Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort.

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2'-5'-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype 'gttg' carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

Monomeric C-Reactive Protein in Atherosclerotic Cardiovascular Disease: Advances and Perspectives.

This review aimed to trace the inflammatory pathway from the NLRP3 inflammasome to monomeric C-reactive protein (mCRP) in atherosclerotic cardiovascular disease. CRP is the final product of the interleukin (IL)-1ß/IL-6/CRP axis. Its monomeric form can be produced at sites of local inflammation through the dissociation of pentameric CRP and, to some extent, local synthesis. mCRP has a distinct proinflammatory profile. In vitro and animal-model studies have suggested a role for mCRP in: platelet activation, adhesion, and aggregation; endothelial activation; leukocyte recruitment and polarization; foam-cell formation; and neovascularization. mCRP has been shown to deposit in atherosclerotic plaques and damaged tissues. In recent years, the first published papers have reported the development and application of mCRP assays. Principally, these studies demonstrated the feasibility of measuring mCRP levels. With recent advances in detection techniques and the introduction of first assays, mCRP-level measurement should become more accessible and widely used. To date, anti-inflammatory therapy in atherosclerosis has targeted the NLRP3 inflammasome and upstream links of the IL-1ß/IL-6/CRP axis. Large clinical trials have provided sufficient evidence to support this strategy. However, few compounds target CRP. Studies on these agents are limited to animal models or small clinical trials.

Adjuvant cardioprotection in cardiac surgery: update.

Cardiac surgery patients are now more risky in terms of age, comorbidities, and the need for complex procedures. It brings about reperfusion injury, which leads to dysfunction and/or loss of part of the myocardium. These groups of patients have a higher incidence of postoperative complications and mortality. One way of augmenting intraoperative myocardial protection is the phenomenon of myocardial conditioning, elicited with brief nonlethal episodes of ischaemia-reperfusion. In addition, drugs are being tested that mimic ischaemic conditioning. Such cardioprotective techniques are mainly focused on reperfusion injury, a complex response of the organism to the restoration of coronary blood flow in ischaemic tissue, which can lead to cell death. Extensive research over the last three decades has revealed the basic mechanisms of reperfusion injury and myocardial conditioning, suggesting its therapeutic potential. But despite the enormous efforts that have been expended in preclinical studies, almost all cardioprotective therapies have failed in the third phase of clinical trials. One reason is that evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. Ischaemic conditioning, which is among these, is also limited by this. At present, the prevailing belief is that such options of treatment exist, but their full employment will not occur until subquestions and methodological issues with the transfer into clinical practice have been resolved.

Plasma urokinase antigen and C-reactive protein predict angina recurrence after coronary angioplasty.

This study evaluates the predictive value of several biochemical indices of the coagulation-fibrinolysis system, platelet function, and inflammatory state for angina recurrence after successful percutaneous transluminal coronary angioplasty (PTCA). We measured preprocedural and follow-up plasma levels of C-reactive protein (CRP), fibrinogen, and urokinase plasminogen activator antigen (uPA), plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator activity, and adenosine diphosphate-induced platelet aggregation in 53 patients with chronic stable angina who underwent successful elective PTCA of single hemodynamically significant lesions in coronary arteries. All patients were followed up for 12 months after PTCA. The Cox proportional hazards model was used to assess the association of variables with angina recurrence rate. At the end of the follow-up, 16 patients had angina recurrence. Among 36 clinical, biochemical, and angiographic variables, the duration of stable angina more than 12 months before PTCA (χ (2) = 5.73; P = 0.02, hazard ratio (HR) 3.7, 95 % confidence interval (CI) 1.26-10.6), high baseline levels of CRP (>7 mg/l) (χ (2) = 8.34; P = 0.004, HR 2.9, 95 % CI 1.4-5.9), uPA antigen baseline (>1 ng/ml) (χ (2) = 17.11; P = 0.0001, HR 11.5, 95 % CI 3.6-36.7) and 48 h after PTCA (χ (2) = 15.73; P = 0.0001, HR 8.8, 95 % CI 3.01-25.96), baseline PAI-1 activity (>18 IU/ml) (χ (2) = 9.37; P = 0.002, HR 7.6, 95 % CI 2.07-27.84) were significant predictors of recurrent angina by univariate analyses. According to stepwise multivariate analyses, only the levels of plasma uPA antigen and serum CRP were shown to be significant independent predictors of angina recurrence (multivariate uPA χ (2) = 8.22, P = 0.004, HR 6.2, 95 % CI 1.78-21.67; CRP χ (2) = 4.09, P = 0.04, HR 1.9, 95 % CI 1.02-3.68). High preprocedural plasma uPA and serum CRP levels are indicative of angina recurrence after successful PTCA, and are valuable for the prognosis of restenosis.

Polymorphonuclear blood leukocytes and restenosis after intracoronary implantation of drug-eluting stents.

Peripheral blood contents of osteonectin-positive progenitor cells and polymorphonuclear granulocytes were examined by flow cytometry in 38 patients after myocardial revascularisation with drug-eluting stents. Repeat coronary angiography performed 6-12 months after stent implantation revealed in-stent restenosis in 15 patients and its absence in 23 patients. The plasma levels of osteonectin-positive progenitor cells, neutrophils, and basophils did not differ in patients with and without restenosis. Eosinophil blood levels in patients with and without restenosis were 262+/-68 and 124+/-67 cells/microL (mean+/-SD, p<0.001), respectively. Only one of 19 patients (5%) with eosinophil content lower than the distribution median for the entire group developed restenosis, whereas in the group with eosinophil contents higher than the median (n=19) restenosis occurred in 14 patients (74%, p<0.001). Our findings suggest that the frequency of restenoses after stenting is related to high peripheral blood eosinophil content.

Circulating stromal osteonectin-positive progenitor cells and stenotic coronary atherosclerosis.

The level of circulating stromal progenitor cells carrying osteonectin (ON), a marker of osteogenic differentiation, was evaluated by flow cytometry in blood of patients with coronary artery disease (CAD). Ninety-nine patients with CAD were included into the study. Coronary angiography of all patients showed critical stenosis of at least 2 coronary arteries or their major branches. The control groups included 8 patients without CAD and 19 healthy volunteers. In control patients, no lesions of the coronary bed were found by angiography. The absence of CAD in the volunteers was confirmed by bicycle stress test. The content of ON-positive cells in blood was examined in various populations of lymphocyte-like cells. It was found that the number of ON+ lymphocyte-like cells with CD41 positivity in blood of patients without coronary stenosis (0.27%+/-0.11%, mean+/-SD) did not differ significantly from corresponding value in healthy volunteers (0.26%+/-0.07%, p=0.94). In CAD patients, the percent of these ON+ cells was 1.01%+/-0.49% and was significantly higher than in blood of healthy volunteers (p<0.0001) and patients without CAD (p<0.0001). High content of ON+ lymphocyte-like cells with CD41 positivity in blood may serve as noninvasive marker of arterial atherosclerosis.

Circulating bone marrow stem/progenitor cells in vascular atherogenesis and in the noninvasive diagnosis of coronary stenosis.

Using autopsy specimens and clonal technique, the authors showed that hematopoietic and stromal stem colony-forming units are present in human atheromatous vascular intima. Stromal colony-forming units were also detected in the mononuclear fraction of the blood of patients with hyperlipidemia and coronary stenosis, and were not found in the peripheral blood of normolipidemic volunteers. Using flow cytometry, the absence of stromal circulating colony-forming units in healthy volunteers and their presence in coronary patients was confirmed. It was thought that the presence of circulating stromal precursors with a certain phenotype and variations in their level in blood could serve as an informative noninvasive indicator of coronary stenosis.