Randomised, double-blind, placebo-controlled study evaluating the effect of allopurinol on the risk of cardiovascular events in patients with high and very high cardiovascular risk, including the presence of long-COVID-19 syndrome: the ALL-VASCOR study protocol.

INTRODUCTION: Numerous studies, but not all, have suggested a positive effect of allopurinol on the cardiovascular system. The randomised, double-blind, placebo-controlled study evaluating the effect of allopurinol on the risk of cardiovascular events in patients with high and very high cardiovascular risk, including the presence of long-COVID-19 syndrome (ALL-VASCOR) study aims to evaluate the efficacy of allopurinol therapy for improving cardiovascular outcomes in patients at high and very high cardiovascular risk excluding ischaemic heart disease. This is particularly important due to the high cost of cardiovascular disease treatment and its status as one of the leading causes of mortality. METHODS AND ANALYSIS: The ALL-VASCOR study is a randomised, double-blind, placebo-controlled, multicentre trial that examines the effect of allopurinol therapy (200-500 mg of allopurinol daily) versus an equivalent dose of placebo on the risk of cardiovascular events in 1116 patients aged 40-70 with serum uric acid levels above 5 mg/dL at high and very high risk of cardiovascular disease. The ALL-VASCOR study will also assess the occurrence of long-COVID-19 syndrome. The study will measure primary and secondary as well as additional endpoints and the planned intervention will end on 31 July 2028 unless advised otherwise by the Safe Monitoring Board or other applicable authorities. Participant recruitment is planned to begin in March 2024 in Poland. ETHICS AND DISSEMINATION: The study was ethically approved by the Bioethics Committee of Poznan University of Medical Sciences (No 03/23, 12 January 2023). The results are expected after 2028 and will be disseminated in peer-reviewed journals and at international conferences. PROTOCOL VERSION NUMBER: 01-15 November 2022. TRIAL REGISTRATION NUMBER: EudraCT: 2022-003573-32, 27 October 2022, ClinicalTrials: NCT05943821, 13 July 2023.

Assessment of COVID-19 risk factors of early and long-term mortality with prediction models of clinical and laboratory variables.

BACKGROUND: Coronavirus disease (COVID-19) may lead to serious complications and increased mortality. The outcomes of patients who survive the early disease period are burdened with persistent long-term symptoms and increased long-term morbidity and mortality. The aim of our study was to determine which baseline parameters may provide the best prediction of early and long-term outcomes. METHODS: The study group comprised 141 patients hospitalized for COVID-19. Demographic data, clinical data and laboratory parameters were collected. The main study endpoints were defined as in-hospital mortality and 1-year mortality. The associations between the baseline data and the study endpoints were evaluated. Prediction models were created. RESULTS: The in-hospital mortality rate was 20.5% (n = 29). Compared with survivors, nonsurvivors were significantly older (p = 0.001) and presented comorbidities, including diabetes (0.027) and atrial fibrillation (p = 0.006). Assessment of baseline laboratory markers and time to early death revealed negative correlations between time to early death and higher IL-6 levels (p = 0.032; Spearman rho - 0.398) and lower lymphocyte counts (p = 0.018; Pearson r -0.438). The one-year mortality rate was 35.5% (n = 50). The 1-year nonsurvivor subgroup was older (p < 0.001) and had more patients with arterial hypertension (p = 0.009), diabetes (p = 0.023), atrial fibrillation (p = 0.046) and active malignancy (p = 0.024) than did the survivor subgroup. The model composed of diabetes and atrial fibrillation and IL-6 with lymphocyte count revealed the highest value for 1-year mortality risk prediction. CONCLUSIONS: Diabetes and atrial fibrillation, as clinical factors, and LDH, IL-6 and lymphocyte count, as laboratory determinants, are the best predictors of COVID-19 mortality risk.

Obesity in Hypertensive Patients Is Characterized by a Dawn Phenomenon in Systolic Blood Pressure Values and Variability.

One of the causes of hypertension is excess weight gain, which can also affect the course of this disease. Both the diagnosis and management of hypertension commonly use ambulatory blood pressure monitoring; the results of which correlate more strongly with cardiovascular diseases and cardiovascular death than office blood pressure monitoring. We evaluated blood pressure values and their variability from hour to hour to see if and when they differed between hypertensive patients with and without obesity. The study included 1345 patients who underwent 24 h ambulatory blood pressure monitoring and then were divided into groups according to body mass index and waist circumference. The obtained data were analyzed according to the subjects' wake-up time, and short-term blood pressure variability parameters were calculated as the mean of the absolute values of the differences between consecutive measurements. The systolic blood pressure in obese subjects was significantly higher between 1 and 5 h before waking than in normal-weighted individuals. In turn, the variability in systolic and diastolic blood pressure was higher with increasing body mass index. The difference in systolic blood pressure values and blood pressure variability was most prominent in the last 5 h of sleep in obese patients.

Target Blood Pressure Values in Ambulatory Blood Pressure Monitoring.

INTRODUCTION: 2018 ESC/ESH guidelines have recommended 24-h ambulatory blood pressure monitoring to assess hypotensive therapy in many circumstances. Recommended target blood pressure in office blood pressure measurements is between 120/70 and 130/80 mmHg. Such targets for 24-h ambulatory blood pressure monitoring lacks. AIM: We aimed to define target values of blood pressure in 24-h ambulatory blood pressure monitoring in hypertensive patients. METHODS: Office blood pressure measurements and 24-h ambulatory blood pressure monitoring data were collected from 1313 hypertensive patients and sorted following increasing systolic (SBP)/diastolic (DBP) blood pressure in office blood pressure measurements. The corresponding 24-h ambulatory blood pressure monitoring to office blood pressure measurements values were calculated. RESULTS: Values 130/80 mmHg in office blood pressure measurements correspond in 24-h ambulatory blood pressure monitoring: night-time SBP/DBP mean: 113.74/66.95 mmHg; daytime SBP/DBP mean: 135.02/81.78 mmHg and 24-h SBP/DBP mean: 130.24/78.73 mmHg. Values 120/70 mmHg in office blood pressure measurements correspond in 24-h ambulatory blood pressure monitoring: night-time SBP/DBP mean: 109.50/63.43 mmHg; daytime SBP/DBP mean: 131.01/78.47 mmHg and 24-h SBP/DBP mean: 126.36/75.31 mmHg. CONCLUSIONS: The proposed blood pressure target values in 24-h ambulatory blood pressure monitoring complement the therapeutic target indicated in the ESC/ESH recommendations and improves 24-h ambulatory blood pressure monitoring usefulness in clinical practice.

Management of High-Risk Atherosclerotic Patients by Statins May Be Supported by Logistic Model of Intima-Media Thickening.

While the use of statins in treating patients with atherosclerosis is an undisputed success, the questions regarding an optimal starting time for treatment and its strength remain open. We proposed in our earlier paper published in Int. J. Mol. Sci. (2019, 20) that the growth of intima-media thickness of the carotid artery follows an S-shape (i.e., logistic) curve. In our subsequent paper in PLoS ONE (2020, 15), we incorporated this feature into a logistic control-theoretic model of atherosclerosis progression and showed that some combinations of patient age and intima-media thickness are better suited than others to start treatment. In this study, we perform a new and comprehensive calibration of our logistic model using a recent clinical database. This allows us to propose a procedure for inferring an optimal age to start statin treatment for a particular group of patients. We argue that a decrease in the slope of the IMT logistic growth curve, induced by statin treatment, is most efficient where the curve is at its steepest, whereby the efficiency means lowering the future IMT levels. Using the procedure on an aggregate group of severely sick men, 38 years of age is observed to correlate with the steepest point of the logistic curve, and, thus, it is the preferred time to start statin treatment. We believe that detecting the logistic curve's steepest fragment and commencing statin administration on that fragment are courses of action that agree with clinician intuition and may support decision-making processes.

Insulin Resistance in Adults with Type 1 Diabetes is Associated with Lower Vitamin D Serum Concentration.

AIM: Type 1 diabetes mellitus (T1DM) is a disease characterized by an absolute deficiency of endogenous insulin secretion. Insulin resistance (IR) may develop among patients with T1DM. Vitamin D deficiency was reported to be a risk factor in the development of IR. The aim of the study was to assess the relationship between serum concentrations of 25-hydroxyvitamin D (25(OH)D) and IR among patients with T1DM. METHODS: The test group consisted of 110 adult patients [males=65 (59%)] with T1DM. Participants were recruited in Poland between 1st October and 30th April in 2015/2016 and 2016/2017. VD serum level was assessed by ELISA array. IR was assessed by estimated Glucose Disposal Rate (eGDR). RESULTS: In the study group 21 (19%) patients were recognized as IR according to eGDR cut-offs (<7.5 mg/kg/min), 52 (47.3%) patients had VD deficiency (25(OH)D<20 ng/ml), 16 (14.5%) patients had 25(OH)D<10 ng/ml. Only 6 (5%) participants reported VD supplementation. Patients with IR, according to eGDR cut-off revealed significantly lower 25(OH)D serum level 15.7 (9.2-28.4) vs. 22.1 (13.0-38.4) ng/ml; p=0.04 as compared to patients without IR. R Spearman analysis found a positive relationship between VD and eGDR (Rs=0.27; p<0.01). Logistic regression analysis revealed significant relationship between the presence of IR and VD serum level/presence of 25(OH)D serum level below 10 ng/ml, both models adjusted to sex, age, BMI, LDL and triglycerides, accordingly (OR=0.95, CI: 0.90-0.99; p=0.04) and (OR=4.19, CI: 1.04-16.93; p=0.04). CONCLUSION: The serum concentration of Vitamin D is negatively associated with insulin resistance in patients with T1DM and may have clinical implications.

Human Epididymis Protein 4 (HE4) Reference Limits in Polish Population of Healthy Women, Pregnant Women, and Women with Benign Ovarian Tumors.

OBJECTIVES: Defining precisely the normal range of HE4 protein is crucial for the proper interpretation of tumor marker results and for a more efficient diagnosis of ovarian malignancy. The aim of our study was to evaluate a reference limit of HE4 protein in a population to promote and facilitate the common use of HE4 protein assays. We also tried to identify potential association of HE4 levels with other conditions such as smoking, age, BMI, and creatinine levels. METHODS: Blood samples were collected from 617 patients divided into three groups: healthy, pregnant, and with benign ovarian tumors. Serum HE4 concentrations were measured following a standard procedure. HE4 reference ranges for each group and association of HE4 levels with BMI, creatinine, and smoking were investigated. RESULTS: HE4 reference limit for healthy patients equals 85 pmol/l, which becomes 73 pmol/l and 93 pmol/l for pre and postmenopausal subgroups, respectively. There is a statistically significant correlation between HE4 serum level and smoking (p = 0.000001) and there is no correlation with creatinine. But if we take into account age and smoking, in multivariate analysis, there is a correlation. For pregnant, the upper limit values of normal HE4 levels are 55 pmol/l (median = 40 pmol/l), 80 pmol/l (median = 43 pmol/l), and 106 pmol/l (median = 53 pmol/l) for the first, second, and third trimesters, respectively. CONCLUSIONS: HE4 protein value strongly depends on the patient's age and smoking. The serum concentration of HE4 marker increases with the duration of pregnancy. Understanding the normal range of HE4 protein enables the correct interpretation of marker measurements. This may result in an earlier and more effective diagnosis of ovarian cancer.

The concentration of tumor necrosis factor in the blood serum and in the urine and selected early organ damages in patients with primary systemic arterial hypertension.

Arterial hypertension is considered to be an inflammatory condition with low intensity. Therefore, an elevated concentration of inflammatory cytokines can be expected in patients with systemic arterial hypertension, including tumor necrosis factor (TNF).The study included a group of 96 persons aged 18 to 65 years: 76 patients with primary arterial hypertension and 20 healthy individuals (control group). Blood pressure was measured in all individuals using the office and ambulatory blood pressure monitoring (ABPM) measurement, blood was collected for laboratory tests [tumor necrosis factor (TNF), tumor necrosis factor receptor 1 (TNFR1)], and 24-hour urine collection was performed in which albuminuria and TNF concentration were assessed. Moreover, assessment of the intima-media thickness (IMT) in ultrasonography and left ventricular mass index (LVMI) in echocardiography were carried out.Statistically elevated TNF concentration in the blood serum (P = .0001) and in the 24-hour urine collection (P = .0087) was determined in patients with hypertension in comparison with the control group. The TNF and TNFR1 concentration in the serum and TNF in the 24-hour urine in the group of patients with arterial hypertension and organ damages and without such complications did not differ statistically significantly.We observed a positive and statistically significant correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension (r = 0.369, P < .05)Patients with arterial hypertension are characterized by higher TNF concentrations in blood serum and higher TNF excretion in 24-hour urine than healthy persons.TNF and TNFR1 concentration in blood serum and TNF excretion in 24-hour urine in patients with early organ damages due to arterial hypertension do not differ significantly from those parameters in patients with arterial hypertension without organ complications.There is a positive correlation between TNFR1 concentration in the serum and TNF urine excretion in patients with hypertension.

Is cathelicidin a novel marker of diabetic microangiopathy in patients with type 1 diabetes?

AIM: The aim was to evaluate the relationship between higher serum cathelicidin levels with the occurrence of chronic microangiopathic complications in patients with diabetes mellitus type 1 (DM1). METHODS: The study group consisted of 62 patients with DM1 (35 men), aged 30 (24-38) years and with duration of DM1 12 (9-17) years. Patients were divided into two groups depending on the level of cathelicidin, with cut-off point 24.5ng/ml (median value for the whole group) and according to the presence or absence of any microangiopathy. RESULTS: The group with higher serum level of cathelicidin (n=31) in comparison with patients with lower levels (n=31) had higher serum level of total cholesterol [5.0(4.5-5.6) vs 4.5(3.9-5.0) mmol/l; p=0.04], HDL cholesterol [1.9(1.5-2.1) vs 1.4(1.3-1.8) mmol/l; p=0.009], LDL cholesterol [2.6(2.2-3.1) vs 2.3(1.9-2.8) mmol/l; p=0.03] and higher TSH value [1.8(1.5-2.6) vs 1.4(0.9-2.1) mIU/L; p=0.01]. Moreover, higher serum levels of cathelicidin were in women than men (58% vs 29%, p=0.02) and in patients with vs without microangiopathy (45% vs 19%, p=0.03). In the multiple regression model higher serum level of cathelicidin was related to the presence of microangiopathy, independently from sex, waist to hip ratio, serum total cholesterol level and TSH. CONCLUSIONS: Patients with type 1 diabetes and presence of microangiopathy characterize higher level of serum cathelicidin. This observation may have important clinical implication and needs further investigations.