Coronary calcium burden did not correlate with classical risk factors in patients with JAK2 V167F positive ET.• Carotid artery stiffness progressed significantly faster in ET patients than in control subjects during 4 years of follow-up.• JAK2 V167F mutation promotes stiffening of the carotid arteries and acts as a non-classical risk factor for atherosclerosis.

Introduction: Although there is evidence of beneficial effects of levosimendan on heart and renal function in patients with advanced chronic heart failure, the impact of levosimendan on liver function remains undefined. Hypothesis: We investigated the effects of levosimendan on liver function in patients with advanced chronic heart failure. Methods: We enrolled 299 patients with chronic heart failure (NYHA class 3) and left ventricular ejection fraction <30%, aged between 18 and 80 years. 150 patients were randomized to receive levosimendan (0.1 mcg/kg/min infusion for 24 hours; LS Group), and 149 received no levosimendan (Controls). Liver function was evaluated at baseline and again at 3 months by measuring total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gGT) and lactate dehydrogenase (LDH). Results: At baseline, the groups did not differ in age (59±11 years in LS Group vs. 60±10 years in Controls; P=0.74), sex (male: 77% vs. 75%; P=0.36), heart failure etiology (ischemic: 45% vs. 47%; P=0.64), left ventricular ejection fraction (27±2% vs. 26±3%; P=0.97), and plasma NT-proBNP levels (4758±3912 pg/mL vs. 5111±4271 pg/mL; P=0.71). Liver function tests of both groups at the time of enrollment were comparable. At 3 months we found a significant improvement in liver function in LS Group, but not in Controls, with a decrease in total bilirubin (21.9±16.4 μmol/L to 18.5±13.1 μmol/L in LS Group vs. 22.1±17.1 μmol/L to 22.0±17.3 μmol/L in Controls; P<0.001), direct bilirubin (8.6±6.4 μmol/L to 7.1±5.2 μmol/L vs. 8.7±6.6 μmol/L to 8.8±6.7 μmol/L; P<0.001), AST (1.18±0.98 μkat/L to 0.42±0.40 μkat/L vs. 1.16±0.92 μkat/L to 1.15±0.87 μkat/L; P=0.03), ALT (0.73±0.71 μkat/L to 0.50±0.49 μkat/L vs. 0.75±0.77 μkat/L to 0.74±0.70 μkat/L; P=0.006), gGT (2.25±2.30 μkat/L to 1.87±1.94 μkat/L vs. 2.23±2.18 μkat/L to 2.22±2.16 μkat/L; P=0.003) and LDH (3.66±2.46 μkat/L to 3.36±1.96 μkat/L vs. 3.58±2.77 μkat/L to 3.62±2.82 μkat/L; P=0.006). Conclusions: Levosimendan appears to improve long-term liver function in advanced chronic heart failure patients. Thus, repetitive levosimendan infusions may potentially slow the progression of cardio-hepatic syndrome to cardiac cirrhosis.

INTRODUCTION Essential thrombocythemia (ET) is a classic Philadelphia chromosome-negative myeloproliferative neoplasm with low progression rate to secondary myelofibrosis and transformation to acute leukemia. Patient survival is prolonged and the main clinical focus in ET patients is prevention of thrombotic and hemorrhagic complications. Chronic inflammation may be one of the main reasons for progression and complications in ET. The somatic JAK2 V617F mutation found in about half of the patients with ET is associated with dysregulation and overexpression of inflammatory genes resulting in massive production of cytokines and other inflammatory mediators. In spite of knowing that chronic inflammation is an important risk factor for the development of atherosclerosis in patients with chronic inflammatory diseases, such as rheumatoid arthritis, type 2 diabetes mellitus and systemic lupus erythematosus no clinical study has been published in patients with ET about deterioration of arterial function. Therefore, we tested patients with JAK2 V617F positive ET in comparison with age-and sex-matched, apparently healthy control subjects whether they show more advanced progression of arterial stiffness and pulse-wave velocity - parameters that increase with age and are associated with adverse cardiovascular outcomes. PATIENTS AND METHODS Thirty six patients with JAK2 V617F positive ET, without clinically apparent atherosclerotic disease and 38 apparently healthy individuals were enrolled in our study after giving their informed consent. The 10-year risk for coronary disease was assessed at inclusion by the Framingham risk equation. All subjects underwent two separate clinical visits for ultrasound examination of the extracranial carotid arteries (using Aloka prosound α7, Hitachi Aloka Medical, Ltd., Japan). Echo-tracking of the common carotid arterial wall 2 cm proximal to the bulb was used to assess the β-stiffness index and to estimate the pulse wave velocity. The first measurement was done between January 2014 and August 2015 and the second 3-4 years later between January and July 2018. Continuous variables were tested for normality and are presented as median values and inter-quartile range (QR) or mean values and standard deviation (SD). The differences between groups were evaluated either by the Mann-Whitney test or the Student's t-test for continuous data, or by the chi-square test for the sex distribution. RESULTS Patients with ET and control subjects did not differ in age and sex distribution (age at inclusion 57.5 (QR 45.8 - 64.9) vs 59.2 (QR 53.6 - 67.8) years, p = 0.17, male/female 12/24 vs. 14/24, p = 0.76) or in the predicted 10-year risk of coronary disease by the Framingham equation (6.84 (3.27-11.82) vs. 7.20 (3.61-10.37), p = 0.87) at inclusion in the study. The mean β-stiffness index for patients with JAK2 V617F positive ET was 7.71 (standard deviation (SD) 2.42) at the first visit and 9.67 (SD 2.31) at the second visit, while the mean β-stiffness index for control subjects was 8.73 (SD 2.77) at the first visit and 8.97 (SD 1.91) at the second visit. Individual pairs of data are shown in Fig 1a. The increase in β-stiffness index between the first and the second visit for patient with JAK2 V617F positive ET was 1.95 (SD 2.17) and for control subjects 0.24 SD (1.96), p < 0.001 (Fig. 2a). The mean pulse wave velocity for patients with JAK2 V617F positive ET was 6.20 m/s (SD1.04 m/s) at the first visit and 6.92 m/s (SD 0.93 m/s) at the second visit, while in control subjects it was 6.57 m/s (SD 1.00 m/s) at the first visit and 6.66 m/s (SD 0.79 m/s) at the second visit. Individual pairs of data are shown in Fig 1b. The difference in pulse wave velocity between the first and the second visit for patients with JAK2 V617F positive ET was 0.72 m/s (SD 0.92 m/s) and for control subjects 0.09 m/s (SD 0.71 m/s), p < 0.001 (Figure 2b). CONCLUSIONS Patients with JAK2 V617F positive ET had accelerated progression of arterial stiffness of the carotid arteries and estimated pulse wave velocity in the 3-4 year observation period compared with control subjects matched for age, sex and Framingham cardiovascular risk score. Disclosures No relevant conflicts of interest to declare.