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Abstract Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p

Abstract Elevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75–129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669–0.899; FGF23d2: AUC 0.766; 95%CI 0.631–0.901; SHF: AUC 0.771; 95%CI 0.651–0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.

Abstract Background In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. Methods In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. Results Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p

Myocardial infarction is remains the leading cause of death in developed countries. Recent data show that the composition of the extracellular matrix might differ despite similar heart function and infarction sizes. Because collagen is the main component of the extracellular matrix, we hypothesized that changes in inflammatory cell recruitment influence the synthesis of different collagen subtypes in myofibroblasts, thus changing the composition of the scar. We found that neutrophils sustain the proliferation of fibroblasts, remodeling, differentiation, migration and inflammation, predominantly by IL-1 and PPARγ pathways (n = 3). They also significantly inhibit the mRNA expression of fibrillar collagen, maintaining a reduced stiffness in isolated myofibroblasts (n = 4–5). Reducing the neutrophil infiltration in CCR1−/− resulted in increased mRNA expression of collagen 11, moderate expression of collagen 19 and low expression of collagen 13 and 26 in the scar 4 weeks post infarction compared with other groups (n = 3). Mononuclear cells increased the synthesis of all collagen subtypes and upregulated the NF-kB, angiotensin II and PPARδ pathways (n = 3). They increased the synthesis of collagen subtypes 1, 3, 5, 16 and 23 but reduced the expression of collagens 5 and 16 (n = 3). CCR2−/− scar tissue showed higher levels of collagen 13 (n = 3), in association with a significant reduction in stiffness (n = 4–5). Upregulation of the inflammation-related genes in myofibroblasts mostly modulated the fibrillar collagen subtypes, with less effect on the FACIT, network-forming and globular subtypes (n = 3). The upregulation of proliferation and differentiation genes in myofibroblasts seemed to be associated only with the fibrillar collagen subtype, whereas angiogenesis-related genes are associated with fibrillar, network-forming and multiplexin subtypes. In conclusion, although we intend for our findings to deepen the understanding of the mechanism of healing after myocardial infarction and scar formation, the process of collagen synthesis is highly complex, and further intensive investigation is needed to put together all the missing puzzle pieces in this still incipient knowledge process.

Abstract Background Non-cemented acetabular cup components demonstrated different clinical performance depending on their surface texture or bearing couple. However, clinical osseointegration needs to be proved for each total joint arthroplasty (TJA) design. Aim of this study was to detect the in vivo migration pattern of a non-cemented cup design, using model-based roentgen stereophotogrammetric analysis with elementary geometrical shape models (EGS-RSA) to calculate early cup migration. Methods Interchangeable applicability of the model-based EGS-RSA method next to gold standard marker-based RSA method was assessed by clinical radiographs. Afterwards, in vivo acetabular cup migration for 39 patients in a maximum follow up of 120 months (10 years) was calculated using model-based EGS-RSA. Results For the axes with the best predictive capability for acetabular cup loosening, mean (±SD) values were calculated for migration and rotation of the cup. The cup migrated 0.16 (±0.22) mm along the cranio-caudal axis after 24 months and 0.36 (±0.72) mm after 120 months, respectively. It rotated − 0.61 (±0.57) deg. about the medio-lateral axis after 24 months and − 0.53 (±0.67) deg. after 120 months, respectively. Conclusions Interchangeable applicability of model-based EGS-RSA next to gold standard marker-based RSA method could be shown. Model-based EGS-RSA enables an in vivo migration measurement without the necessity of TJA specific surface models. Migration of the investigated acetabular cup component indicates significant migration values along all the three axes. However, migration values after the second postoperative year were within the thresholds reported in literature, indicating no risk for later aseptic component loosening of this TJA design.

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Aim: Recruitment of neutrophils to the heart following acute myocardial infarction (MI) initiates inflammation and contributes to adverse post-infarct left ventricular (LV) remodeling. However, therapeutic inhibition of neutrophil recruitment into the infarct zone has not been beneficial in MI patients, suggesting a possible dual role for neutrophils in inflammation and repair following MI. Here, we investigate the effect of neutrophils on cardiac fibroblast function following MI. Methods and Results: We found that co-incubating neutrophils with isolated cardiac fibroblasts enhanced the production of provisional extracellular matrix proteins and reduced collagen synthesis when compared to control or co-incubation with mononuclear cells. Furthermore, we showed that neutrophils are required to induce the transient up-regulation of transforming growth factor (TGF)-ß1 expression in fibroblasts, a key requirement for terminating the pro-inflammatory phase and allowing the reparatory phase to form a mature scar after MI. Conclusion: Neutrophils are essential for both initiation and termination of inflammatory events that control and modulate the healing process after MI. Therefore, one should exercise caution when testing therapeutic strategies to inhibit neutrophil recruitment into the infarct zone in MI patients.

Fibroblast growth factor−23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical “mineral metabolism” actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered.

Hip dislocations during sporting activities represent only 2%–5% of all hip dislocations. Most hip dislocations in sports can be categorised as “less complicated traumatic hip dislocations” by the Stewart-Milford classification due to the fact that minimal force is involved. The incidence of avascular necrosis of the femoral head greatly increases if the time to reduction is more than six hours. We report the case of a 38-year-old football player who suffered hip dislocation while kicking the ball with the medial aspect of the right foot in an external rotated manner of the right hip. Closed reduction was performed within 2 hours; postoperative follow-up was uneventful. Six months later the patient is out of any complaints; there is no sign of AVN of the femoral head.