Mazur, Piotr K

Aortic stenosis (AS) is associated with hypofibrinolysis, but its mechanism is poorly understood. We investigated whether LDL cholesterol affects plasminogen activator inhibitor 1 (PAI-1) expression, which may contribute to hypofibrinolysis in AS. Stenotic valves were obtained from 75 severe AS patients during valve replacement to assess lipids accumulation, together with PAI-1 and nuclear factor-κB (NF-κB) expression. Five control valves from autopsy healthy individuals served as controls. The expression of PAI-1 in valve interstitial cells (VICs) after LDL stimulation was assessed at protein and mRNA levels. PAI-1 activity inhibitor (TM5275) and NF-κB inhibitor (BAY 11-7082) were used to suppress PAI-1 activity or NF-κB pathway. Clot lysis time (CLT) was performed to assess fibrinolytic capacity in VICs cultures. Solely AS valves showed PAI-1 expression, the amount of which was correlated with lipid accumulation and AS severity and co-expressed with NF-κB. In vitro VICs showed abundant PAI-1 expression. LDL stimulation increased PAI-1 levels in VICs supernatants and prolonged CLT. PAI-1 activity inhibition shortened CLT, while NF-κB inhibition decreased PAI-1 and SERPINE1 expression in VICs, its level in supernatants and shortened CLT. In severe AS, valvular PAI-1 overexpression driven by lipids accumulation contributes to hypofibrinolysis and AS severity.

Background The management of severe mitral regurgitation (MR) after transcatheter edge‐to‐edge repair (TEER) remains a clinical conundrum. Considering the growing volume of TEER, more outcomes data for mitral surgery in this cohort are needed. Methods and Results Symptomatic patients with persistent or recurrent severe MR after TEER evaluated between May 2014 and June 2021 were included. The primary outcome was all‐cause mortality in patients who were treated with surgery versus medical therapy. The Kaplan–Meier and Cox regression methods were used to report risk‐adjusted survival analyses. Among the 142 included patients, 44 (31.0%) underwent mitral surgery. Patients who underwent surgery were younger than those treated medically (74.1±8.9 versus 78.6±10.5 years, P =0.01). Major comorbidities were similar except obesity, sleep apnea, left ventricular dimensions, and ejection fraction. Society of Thoracic Surgeons Predicted Risk of Operative Mortality was 9.0±4.7 versus 7.9±4.9 in the surgical versus medical therapy groups, respectively, P =0.22. Time from TEER to detection of severe MR was similar in both groups (median [interquartile range] 97.5 [39.5–384] versus 93.5 [40–389] days in the surgical versus medical groups, respectively [ P >0.05]). In the surgical group, valve replacement was performed in all patients. Operative mortality was 4.5% (observed/expected ratio 0.55), and major complications were uncommon. After risk‐adjustment, surgery was associated with significantly lower all‐cause mortality (adjusted hazard ratio, 0.33 [95% CI, 0.12–0.92], P =0.001) compared with medial therapy. Conclusions Compared with medical therapy, mitral surgery in patients with severe persistent or recurrent MR after TEER is associated with lower mortality despite the high‐risk profile of these patients. Patients with severe MR after TEER should be considered for surgery at a referral mitral surgical center.

Functional point-of-care tests (POCTs) have evolved into useful tools for diagnosing disorders of blood coagulation and fibrinolysis. We aimed to describe the in vivo association between standard and functional parameters of coagulation and fibrinolysis in the setting of acute hemodilution induced by an infusion of balanced crystalloid or synthetic gelatine solutions. This prospective randomized crossover in vivo study included healthy male volunteers aged 18–30 years. Enrolled participants were randomly assigned to receive either the Optilyte® or Geloplasma® infusion. Laboratory analysis included conventional coagulation parameters and rotational thromboelastometry (ROTEM) assays. A total of 25 healthy Caucasian males were included. ROTEM viscoelastic assays presented moderate to strong correlations with conventional coagulation tests, regardless of the fluid type utilized. Irrespectively of the extent of hemodilution, significant correlations remained unaffected. The strongest associations were found between the ROTEM clot formation and clot strength and the fibrinogen concentration and platelet count, and between the ROTEM clotting time and the APTT and PT. This in vivo experimental study in healthy male volunteers demonstrated that ROTEM may be used as a credible alternative to standard laboratory tests to assess blood coagulation and fibrinolysis in the setting of fluid resuscitation with both crystalloid and colloid solutions. The study was registered online in the ClinicalTrials.gov database (NCT05148650).

Prudent administration of fluids helps restore or maintain hemodynamic stability in the setting of perioperative blood loss. However, fluids may arguably exacerbate the existing coagulopathy. We sought to investigate the influence of balanced crystalloid and synthetic gelatine infusions on coagulation and fibrinolysis in healthy volunteers. This prospective randomized crossover study included 25 males aged 18–30 years. Infusions performed included 20 mL/kg of a balanced crystalloid solution (Optilyte®) or 20 mL/kg of gelatine 26.500 Da (Geloplasma®) in a random order over a period of 2 weeks. Laboratory analysis included conventional coagulation parameters and rotational thromboelastometry (ROTEM) assays. We confirmed a decrease in fibrinogen concentration and the number of platelets, and prolongation of PT after infusions. Compared to baseline values, differences in the ROTEM assays’ results after infusions signified the decrease in coagulation factors and fibrinogen concentration, causing impaired fibrin polymerization and clot structure. The ROTEM indicator of clot lysis remained unaffected. In the case of both Optilyte® and Geloplasma®, the results suggested relevant dilution. Gelatine disrupted the process of clot formation more than balanced crystalloid. Infusions of both crystalloid and saline-free colloid solutions causing up to 30% blood dilution cause significant dilution of the coagulation factors, platelets, and fibrinogen. However, balanced crystalloid infusion provides less infusion-induced coagulopathy compared to gelatine.

Calcific aortic stenosis (CAS) is the most common cause of acquired valvular heart disease in adults with no available pharmacological treatment to inhibit the disease progression to date. This review provides an up-to-date overview of current knowledge of molecular mechanisms underlying CAS pathobiology and the related treatment pathways. Particular attention is paid to current randomized trials investigating medical treatment of CAS, including strategies based on lipid-lowering and antihypertensive therapies, phosphate and calcium metabolism, and novel therapeutic targets such as valvular oxidative stress, coagulation proteins, matrix metalloproteinases, and accumulation of advanced glycation end products.

Background: Renal replacement therapy (RRT) can be used to rewarm patients in deep hypothermia. However, there is still no clear evidence for the effectiveness of RRT in this group of patients. This systematic review aims to summarize the rewarming rates during RRT in patients in severe hypothermia, below or equal to 32 °C. Methods: This systematic review was registered in the PROSPERO International Prospective Register of Systematic Reviews (identifier CRD42021232821). We searched Embase, Medline, and Cochrane databases using the keywords hypothermia, renal replacement therapy, hemodialysis, hemofiltration, hemodiafiltration, and their abbreviations. The search included only articles in English with no time limit, up until 30 June 2021. Results: From the 795 revised articles, 18 studies including 21 patients, were selected for the final assessment and data extraction. The mean rate of rewarming calculated for all studies combined was 1.9 °C/h (95% CI 1.5–2.3) and did not differ between continuous (2.0 °C/h; 95% CI 0.9–3.0) and intermittent (1.9 °C/h; 95% CI 1.5–2.3) methods (p > 0.9). Conclusions: Based on the reviewed literature, it is currently not possible to provide high-quality recommendations for RRT use in specific groups of patients in accidental hypothermia. While RRT appears to be a viable rewarming strategy, the choice of rewarming method should always be determined by the specific clinical circumstances, the available resources, and the current resuscitation guidelines.

AbstractSevere accidental hypothermia carries high mortality and morbidity and is often treated with invasive extracorporeal methods. Continuous veno‐venous hemodiafiltration (CVVHDF) is widely available in intensive care units. We sought to provide theoretical basis for CVVHDF use in rewarming of hypothermic patients. CVVHDF system was used in the laboratory setting. Heat balance and transferred heat units were evaluated for the system without using blood. We used 5L of crystalloid solution at the temperature of approximately 25°C, placed in a thermally insulated tank (representing the “central compartment” of a hypothermic patient). Time of warming the central compartment from 24.9 to 30.0°C was assessed with different flow combinations: “blood” (central compartment fluid) 50 or 100 or 150 mL/min, dialysate solution 100 or 1500 mL/h, and substitution fluid 0 or 500 mL/h. The total circulation time was 1535 minutes. There were no differences between heat gain values on the filter depending on blood flow (P = .53) or dialysate flow (P = .2). The mean heating time for “blood” flow rates 50, 100, and 150 mL/min was 113.7 minutes (95% CI, 104.9‐122.6 minutes), 83.3 minutes (95% CI, 76.2‐90.3 minutes), and 74.7 minutes (95% CI, 62.6‐86.9 minutes), respectively (P < .01). The respective median rewarming rate for different “blood” flows was 3.6°C/h (IQR, 3.0‐4.2°C/h), 4.8 (IQR, 4.2‐5.4°C/h), and 5.4 (IQR, 4.8‐6.0°C/h), respectively (P < .01). The dialysate flow did not affect the warming rate. Based on our experimental model, CVVHDF may be used for extracorporeal rewarming, with the rewarming rates increasing achieved with higher blood flow rates.