Diastolic dysfunction inhibits mechanical dyssynchrony in cardiac resynchronization therapy patients: a combined clinical-computational study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie grant agreement No. 860745. Background In heart failure patients treated with cardiac resynchronization therapy (CRT), both the presence of typical left bundle branch block (LBBB) mechanics and a relatively preserved diastolic function are associated with better clinical outcomes. However, the mechanistic interaction between both phenomena has never been investigated. Aim In this combined clinical-computational study, we explored the potential interaction between LBBB mechanics and the severity of diastolic dysfunction. Methods In 219 CRT candidates, left atrial pressure (LAP) was retrospectively estimated using the multiparametric guideline approach, where patients were classified into elevated (eLAP, 49%), normal (nLAP, 40%) and undetermined (uLAP, 11%) LAP. nLAP and uLAP were together referred to as non-elevated LAP (non-eLAP, 51%). Typical LBBB mechanical behavior was quantified using two speckle-tracking echocardiography-based indices, being systolic stretch index (SSI) and global myocardial wasted work (GWW). Both indices positively correlate with the mechanical interaction between septal and lateral walls in typical LBBB as previously shown. CRT response was quantified as change of LV end-systolic volume (LVESV) at follow-up (12±6 months) relative to baseline. We used the CircAdapt computer model of the human heart and circulation to investigate the effects of eccentric remodeling and diastolic dysfunction (i.e. myocardial stiffening) on SSI and GWW in virtual hearts with a constant LBBB-like septal-to-lateral conduction delay, i.e. a 25-ms and 75-ms mechanical activation delay of the septum and LV free wall with respect to the right ventricular free wall. Results Before CRT, patients with non-eLAP showed more typical LBBB mechanical behavior (Fig. 1), as suggested by higher SSI and higher GWW compared to patients with non-eLAP (SSI: 4.6±3.2 vs 3.4±3.5 %, P=0.02, GWW: 368±131 vs 309±127 mmHg*%, P=0.03). At follow-up, patients with eLAP showed significantly less LV reverse remodeling compared to patients with non-eLAP (relative decrease of LVESV: 30±26% vs 46±34 P=0.001). Our simulations (Fig. 2) revealed that eccentric remodeling amplifies mechanical dyssynchrony, characterized by increased septal rebound stretch (second row) and increased wasted work (third and bottom rows), while LAP remained normal (top row). In contrast, increasing myocardial stiffness led to elevated LAP (top row), but a pronounced reduction of mechanical dyssynchrony (second, third and bottom rows). Conclusion The presented combination of clinical data and virtual patient simulations revealed that diastolic dysfunction, in particular myocardial stiffening, inhibits mechanical dyssynchrony induced by LBBB. In contrast, eccentric remodeling amplifies the LBBB mechanical substrate. These data further explain why baseline dyssynchrony measures like septal rebound stretch and wasted work are well associated with reverse remodeling and clinical outcome after CRT.