Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke.

Acute ischemic stroke is a major cause of morbidity and mortality worldwide, and genetic factors play a role in the risk of stroke. Single nucleotide polymorphisms (SNPs) in the VKORC1, CYP4F2, and GGCX genes have been linked to clinical outcomes, such as bleeding and cardiovascular diseases. This study aimed to investigate the association between specific polymorphisms in these genes and the risk of developing the first episode of acute ischemic stroke in patients without a known embolic source. This retrospective, cross-sectional, observational, analytical, case-control study included adult patients diagnosed with acute ischemic stroke. The SNPs in VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 genes were genotyped and analyzed together with the demographic and clinical factors of the 2 groups of patients. The presence of SNPs in VKORC1 or CYP4F2 genes significantly increased the risk of ischemic stroke in the context of smoking, arterial hypertension, and carotid plaque burden. The multivariate logistic model revealed that smoking (odds ratio [OR] = 3.920; P < .001), the presence of carotid plaques (OR = 2.661; P < .001) and low-density lipoprotein cholesterol values >77 mg/dL (OR = 2.574; P < .001) were independently associated with stroke. Polymorphisms in the VKORC1 and CYP4F2 genes may increase the risk of ischemic stroke in patients without a determined embolic source. Smoking, the presence of carotid plaques, and high low-density lipoprotein cholesterol levels were reconfirmed as important factors associated with ischemic stroke.

Basic cardiovascular risk assessment in naïve patients with colon cancer.

Cardiovascular assessment of oncological patients suggests that cancer can lead to subclinical damage of the heart. The aim of the present study was to analyze the value of baseline cardiovascular biomarkers in patients with newly diagnosed colon cancer prior to treatment. Additionally, another aim was to establish baseline cut-off alert values for this low-intensity neoplastic damage. A total of 51 patients with newly diagnosed colon cancer, without history of cardiac disease, were enrolled in a prospective, cross-sectional study. All patients underwent clinical, biochemical and basic echocardiographic evaluation before starting treatment. Patients were assessed for myocardial damage using high-sensitivity troponin T (hs-TnT), creatine kinase-MB (CK-MB) and N-terminal-pro B-type natriuretic peptide (NT-proBNP). A group of 28 healthy controls was included for comparison. Cardiac ultrasound revealed similar left ventricular (LV) ejection fraction but enlarged LV chambers compared with the control group (LV at end systole, 29.50 vs. 26.00 mm; LV at end diastole, 44.50 vs. 38.00 mm; P<0.001 in both cases). The levels of cardiovascular biomarkers of myocardial damage were higher in the patients than in the control group (CK-MB, 17.00 vs. 11.00 IU/l, P<0.001; hs-TnT, 8.20 vs. 3.00 ng/l, P<0.001; NT-proBNP, 155.40 vs. 48.50 pg/ml, P=0.001). In multivariate analysis, CK-MB and hs-TnT retained statistical significance (P=0.004 and P=0.045, respectively). Moreover, it was demonstrated that new cut-offs for hs-TnT (8.00 ng/l) and NT-proBNP (220.00 pg/ml) can identify cardiac damage in patients ≥65 years old. Thus, the present study confirmed the hypothesis that a basic cardiovascular assessment of treatment-naïve patients with colon cancer can identify important pre-treatment myocardial impact. Adapted cut-off values should be set for cardiovascular biomarkers in the cancer population, different from those currently accepted for acute coronary syndromes or heart failure.

Liver Injury and Elevated FIB-4 Define a High-Risk Group in Patients with COVID-19.

Liver involvement in Coronavirus Disease 2019 (COVID-19) has been widely documented. However, data regarding liver-related prognosis are scarce and heterogeneous. The current study aims to evaluate the role of abnormal liver tests and incidental elevations of non-invasive fibrosis estimators on the prognosis of hospitalized COVID-19 patients. We conducted a retrospective cohort study to investigate the impact of elevated liver tests, non-invasive fibrosis estimators (the Fibrosis-4 (FIB-4), Forns, APRI scores, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio), and the presence of computed tomography (CT)-documented liver steatosis on mortality in patients with moderate and severe COVID-19, with no prior liver disease history. A total of 370 consecutive patients were included, of which 289 patients (72.9%) had abnormal liver biochemistry on admission. Non-survivors had significantly higher FIB-4, Forns, APRI scores, and a higher AST/ALT ratio. On multivariate analysis, severe FIB-4 (exceeding 3.25) and elevated AST were independently associated with mortality. Severe FIB-4 had an area under the receiver operating characteristic (AUROC) of 0.73 for predicting survival. The presence of steatosis was not associated with a worse outcome. Patients with abnormal liver biochemistry on arrival might be susceptible to a worse disease outcome. An FIB-4 score above the threshold of 3.25, suggestive of the presence of fibrosis, is associated with higher mortality in hospitalized COVID-19 patients.

CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation.

INTRODUCTION: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. PATIENTS AND METHODS: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. RESULTS: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. CONCLUSIONS: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.

Isolated very low QRS voltage predicts response to tilt-table testing in patients with neurally mediated syncope.

BACKGROUND: A number of patients with neurally mediated syncope (NMS) have isolated QRS complexes of very low voltage (≤0.3 mV) in the frontal plane leads on the 12-lead electrocardiogram (ECG). HYPOTHESIS: The aim of this study was to assess the importance of QRS voltage in predicting response to tilt-table testing (TTT) in patients with suspected NMS. METHODS: We included 216 patients (age: 49 ± 20 years, 103 men) with suspected NMS who had either a positive or negative response to TTT (n = 91 TTT+, and n = 125 TTT-). The QRS voltage was measured in mV on 12-lead ECGs performed within 3 days of the TTT. The lowest QRS voltage (QRSmin), as well as the voltage in each of the 12 leads was also determined. RESULTS: Very low voltage (QRSmin  ≤ 0.3 mV) in the frontal leads was significantly more prevalent in the TTT+ group than in the TTT- group (74 vs 22%, respectively; P  < .001). Patients in the TTT+ group had significantly lower QRSmin when compared to patients in the TTT- group. QRSmin predicted a positive tilt-table test in a multivariate model that also included patient gender, height, history of presyncope, QRS duration, and left ventricular end-diastolic diameter indexed to height. ROC analysis showed that QRSmin of ≥0.3 mV discriminated between TTT+ and TTT- patients with a sensitivity of 78% and specificity of 68%. CONCLUSION: Isolated very low QRS voltage in the frontal leads predicts a positive response to TTT in patients with suspected NMS.

VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding.

BACKGROUND AND AIMS: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists. METHODS: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism. RESULTS: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001). CONCLUSION: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB.

VKORC1 -1639 G>A Polymorphism in Romanian Patients With Deep Vein Thrombosis.

AIM: The purpose of the research was to study the influence of several genetic factors, especially the -1693 G>A polymorphism of the VKORC1 gene, on the risk of acute unprovoked lower extremity deep vein thrombosis (DVT). MATERIALS AND METHODS: The study included 127 patients (median age 63 [53.2; 72] years; 61 [48%] women and 66 [52%] men) who were diagnosed with acute lower extremity DVT and 114 controls (median age 62 [53; 73] years; 64 [56.1%] women and 50 [43.9%] men) without DVT. We recorded data regarding the history of DVT and the presence of varicose veins. We determined the genotypes for factor V Leiden (FVL) mutation, prothrombin G20210A mutation, VKORC1 -1639 G>A mutation, and PAI-1 -675 4G/5G polymorphism. RESULTS AND CONCLUSION: Varicose veins were found in 67 (52.8%) patients and 29 (25.4%) controls (P < .001). FVL was present in 29 (22.8%) patients and 10 (8.8%) controls (P = .005). The VKORC1 (-1693 G>A) GG genotype was found in 42 (33.1%) patients and 41 (36%) controls, the GA genotype in 71 (55.9%) patients and 47 (41.2%) controls, and AA genotype in 14 (11%) patients and 26 (22.8%) controls (P = .020). Multivariate analysis showed that the presence of varicose veins, FVL, and VKORC1 -1639 G>A was independently associated with the risk of DVT. The VKORC1 (-1693 G>A) AA genotype was associated with fewer cases of DVT (odds ratio = 0.435; 95% confidence interval 0.205-0.991; P = .031).

PAI-1 4G/5G and MTHFR C677T polymorphisms increased the accuracy of two prediction scores for the risk of acute lower extremity deep vein thrombosis.

AIM: This study investigates the accuracy of two scores in predicting the risk of acute lower extremity deep vein thrombosis. PATIENTS AND METHODS: The study included 170 patients [85 (50%) women and 85 (50%) men] who were diagnosed with acute lower extremity deep vein thrombosis (DVT) with duplex ultrasonography. Median age was 62 (52.75; 72) years. The control group consisted of 166 subjects [96 (57.8%) women and 70 (42.2%) men], without DVT, matched for age (± one year) to those in the group with DVT. The patients and controls were selected from those admitted to the internal medicine, cardiology and geriatrics wards within the Municipal Hospital of Cluj-Napoca, Romania, between October 2009 and June 2011. Clinical, demographic and lab data were recorded for each patient. For each patient we calculated the prior risk of DVT using two prediction scores: Caprini and Padua. RESULTS: According to the Padua score only 93 (54.7%) patients with DVT had been at high risk of developing DVT, while 48 (28.9%) of controls were at high risk of developing DVT. When Padua score included PAI-1 4G/5G and MTHFR C677T polymorphisms, the sensitivity increased at 71.7%. Using the Caprini score, we determined that 147 (86.4%) patients with DVT had been at high risk of developing DVT, while 103 (62%) controls were at high risk of developing DVT. A Caprini score higher than 5 was the strongest predictor of acute lower extremity DVT risk. CONCLUSIONS: The Caprini prediction score was more sensitive than the Padua score in assessing the high risk of DVT in medical patients. PAI-1 4G/5G and MTHFR C677T polymorphisms increased the sensitivity of Padua score.

An acenocoumarol dose algorithm based on a South-Eastern European population.

AIM: To develop and validate an algorithm for the prediction of therapeutic dose of acenocoumarol in Romanian patients. METHODS: The inclusion criteria for entry to the study was age ≥ 18 years and starting acenocoumarol treatment for at least one of the following clinical indications: acute deep vein thrombosis of the lower limbs, persistent or permanent atrial fibrillation, and/or the presence of valvular prostheses requiring prolonged oral anticoagulant therapy. The patients were followed up for 3 months. Patients admitted to the internal medicine, cardiology, and geriatrics wards of the Municipal Clinical Hospital, Cluj-Napoca and "Niculae Stancioiu" Heart Institute between October 2009 and June 2011 who fulfilled the inclusion criteria were included in the study. Clinical and demographic data that could influence the acenocoumarol stable dose were recorded for each patient. Genetic analysis included the genotyping the CYP2C9*2 and *3, and the VKORC1 -1693 G > A polymorphisms. The patients were randomly divided into two groups: (1) the main group on which the development of the clinical and genetic algorithms for acenocoumarol dose prediction was based; (2) the validation group. RESULTS: The study included 301 patients, of whom 155 were women (51.5 %) and 146 were men (48.5 %). The median age of the patient cohort was 66 (women, 57; men, 73) years. After randomization the main group comprised 200 patients (66.4 %) and the validation group 101 patients (33.6 %). Age and body mass index explained 18.8 % (R (2)) of the variability in acenocoumarol weekly dose in patients in the main group. When the genetic data were added to the algorithm, the CYP2C9*2 and *3 polymorphisms and the VKORC1 -1693 G > A polymorphism accounted for 4.7 and 19. 6 % of acenocoumarol dose variability, respectively. For the main group, we calculated a mean absolute error of 5 mg/week (0.71 mg/day). In the validation group, clinical parameters explained 22.2 % of the weekly acenocoumarol dose variability. Genetic polymorphisms increased the R(2) coefficient to 32.8 %. CONCLUSION: We have developed and validated an accurate algorithm for prediction of the stable therapeutic dose of acenocoumarol in a Romania population.

The impact of the CYP2C9 and VKORC1 polymorphisms on acenocoumarol dose requirements in a Romanian population.

AIM: To investigate the genotype-phenotype correlation in Romanian patients treated with acenocoumarol. MATERIAL AND METHODS: We studied 301 consecutive patients who required treatment with acenocoumarol, admitted within the Municipal Hospital of Cluj-Napoca and the Heart Institute "Niculae Stanciou" in Cluj-Napoca over a 3-year period. For each patient we recorded clinical parameters which could interfere with the achievement of stable therapeutic international normalized ratio (INR). We performed genetic analysis which consisted of genotyping the CYP2C9 gene and the VKORC1 gene. Patients were divided in three groups according to the acenocoumarol dose needed to reach a stable INR: the low dose group (≤7mg/week), the medium dose group (>7mg and <28mg/week) and the high acenocoumarol dose group (>28mg/week). RESULTS: We found that patients' age was significantly different between groups (p<0.001). No differences existed between groups regarding the pathologies which required anticoagulation therapy or the concomitant treatment. The following parameters increased the odds of receiving a low dose of acenocoumarol: patient's age over 65years (OR, 3.2; p=0.01; 95%CI: 1.24-8.25), the presence of the CYP2C9*3 allele (OR, 3.4; p=0.006; 95%CI: 1.41-8.34), and the GA or AA genotype of c.-1639G>A polymorphism of VKORC1 (OR, 6.5; p=0.01; 95%CI: 1.38-30.5; respectively OR, 11.6; p=0.003; 95%CI: 2.26-59.58). A high acenocoumarol dose was less likely to be administered to an elderly patient (OR, 0.24; p=0.001; 95%CI: 0.1-0.56) or to a patient with the GA or AA genotype (OR, 0.2; p<0.001; 95CI%: 0.09-0.45; respectively OR, 0.05; p=0.006; 95%CI: 0.007-0.43). CONCLUSION: The stable therapeutic dose of acenocoumarol is dependent of patient's age, the presence of the CYP2C9*3 allele and the c.-1639G>A polymorphism of VKORC1.

Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe.

The CYP2C9 enzyme metabolizes a wide range of relevant drugs, among which are oral anticoagulants. VKORC1 is the pharmacodynamic target of the oral anticoagulants. The genetic polymorphisms CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A are the major determinants of the inter-individual variability in the dosage requirements of oral anticoagulants. This study provides a first evaluation of these 3 polymorphisms in a Romanian population. A total of 332 Romanian individuals were genotyped for the CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms using the PCR-RFLP technique. Sixty-two individuals (18.7%) were heterozygous for CYP2C9*2, whereas 47 individuals (14.1%) were heterozygous for CYP2C9*3. Fourteen individuals (4.2%) had a CYP2C9*2 homozygous, CYP2C9*3 homozygous or CYP2C9*2/CYP2C9*3 compound heterozygous genotype. These individuals are predicted to have the lowest CYP2C9 enzymatic activity. The allele frequencies of the CYP2C9*2 and CYP2C9*3 polymorphisms were 11.3% and 9.3% respectively. For the VKORC1 -1639 G>A polymorphism, there were 170 heterozygotes (51.2%) and 55 (16.6%) homozygotes for the A allele. The frequency of the A allele was 42.2%. Overall, the distribution of the CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms observed in our cohort is in accordance with other Caucasian populations. A large number of Romanians are expected to harbour at least one CYP2C9 variant allele and/or one VKORC1 -1639 G>A allele. This frequency has major implications in the pharmacogenomics of oral anticoagulants in Romanians.

Carotid ultrasound.

Carotid duplex ultrasonography is a noninvasive technique for hemodynamically significant stenosis detection and cardiovascular risk estimation. Anatomic information of carotid arteries is provided by B-mode scanning. Hemodynamic features are displayed color-flow and pulsed Doppler imaging. Examination technique, normal carotid anatomy and flow pattern, and potential limitations are presented.

Concomitant acute deep venous thrombosis and superficial thrombophlebitis of the lower limbs.

INTRODUCTION: Some patients may have deep venous thrombosis (DVT) and superficial thrombophlebitis (ST) of the lower limbs at the same time. AIMS: To analyze the frequency of risk factors for thrombosis (RF), other than thrombophilias, in patients with concomitant DVT and ST. PATIENTS AND METHODS: Clinical examination, plasma D-dimers and duplex ultrasonography were performed in 88 consecutive patients (mean age 64.9 +/-13.9 years) admitted in Medical Clinic in 2007. Patients with DVT were divided into two groups: A (with ST - 30 subjects, 34.1%) and B (without ST - 58 patients, 65.9%). RESULTS: Conditions known as RF were the following (Group A versus B): varicose veins (17 vs 21 patients, p=0.11), obesity (12 vs 19, p=0.66), previous venous thromboembolism (8 vs 16, p=0.87), malignancy (4 vs 10, p=0.44), chronic obstructive lung disease (4 vs 7, p=0.56), sepsis (2 vs 3, p=0.56), stroke and chemotherapy (1 vs 2, p=0.73), bed rest more than three days (1 vs 7, p=0.17), major surgery (1 vs 1, p=0.57), family history of DVT (1 vs 0, p=0.57), immobilizing plaster cast (0 vs 1, p=0.57). CONCLUSION: One third of patients with DVT had ST. None of those conditions considered as RF for DVT correlated with DVT-ST association.

Chronic thrombotic scarring in patients with acute deep venous thrombosis of the lower limbs.

UNLABELLED: Some patients with acute deep venous thrombosis of the lower limbs may present risk factors for recurrent disease. AIMS: To analyze the most important conditions related to recurrent deep venous thrombosis of the lower limbs, other than thrombophilias. PATIENTS AND METHODS: We examined 88 consecutive patients (47 males-53.41%, average age 64.9 +/-13.9 years) admitted to a Medical Clinic in 2007. Duplex ultrasonography was performed to assess acute deep venous thrombosis and post-thrombotic syndrome. Anamnesis and physical examination were used to detect risk factors for recurrent disease. The 28 subjects with acute deep venous thrombosis and post-thrombotic syndrome were included in group A (31.82%). Group B comprised 60 patients (68.18%) with acute deep venous thrombosis without post-thrombotic syndrome. RESULTS: Risk factors for recurrent disease in groups A and B were the following: personal history of deep venous thrombosis of the lower limbs (17 subjects versus 7, p<0.0001), varicose veins (14 vs 24, p=0.51), obesity (13 vs 18, p=0.21), malignancy (6 vs 8, p=0.25), chronic obstructive lung disease (5 vs 6, p=0.24), prolonged immobilization (1 vs 7, p=0.21), major surgery (1 vs 1, p=0.54), stroke (0 vs 3, p=0.62), family history of deep venous thrombosis, immobilizing plaster cast, and congestive heart failure (0 vs 1, p=0.54). Location of thrombi in patients in groups A and B was as follows: 18 patients in group A vs 25 subjects in group B on the left side and 13 patients in group A vs 20 patients in group B on the right side (p=0.02). CONCLUSION: Post-thrombotic syndrome correlated with personal history of deep venous thrombosis and previous deep venous thrombosis located in the left lower limb.

Abdominal aortic aneurysm--online methods of patient education.

The authors present some of the most important online methods of patient education on diagnosis and treatment of abdominal aortic aneurysm (easy-to-read articles, medical journal with patient pages, patient guides, brochures, illustrations, animations, and frequently asked questions).

Deep vein thrombosis--online methods of patient education.

The authors present some of the most important online patient information methods on all aspects of deep vein thrombosis of the lower limbs and, in particular, the diagnosis using Doppler ultrasound (easy-to-understand articles, brochures, guides, patient page, frequently asked questions, illustrations, forums, blogs).

The ankle-brachial index-a classification of the patient education websites.

The authors present a classification of the most important types of online resources regarding the ankle-brachial index, for patients with peripheral arterial disease and other interested people (websites of national institutes, universities of medicine, regional hospitals, medical societies and associations etc).