Stress–strain phenotyping, reverse remodelling and therapeutic responsiveness in HFrEF: Predictive value of end-systolic wall stress and global longitudinal strain

Background: Left ventricular (LV) reverse remodelling (LVRR) is a key therapeutic objective in heart failure (HF) with reduced ejection fraction (HFrEF), yet only a subset of patients exhibit meaningful recovery despite guideline-directed medical therapy (GDMT). End-systolic wall stress (ESWS) and global longitudinal strain (GLS) reflect complementary aspects of myocardial mechanics. This study evaluated whether their integrated assessment predicts LVRR and clinical outcomes. Methods: A total of 196 consecutive HFrEF patients (LV ejection fraction <40%) were prospectively enrolled and underwent clinical and echocardiographic evaluation at baseline and after 6.5 ± 2.0 months. LVRR was defined as an absolute increase in LV ejection fraction >10% to ≥35% plus a ≥ 15% reduction in end-systolic volume. ESWS was calculated using a validated meridional formula integrating brachial systolic pressure, end-systolic internal diameter, and posterior wall thickness, and GLS was derived by speckle-tracking echocardiography. Predictors of LVRR were assessed using multivariable logistic regression and receiver-operating characteristic analysis. Patients were stratified into four mechanical phenotypes based on optimal ESWS and GLS thresholds. Results: LVRR occurred in 38% of patients. GLS and ESWS were independent predictors of LVRR (area under the curve 0.82 and 0.78, respectively), with optimal cut-offs of -12.1% and 160 kdyne/cm2. Patients with preserved GLS and low ESWS showed the highest probability of LVRR, the greatest improvement in haemodynamic profile, and the lowest incidence of appropriate implantable cardioverter-defibrillator shocks. Conversely, high ESWS combined with impaired GLS identified patients with a low occurrence of LVRR, persistently elevated filling pressures, reduced ventricular efficiency, and the poorest survival. Conclusions: Integrated stress-strain phenotyping using ESWS and GLS identifies distinct stress-strain phenotypes associated with high or low myocardial recovery potential in HFrEF. This approach improves the prediction of LVRR, therapeutic responsiveness, and prognosis, and may support earlier selection of candidates for advanced HF therapies.