but prognostic and therapeutic biomarkers are lacking. Amyloid-beta metabolism and circulating amyloid-β 1-40 (Aβ1-40), a 40 amino-acid long peptide, have been linked to myocardial ageing, cardiac remodeling, increased risk for HF and worse HF outcomes. Purpose To evaluate the associations between circulating and tissue markers of amyloid metabolism and: i) myocardial remodeling and hemodynamic status in advanced HF, ii) post-LVAD myocardial recovery. Methods Plasma Αβ1-40, by ELISA was measured in 98 consecutive patients with advanced HF before LVAD implantation and in 20 of them at 3-12 months after LVAD implantation. Response to LVAD was defined as LVEF >40% and LV end-diastolic diameter≤ 59 mm at 3 to 12 months after. RNA sequencing was performed on myocardial tissue from a separate advanced HF cohort (n=82) pre- and post- LVAD implantation to evaluate changes in key regulators of Aβ1 metabolism. Results Most patients were males (N=85, 85.9%), with a mean age of 57.0 years (SD=16.3), and median HF symptoms duration of 72 months [interquartile range =14-120). After multivariable adjustment for biologically plausible confounders, baseline Aβ1-40 was independently associated with RAP (18.7% increase per 1-SD increase of Αβ1-40), PCWP (12.6% increase per 1-SD increase of Αβ1-40), LVEF (8.5% decrease per 1-SD increase of Αβ1-40) and estimated arterial stiffness as calculated by estimated pulse wave velocity (ePWV, 2.9% increase per 1-SD increase of Αβ1-40) (Figure 1A). Responders significantly decreased circulating levels of Aβ1-40 compared to non-responders (p for interaction=0.013) (Figure 1B). BACE1 and BACE1-AS expression, the main cleavage enzyme promoting synthesis of Aβ1-40 and its regulatory microRNA, was reduced in the myocardium of LVAD responders (p=0.029 and p=0.022, respectively), while there was no significant change in non-responders (p=0.198 and p=0.294, respectively). Conclusions Circulating Αβ1-40 is associated with markers of myocardial remodeling and hemodynamic status in advanced HF as well as with myocardial recovery after LVAD support. The observed changes in BACE1 and BACE1-AS expression provide mechanistic data linking Aβ1-40 metabolism to HF and recovery. Further investigation is warranted to clarify the role of this peptide as a possible biomarker of reverse cardiac remodeling and myocardial recovery.

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