Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. All these factors contribute to direct damage at the myocardial, vascular and renal level. Vericiguat restores the deficiency in this signaling pathway, through stimulation and activation of sGC, aiming to increase cGMP levels, with a reduction in HF-related oxidative stress and endothelial dysfunction. Two main clinical trials were developed in this setting: the SOCRATES-REDUCED phase II study and the VICTORIA phase III study. They found that vericiguat is safe, well tolerated and effective with an absolute event-rate reduction in patients affected by HF with reduced ejection fraction (HFrEF) and recent cardiac decompensation. In patients with HF with preserved ejection fraction (HfpEF), the SOCRATES-PRESERVED trial demonstrated an improvement in quality of life and health status, but the proven beneficial effects with vericiguat are still limited. Further studies are needed to correctly define the role of this drug in heart failure syndromes. Our paper reviews the potential applications and pharmacological characteristics of vericiguat in HFrEF and HFpEF.

Funding Acknowledgements Type of funding sources: None. Background Myocardial work (MW) estimation by pressure-strain loops using an implemented speckle tracking software has showed to estimate LV contractile properties overcoming the load-dependency limit of left ventricular (LV) global longitudinal strain (GLS). This has proved useful particularly in clinical setting characterized by frequent hemodynamic variations, such as heart failure and valvular heart disease. However, the variation of MW parameters across different stages of mitral regurgitation (MR) and its impact on symptoms has never been investigated. Objective The aim of this observational study was to assess the variations of MW and deformation parameters of left heart chambers in mild, moderate and severe MR. Methods Consecutive patients with mild, moderate and severe MR were prospectively enrolled. Exclusion criteria were: chronic atrial fibrillation, valvular heart prosthesis, previous cardiac surgery. Clinical evaluation, blood sample tests, ECG and echocardiography were performed. Speckle tracking analysis completed by myocardial work were performed offline. Patients were then divided into groups first according to MR severity. Differences among the groups were analyzed by student T test (or non-parametric tests for non-normally distributed variables) and predictors of symptoms (as NYHA class ≥ 2) were explored by logistic regression analysis. Results Overall, 120 patients were enrolled (40 mild, 40 moderate, 40 severe MR). LV GLS improved according to severity, while Global PALS reduced according to MR severity. Global constructive work (GCW) and global wasted work (GWW) significantly improved in patients with moderate and severe MR, while global work efficiency (GWE) showed a trend towards reduction in patients with higher grades of MR. Global work index did not change significantly in the three groups (Fig.1). Among strain parameters, global PALS emerged as a predictor of NYHA class (R2=0.2, p<0.001) These results are explained by the pathophysiology of MR, characterized by a mechanism of attempted LV compensation to volume overload with increased contractility parallel to the disease progress, although with low efficacy on increasing LV stroke volume and increased wasted work; while LA and diastolic function have an early reduction which is associated with the occurrence of symptoms. Conclusions Myocardial deformation parameters of the left heart chambers accurately reflect the pathophysiologic mechanisms of MR stages and are associate with the burden of symptoms.