A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

Increased Levels of Platelets and Endothelial-Derived Microparticles in Patients With Non-Valvular Atrial Fibrillation During Rivaroxaban Therapy.

It is known that atrial fibrillation (AF) is associated with the procoagulant state. Several studies have reported an increase of circulating microparticles in AF, which may be linked to a hypercoagulable state, atrial thrombosis and thromboembolism. We evaluated in our study alterations in both platelet (PMP, CD42b) and endothelial-derived (EMP, CD144) microparticle levels on anticoagulant therapy with rivaroxaban in nonvalvular AF. After administration of rivaroxaban, PMP levels were increased (median, [IQR] 35.7 [28.8-47.3] vs. 48.4 [30.9-82.8] cells/µL; P = 0.012), along with an increase in EMP levels (14.6 [10.0-18.6] vs. 18.3 [12.9-37.1] cells/µL, P < 0.001). In the multivariable regression analysis, the independent predictor of post-dose change in PMPs was statin therapy (HR -0.43; 95% CI -0.75,-0.10, P = 0.011). The post-dose change in EMPs was also predicted by statin therapy (HR -0.34; 95% CI -0.69, -0.01, P = 0.046). This study showed an increase in both EMPs and PMPs at the peak plasma concentration of rivaroxaban. Statins have promising potential in the prevention of rivaroxaban-related PMP and EMP release. The pro-thrombotic role of PMPs and EMPs during rivaroxaban therapy requires further study.

Polish regional differences in patient knowledge on atrial fibrillation and its management as well as in patterns of oral anticoagulant prescription.

BACKGROUND The Jessa Atrial Fibrillation Knowledge Questionnaire (JAKQ) was successfully used to assess knowledge gaps in patients with atrial fibrillation (AF). AIMS To evaluate the regional differences among Polish patients in their awareness of AF diagnosis and oral anticoagulation use. METHODS A total of 1583 patients with AF at a median (IQR) age of 72 (66-79) years completed the JAKQ in 3 cardiology centers (center I, Kraków; center II, Torun; center III, Kielce) from January 2017 to June 2018. The final analysis included 1525 patients, 32.9% were on vitamin K antagonists (VKAs) and 67.1% on non-VKA oral anticoagulants (NOACs), that is, rivaroxaban and dabigatran (28.9% each), and apixaban (9.3%). RESULTS The mean (SD) score on the JAKQ was 55.5% (18.4%) with better results among patients on VKAs compared with NOACs (58% [18.3%] vs 54.3% [18.4%]; P = 0.0002) with time from AF diagnosis more than 12 months (57.4% [17.5%] vs 50% [19.9%]; P <0.0001). There was a significant difference in the knowledge scores between the 3 centers (I, 59.5%; II, 48.5%; III, 54.3%; P <0.0001). In all centers the number of correct answers correlated inversely with patient's age (r = -0.20; P <0.0001). NOACs were more frequently used in center III. The percentage of correct responses was lower in patients on reduced NOAC doses (35.4% of patients on NOACs), compared with the full-dose NOAC groups in center I (56.9% vs 62.5%; P = 0.012) and II (48.1% vs 56.2%; P = 0.003). CONCLUSIONS Patients from a high-volume academic center showed better knowledge than their peers from district hospitals. There are large regional differences in prescription patterns of oral anticoagulants, including the preferred NOAC.

A novel in-vitro model of human aortic valve mineralization.

BACKGROUND AND AIM OF THE STUDY: The study aim was to develop an in-vitro model of human aortic valve homograft (AVH) mineralization, as a basis for further research on the subject of calcific aortic valve disease (CAVD). METHODS: Human aortic valves were excised during autopsy (12-24 h post-mortem) from donors who had died due to accident or suicide. The mean (±SD) donor age was 32.5 ± 11.4 years. Under sterile conditions each aortic cusp (three cusps per valve) was cut in half to provide a total of 240 tissue samples. AVH mineralization was assessed in solutions with different Ca and P concentrations and CaxPO4 ionic product values. The impact of time on aortic valve mineralization rate was assessed using energy-dispersive X-ray fluorescence (ED-XRF). RESULTS: The model showed that human AVH mineralization can be best observed in a solution with a CaxPO4 ionic product of 2.2 mmol2/l2. The optimum incubation time for observing AVH mineralization was 21 days. CONCLUSION: A novel in-vitro AVH mineralization model was developed for use in future studies.

Fresh-wet storage accelerates aortic homograft calcification.

The studies were focused on the influence of the fresh-wet storage procedure on aortic valve homograft (AVH) mineralization. Thirty-four aortic valves excised at autopsy were investigated. The cusps were divided into halves, the first one was used as a control while the second half was stored in Morgan, Morton, and Parker's Medium 199 supplemented with an antibiotic mixture at 4 degrees C for 28 days. The elemental compositions of the samples were determined by the energy dispersive X-ray fluorescence method. The Ca/P ratio and Ca concentration was used as markers of the mineralization development. It was found that the AVH mineralization was accelerated by the applied fresh-wet storage procedure. The aggravation of the AVH mineralization was correlated with the Ca content before storage especially in case of old donors. For donors older than 40 years an increase of Ca concentrations by approximately 40% was observed. To limit AVH mineralization due to fresh-wet storage, age of donors should not exceed approximately 40 years. Another method to reduce AVH mineralization relies on a modification of the medium commonly applied in the fresh-wet storage procedure, and research are ongoing.

[Effect of the dispersion of calcium deposits on allogenic aortic valves durability. Mineralization phases]. / Wplyw rozproszenia zlogów wapnia na trwalosc allogennych aortalnych zastawek serca. Fazowosc mineralizacji.

This investigation was aimed at comparison of calcium content and calcium dispersion in allogenic aortic valve leaflets removed due to dysfunction, to establish the influence of both parameters on graft durability. Calcification was assessed histochemically (von Kossa) as well as physicochemically using atomic absorption spectroscopy (AAS). The morpho-metric data (leaflet area involved in the calcification process) were obtained by computer-assisted image analysis system. The dry weight content of leaflet calcium and phosphorus were assessed by atomic absorptive spectroscopy (AAS) and Ca/P ratio was calculated. Calcium dispersion coefficient (Dc) was established according to the formula: Dc = 1/Ca(c)/Ap, where Ca(c) = calcium dry weight concentration; Ap = percent of leaflet area involved in calcification. We found biphasic correlation between calcium concentration and area involved in calcification. The first one was characterized by rising dispersion of calcium deposits while for the second one saturation with hydroxyapatite of formerly calcified areas was predominant, negatively influencing graft durability. Allograft durability was correlated with calcium dispersion (Dc) (p<0.001), while no significant correlation was found with calcium concentration. Decreased Dc was characteristic for 93.8% of low durability grafts (<11.6 years). Our results suggest that lowered calcium dispersion decreasing allograft lifetime and is a better predictor of allograft durability than the total calcium content.