Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Aims Hypertrophic Cardiomyopathies (HCM) are caused in 30-60% by mutations in cardiac sarcomere genes, but can also be an expression of cardiac involvement in multisystemic metabolic diseases, such as Anderson-Fabry disease (AFD). HCM entails a risk of sudden cardiac death (SCD) of 0.9%/year and is the most common cause of SCD in young adults. Recent studies suggested Mechanical Dispersion (MD) by Speckle-Tracking Echocardiography (STE) as an additional arrhythmic risk marker. Aim of the study was to evaluate left ventricle global longitudinal strain (LV-GLS) and MD, in patients with HCM or AFD-Cardiomyopathy and the association with ventricular arrhythmias. Methods and results We evaluated 40 patients with HCM, 57 with AFD (12 with LV-hypertrophy and 45 without) and 40 healthy subjects, between January 2014 and June 2022. We performed a comprehensive echocardiographic study, analyzed systolic and diastolic function, LV-GLS and MD. We also analyzed ventricular arrhythmias (V-AR), including ventricular fibrillation and sustained/non-sustained ventricular tachycardia, by Holter-EKG, in a subset of hypertrophic patients. Data were analyzed by unpaired Student t-test or chi-square/Fisher’s exact test as appropriate, and binary logistic regression (SPSS Statistics ver.26). LV-GLS was significantly lower in the V-AR group compared to patients without V-AR (median - 10.2% versus -14%, P = 0.038), MD was significantly higher in the V-AR group (85.5 ms versus 61.1 ms, P = 0.004). V-AR were found significantly associated with MD (OR, 1.030, 95% CI, 1.003-1.058, P = 0.03) Conclusions MD is a useful additional index in the evaluation of patients with Hypertrophic Cardiomyopathies, and may be a promising prognostic predictor of increased arrhythmic risk.

Background: Left atrial (LA) function is crucial for assessing left ventricular filling in various cardiovascular conditions. Cardiac Amyloidosis (CA) is characterized by atrial myopathy and LA function impairment, with diastolic dysfunction up to restrictive filling pattern, leading to progressive heart failure and arrhythmias. This study evaluates LA function and deformation using speckle tracking echocardiography (STE) in patients with CA compared to a cohort of patients with sarcomeric Hypertrophic Cardiomyopathy (HCM) and a control group. Methods: We conducted a retrospective, observational study (from January 2019 to December 2022) including a total of 100 patients: 33 with ATTR-CA, 34 with HCMs, and 33 controls. Clinical evaluation, electrocardiograms, and transthoracic echocardiography were performed. Echocardiogram images were analyzed in post-processing using EchoPac software for LA strain quantification, including LA-reservoir, LA-conduit, and LA-contraction strain. Results: The CA group exhibited significantly impaired LA function compared to HCMs and control groups, with LA-reservoir median values of −9%, LA-conduit −6.7%, and LA-contraction −3%; this impairment was consistent even in the CA subgroup with preserved ejection fraction. LA strain parameters correlated with LV mass index, LA volume index, E/e’, and LV-global longitudinal strain and were found to be associated with atrial fibrillation and exertional dyspnea. Conclusions: LA function assessed by STE is significantly impaired in CA patients compared to HCMs patients and healthy controls. These findings highlight the potential supportive role of STE in the early detection and management of the disease.

Anderson-Fabry disease (AFD) is a rare X-linked metabolic disorder due to deficiency in lysosomal enzyme activity of a-galactosidase A, resulting in pathological accumulation of glycosphingolipids in several tissues and a progressive multi-organ dysfunction. The Global Longitudinal Strain (GLS) of the left ventricle (LV) by Speckle-tracking echocardiography (STE) has been show to detect subclinical cardiac involvement in many cardiomyopathies. The Mechanical Dispersion (MD), derived from STE is considered able to reflect a heterogeneous myocardial contraction, evaluated in many cardiopathies. A reduction in GLS was associated with myocardial fibrosis in the subclinical stages of AFD cardiomyopathy, but there is no MD data in AFD. The aim of the study was to evaluate the distribution of GLS and MD of LV in patients with AFD. 47 consecutive AFD adult patients treated (37F, 12 M, age 45 + 17 years) were examined by a complete echocardiographic examination from a Vivid E95 ultrasound scanner (Horten, Norway). The STE post-processing was performed by Echopac 2.02, in apical long-axis, 4-chambers, and 2-chambers views to determine GLS and MD. Data were expressed as mean± standard deviation. The comparison between the AFD group and 20 normal subjects (N) was performed with unpaired T-test. Compared to N, the AFD group showed higher values of LVMi, LAVi, E/E’, and MD, but a lower value of GLS (Table). GLS was significantly lower in the basal (sept p<.002; post p<.0001) and mid segments (ant-sept p<.008; post p<.0001; ant p<.001). MD was significantly higher in the inferior (basal p<.003; mid p<.01; apical p<.005) and lateral segments (mid p<.004; apical p<.001). In patients with AFD, MD added to GLS seems to be a promising tool for the early diagnosis of segmental dysfunction . Table1: Results AFD N p< m SD m SD LVMi g/sqm 77.1 29.8 62.3 14.1 0.008 LVEF % 65.7 5 63.6 3.5 0.04 LAVi ml/sqm 25.5 11 18.2 4.5 0.000 E/E" 8.3 3 5.4 1.1 0.000 TV vmax m/s 2.2 0.4 2.1 0.3 - LV GLS % -17 4 -20 2 0.003 LV MD ms 52 38 29 8 0.000

Background Hypertrophic Cardiomyopathy (HCM) is burdened by sudden cardiac death (SCD) risk of 0.9%/year, and is the most common cause of SCD in young adults. It is an autosomal dominant inherited disease caused by mutations in cardiac sarcomere genes, but the hypertrophic phenotype can also be an expression of cardiac involvement in multiorgan metabolic storage diseases, such as Anderson-Fabry disease (AFD). Mechanical Dispersion (MD) by Speckle-Tracking Echocardiography (STE) has recently emerged as an additional arrhythmic risk marker. Purpose Aim of the study was to evaluate LV systolic and diastolic function, global longitudinal strain (GLS) and MD by STE and analyze their association with ventricular arrhythmias in patients with HCM and AFD. Methods We included in our analysis 36 patients with HCM, 54 with AFD, of which 10 with left ventricular hypertrophy (AFD-LVH) and 44 without (AFD-N), and 27 healthy subjects. We performed a comprehensive basic echocardiographic study and analyzed GLS and MD (post-processing through EchoPAC 2.02). We also evaluated ventricular arrhythmias (V-AR), including ventricular fibrillation and sustained and non-sustained ventricular tachycardia, by Holter ECG, and the data obtained by cardiac magnetic resonance (CMR) in hypertrophic patients. Data were analyzed by unpaired Student t-test or chi-square/Fisher's exact test as appropriate, and binary logistic regression (SPSS Statistics ver.26). Results Diastolic function was impaired in HCM and AFD-LVH patients compared to control and AFD without LVH. GLS was significantly lower in the V-AR group compared to patients without V-AR (9.7±2.9 vs 14.1±4, P=0.007), MD was significantly higher in the V-AR group (111±47 vs 68.1±16, P=0.03). We found a significant association between ventricular arrhythmias and GLS (P=0.005) and between ventricular arrhythmias and MD (P<0.001). We found also a significant association of late gadolinium enhancement at CMR with GLS (P=0.005) and MD (P=0.03). Conclusions GLS and MD are useful additional indices in the evaluation of patients with HCM or AFD, also in presence of preserved LV ejection fraction, and promising prognostic predictors to identify patients at high risk for ventricular arrhythmias Figures: MD in an HCM patient (on the left) and in an AFD-LVH patient (on the right).