Association of Maternal and Fetal Single-Nucleotide Polymorphisms in Metalloproteinase (MMP1, MMP2, MMP3, and MMP9) Genes with Preeclampsia

Background. Metalloproteinases (MMPs) play a pivotal role during the process of trophoblast invasion and placentation. The appearance of five functional single-nucleotide polymorphisms (SNP) in the genes of the metalloproteinases most commonly implicated in the implantation process may influence the development of preeclampsia. Methods. Blood samples were collected from 86 mothers and 86 children after preeclampsia and 85 mothers and 85 children with uncomplicated pregnancies. The distribution of genotypes for −1607 1G/2G MMP1, −735 C/T MMP2, −1306 C/T MMP2, −1171 5A/6A MMP3, and −1562C/T MMP9 polymorphisms was determined by RFLP-PCR. Results. The occurrence of 1G/1G MMP1 or 5A/5A MMP3 genotype in the mother or 1G/1G MMP1 or 5A/6A MMP3 genotype in the child is associated with preeclampsia development. Moreover, simultaneous maternal and fetal 1G/1G homozygosity increases the risk of preeclampsia development 2.39-fold and the set of maternal 5A/5A and fetal 5A/6A MMP3 genotypes by over 4.5 times. No association between the carriage of studied MMP2 or MMP9 polymorphisms and the predisposition to preeclampsia was found. Conclusion. The maternal 1G/1G MMP1 and 5A/5A MMP3 and fetal 1G/1G MMP1 and 5A/6A MMP3 gene polymorphisms may be strong genetic markers of preeclampsia, occurring either individually or together

Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes

Objectives: Recurrent reproductive loss (RPL) is a global health issue affecting a significant number of women. Approximately half of miscarriages have an unexplained etiology. Familial aggregation and twins studies prove that some cases of the RPL could have a genetic background. Recent evidences suggest that cytokines (e.g. IL-6, TNF alpha or TGF beta) and matrix metalloproteinases (MMP) are important for maintenance of pregnancy. Single gene polymorphisms (SNP), affecting these proteins production or their function may predispose to the loss of the pregnancy. The aim of this study was to evaluate the association between the following polymorphisms of IL6 (rs1800795), TNF (rs1800629), TGFB1 (rs1800471), MMP1 (rs1799750), MMP2 (rs2285053 and rs243865), MMP3 (rs35068180), MMP9 (rs3918242) and the recurrent pregnancy loss in polish population.Material and methods: Study subjects comprised of 67 patients with a history of recurrent pregnancy loss (≥ 2 miscarriages in history) and 75 controls. The distribution of genotypes for selected polymorphisms were determined by RFLP-PCR.Results: Maternal genotypes GG TNF, or 5A/5A MMP3 may be associated with the recurrent pregnancy loss. No association between the IL6, TGFB1, MMP1, MMP2, or MMP9 studied polymorphisms and the predisposition to miscarriage was found.Conclusions: This study demonstrated a possible association between rs1800629 TNF, rs35068180 MMP3 polymorphisms and recurrent pregnancy loss

The Targeting of Nuclear Factor Kappa B by Drugs Adopted for the Prevention and Treatment of Preeclampsia

Preeclampsia (PE) is characterised by high levels and activity of the transcription factor Nuclear Factor kappa B (NFĸB) in the maternal blood and placental cells. This factor is responsible for the regulation of over 400 genes known to influence processes related to inflammation, apoptosis and angiogenesis, and cellular responses to oxidative stress and hypoxia. Although high NFĸB activity induces hypoxia and inflammation, which are beneficial for the process of implantation, NFĸB level should be reduced in the later stages of physiological pregnancy to favour maternal immunosuppression and maintain gestation. It is believed that the downregulation of NFĸB activity by pharmacotherapy might be a promising way to treat preeclampsia. Interestingly, many of the drugs adopted for the prevention and treatment of preeclampsia have been found to regulate NFĸB activity. Despite this, further innovation is urgently needed to ensure treatment safety and efficacy. The present article summarizes the current state of knowledge about the drugs recommended by cardiology, obstetrics, and gynaecology societies for the prevention and treatment of preeclampsia with regard to their impact on the cellular regulation of NFĸB pathways

Genetic Polymorphisms and the Risk of Myocardial Infarction in Patients Under 45 Years of Age

This study investigates the potential role of 17 chosen polymorphisms in 15 candidate genes and the risk of myocardial infarction in patients under 45 years of age. The study consists of 271 patients with myocardial infarction and 141 controls. The analysis of genetic polymorphisms was performed using the PCR–RFLP method. Of the chosen polymorphisms, two (Leu125Val PECAM1 and A1/A2 FVII) are related to myocardial infarction and two (C677T MTHFR and 5A/6A MMP3) to advanced stenosis in arterial vessels (> 75%). We also found that the frequency of some combinations among the analyzed genes and environmental factors varied between the patient and control groups

Reduction in CgA-Derived CST Protein Level in HTR-8/SVneo and BeWo Trophoblastic Cell Lines Caused by the Preeclamptic Environment

One of the most dangerous complications of pregnancy is preeclampsia (PE), a disease associated with a high risk of maternal and fetal mortality and morbidity. Although its etiology remains unknown, the placenta is believed to be at the center of ongoing changes. One of the hormones produced by the placenta is chromogranin A (CgA). Thus far, its role in pregnancy and pregnancy-related disorders is enigmatic, yet it is known that both CgA and its derived peptide catestatin (CST) are involved in the majority of the processes that are disturbed in PE, such as blood pressure regulation or apoptosis. Therefore, in this study, the influence of the preeclamptic environment on the production of CgA using two cell lines, HTR-8/SVneo and BeWo, was investigated. Furthermore, the capacity of trophoblastic cells to secrete CST to the environment was tested, as well as the correlation between CST and apoptosis. This study provided the first evidence that CgA and CST proteins are produced by trophoblastic cell lines and that the PE environment has an impact on CST protein production. Furthermore, a strong negative correlation between CST protein level and apoptosis induction was found. Hence, both CgA and its derived peptide CST may play roles in the complex process of PE pathogenesis

Diagnostic Usefulness of Spiroergometry and Risk Factors of Long COVID in Patients with Normal Left Ventricular Ejection Fraction

The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic has brought forth various clinical manifestations and long-term complications, including a condition known as long COVID. Long COVID refers to a persistent set of symptoms that continue beyond the acute phase of the disease. This study investigated the risk factors and the utility of spiroergometry parameters for diagnosing patients with long COVID symptoms. The 146 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with normal left ventricular ejection fraction and without respiratory diseases were included and divided into two groups: the group demonstrating long COVID symptoms [n = 44] and the group without long COVID symptoms [n = 102]. The clinical examinations, laboratory test results, echocardiography, non-invasive body mass analysis, and spiroergometry were evaluated. ClinicalTrials.gov Identifier: NCT04828629. Patients with long COVID symptoms had significantly higher age [58 (vs.) 44 years; p p = 0.02)], left atrial diameter (LA) [37 vs. 35 mm; p = 0.04], left ventricular mass index (LVMI) [83 vs. 74 g/m2, p = 0.04], left diastolic filling velocity (A) [69 vs. 64 cm/s, p = 0.01], the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic mitral annular motion (E/E’) [7.35 vs. 6.05; p = 0.01], and a lower ratio of early to late diastolic transmitral flow velocity (E/A) [1.05 vs. 1.31; p = 0.01] compared to the control group. In cardiopulmonary exercise testing (CPET), long COVID patients presented lower forced vital capacity (FVC) [3.6 vs. 4.3 L; p 2max) [21 vs. 23 mL/min/kg; p = 0.04], respiratory exchange ratio (RER) [1.0 vs. 1.1; p = 0.04], forced expiratory volume in one second (FEV1) [2.90 vs. 3.25 L; p = 0.04], and a higher ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC%) [106 vs. 100%; p = 0.0002]. The laboratory results pointed out that patients with long COVID symptoms also had a lower rate of red blood cells (RBC) [4.4 vs. 4.6 × 106/uL; p = 0.01]; a higher level of glucose [92 vs. 90 mg/dL; p = 0.03]; a lower glomerular filtration rate (GFR) estimate by Modification of Diet in Renal Disease (MDRD) [88 vs. 95; p = 0.03]; and a higher level of hypersensitive cardiac Troponin T (hs-cTnT) [6.1 vs. 3.9 pg/mL; p = 0.04]. On the multivariate model, only FEV1/FVC% (OR 6.27, 95% CI: 2.64–14.86; p p < 0.001) in predicting the symptoms of long COVID. Spiroergometry parameters are useful in diagnosing long COVID and differentiating it from cardiovascular disease

Left ventricular diastolic dysfunction as predictor of unfavorable prognosis after ESUS

Objective: Identification of echocardiographic, hemodynamic and biochemical predictors of unfavorable prognosis after embolic strokes of undetermined etiology (ESUS) in patients at age &lt;65. Patients and Methods: Out of 520 ischemic stroke patients we selected 64 diagnosed with ESUS and additional 36 without stroke but with similar risk profile. All patients underwent echocardiography, non-invasive assessment of hemodynamic parameters using SphygmoCor tonometer and measurements of selected biomarkers. Follow-up time was 12 months. Results: Nine percent of patients died, and recurrent ischemic stroke occurred in 9% of patients only in the ESUS group. Atrial fibrillation (AF) occurred in 10% of patients and the ESUS group had a significantly poorer outcome of AF in the first 2 months after hospitalization. The outcome of re-hospitalization was 28% in the ESUS group and 17% in the control group. In the multivariate analysis mean early diastolic (E’) mitral annular velocity (OR 0.75, 95% CI: 0.6–0.94; p=0.01) was significantly associated with cardiovascular hospitalizations. The only independent predictor of recurrent stroke was the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic mitral annular motion (E/E’) (OR 0.75, 95% CI: 0.6–0.94; p=0.01). E/E’ was independently associated with composite endpoint (death, hospitalization and recurrent stroke) (OR 1.90, 95% CI 1.1–3.2, p=0.01). Conclusion: The indices of diastolic dysfunction are significantly associated with unfavorable prognosis after ESUS. There is a robust role for outpatient cardiac monitoring especially during the first 2 months after ESUS to detect potential AF

Białko sST2 w krótkoterminowym rokowaniu po hospitalizacji u chorych z przewlekłą skurczową niewydolnością serca

Background: The prognosis in patients with chronic heart failure (CHF) is poor. ST2 protein is a promising prognostic biomarker for CHF. ST2 belongs to the cardioprotective signalling pathway involving interleukin-33 and its concentration in the serum depends on the biomechanical stress of cardiomyocytes (biomechanical strain). Aim: To determine the prognostic value of ST2 in short term follow-up after hospitalisation among patients with CHF. Methods: The study included 167 patients (mean age 62 years, 83% men) in stable NYHA class I–III with left ventricular ejection fraction (LVEF) of ≤ 45% (average 29.65%, ranges 13–45%). We analysed 58 variables including: demographics, co-morbidities, resting ECG, echocardiographic and coronary arteriography data, basic laboratory tests including N-terminal prohormone B-type natriuretic peptide (NT-proBNP), serum concentration of soluble form of ST2 (sST2) using quantitative ELISA test ST2 Kit (Medical and Biological Laboratories; Japan) and adverse cardiovascular events during a one year observation. In the study, the primary endpoint (death) and the composite endpoint (hospitalisation for HF worsening, worsening in NYHA functional class, the need to increase the dose of diuretics, and/or death in a one year observation) were determined. Results: Patients who died (n = 24; 14.55%) were in more advanced NYHA class, had prolonged QRS duration, higher levels of sST2, NT-proBNP, and lower estimated glomerular filtration rate. From multivariate analysis, the independent variable for the primary endpoint was NT-proBNP (OR = 1.00012; 95% CI 1.00002–1.00022; p = 0.018). 93 (56%) patients reached the composite endpoint. Multivariate analysis revealed that fasting glucose (OR = 1.343; 95% CI 1.041–1.732; p = 0.023) and sST2 (OR = 3.593; 95% CI 1.427–9.05; p = 0.007) independently enhanced the risk of composite endpoint occurrence in a one year observation. Conclusions: In patients with CHF with LVEF ≤ 45%, the prognostic value of sST2 protein in a short-term observation of one year was confirmed. sST2 protein was an independent variable for the composite endpoint, which consisted of worsening NYHA functional class, hospitalisation for worsening of HF, the need to increase the dose of diuretics, and/or death. Wstęp: Rokowanie u pacjentów z przewlekłą niewydolnością serca (CHF) jest niepomyślne. Białko sST2 należące razem z interleukiną 33 do szlaku kardioprotekcyjnego jest obiecującym markerem w CHF. Stężenie białka sST2 w surowicy wzrasta w przypadku mechanicznego odkształcenia kardiomiocytów. Cel: Celem pracy było określenie wartości prognostycznej sST2 w krótkoterminowej obserwacji po hospitalizacji wśród pacjentów z CHF. Metody: Do badania włączono 167 osób (średnia wieku 62 lata, 83% mężczyzn) w I–III klasie wg NYHA, z frakcją wyrzutową lewej komory ≤ 45% (średnio 30%, 13–45%). Przeanalizowano 58 zmiennych, m.in.: dane demograficzne, elektrokardiograficzne, echokardiograficzne, choroby współistniejące, wyniki koronarografii, podstawowe badania laboratoryjne, w tym N-końcowy propeptyd natriuretyczny typu B (NT-proBNP), stężenie sST2 (ilościowy test ELISA ST2 Kit), wystąpienie niekorzystnych zdarzeń sercowo-naczyniowych w ciągu rocznej obserwacji. W badaniu wyznaczono pierwszorzędowy punkt końcowy (zgon w obserwacji rocznej) oraz złożony punkt końcowy (łącznie hospitalizacja z powodu pogorszenia HF, nasilenie klasy NYHA, konieczność zwiększenia dawki leków moczopędnych lub zgon w obserwacji rocznej). Wyniki: U chorych, którzy zmarli (n = 24; 14,55%), występowała bardziej zaawansowana klasa NYHA, wydłużony czas trwania zespołu QRS, wyższe stężenie sST2, NT-proBNP i niższa wartość estymowanego wskaźnika filtracji kłębuszkowej. Z analizy wielowymiarowej jedyną zmienną niezależną dla pierwszorzędowego punktu końcowego było NT-proBNP (OR = 1,00012; 95% CI 1,00002–1,00022; p = 0,018). Złożony punkt końcowy wystąpił u 93 (56%) pacjentów. Analiza wieloczynnikowa wykazała, że stężenie glukozy (OR = 1,343; 95% CI 1,041–1,732; p = 0,023) i sST2 (OR = 3,593; 95% CI 1,427–9,05; p = 0,007) są niezależnymi czynnikami związanymi z ryzykiem wystąpienia złożonego punktu końcowego w rocznej obserwacji. Wnioski: U chorych z CHF z frakcją wyrzutową lewej komory ≤ 45% potwierdzono wartość prognostyczną białka sST2 w obserwacji krótkoterminowej. Białko sST2 było niezależną zmienną dla złożonego punktu końcowego, na który składały się: pogorszenie w zakresie klasy wg NYHA, hospitalizacja z powodu pogorszenia HF, konieczność zwiększenia dawki leków moczopędnych i zgon w obserwacji rocznej.