The study population consisted of 562 patients aged 30-70 years, both women and men consecutively admitted to the hypertension outpatient department between September 2017 and March 2018 with: diagnosed AHU defined as a serum UA ≥ 6 mg/dl (360 μmol/l) [15, 17] and with essential hypertension grade 1 or 2 (BP ≥140/90 and <180/110 mmHg) in accordance with the 2018 ESH/ESC guidelines  with previously confirmed adequate BP control on antihypertensive treatment (below 140/90 mmHg in office measurements). Patients, who received allopurinol (100-300 mg/day) according to Expert consensus  comprised urate lowering therapy (ULT) group (n=50). Then, within 5 days from recruitment of the ULT patient, a control patient with AHU and AH who did not receive allopurinol treatment, with age±3 years and preferably the same gender was recruited in a ratio of 1:1 (n=50 cases and n =50 controls). All patients were given the same dietary advice recommended for AH and AHU. All examinations were performed prior to treatment initiation and after 6 months of follow-up.
The exclusion criteria included: any symptoms of monosodium urate crystal deposition disease, especially gout; coronary heart disease (previous myocardial infarction, coronary angioplasty procedure or coronary artery bypass surgery); symptomatic heart failure more than New York Heart Association (NYHA) class I or reduced ejection fraction < 50%; kidney or liver failure; inflammatory diseases; history of allergy to allopurinol or other serious drug reactions (e.g. Lyell’s syndrome); or treatment change during follow-up. Study flowchart is presented in Figure 1.
The study was performed in accordance with the 1975 Declaration of Helsinki for Human Research and approved by the Jagiellonian University Bioethical Committee (No. 122.6120.94.2017 of April 27th, 2017). A written informed consent was obtained from all patients.
Measurement of peripheral blood pressure
All participants underwent physical examination and office BP measurements (mean of three measurements at one-minute intervals) in standard conditions, after 10 minutes rest, in sitting position on the non-dominant arm with the use of the validated Omron M5-I oscillometric device (Omron Healthcare Co., Japan).
24-hour ambulatory BP monitoring (ABPM) was performed using a SpaceLabs 90207 recorder (SpaceLabs Inc, Richmond, Washington, USA) to confirm BP control. Measurements were taken every 15 minutes during daily activity (06:00–22:00h) and every 20 minutes at night-time (22:00– 06:00 h). For further analyses the mean values of the 24-hour, daytime, and night-time systolic (SBP) and diastolic blood pressure (DBP), and heart rate were calculated. BP measurements were performed according to the ESH/ESC guidelines for the management of hypertension .
Echocardiographic examination using the Vivid®E95 (GE-Healthcare Chicago, IL, USA) device and 2,7-3,6 MHz transducer was performed. Left ventricular mass (LVM) was calculated according to the ASE formula [19, 20]. Left ventricular mass index (LVMI) was calculated LVM/height2.7 . Left atrium volume (LAV) was assessed using the modified Simpson’s method . Left atrium volume index (LAVI) was calculated as LAV/body surface area. Global longitudinal strain (GLS) by speckle tracking echocardiography was measured as the average value of 18 segments, based on three apical imaging planes .
Central blood pressure, pulse wave velocity and intima-media thickness measurements
SphygmoCor (AtCor Medical, Sydney, Australia) device was used to examine arterial stiffness. Carotid-femoral pulse wave velocity (PWV) and central BP in the aorta were measured according to the recommendations of ESH experts [24, 25].
Intima-media thickness (IMT) measurement of common carotid artery was carried out in accordance with the Mannheim consensus with the use of the Vivid®E95 (GE-Healthcare Chicago, IL, USA) and a 10 MHz linear transducer. After at least 10 minutes of patient rest in supine position, good-quality B-mode ultrasound images of left and right common carotid arteries were recorded during five consecutive heart cycles. The intima - media thickness (IMT) of the far wall was measured offline using EchoPAC workstation software. Automatic IMT measurement was based on tracing of 1 cm (starting about 1 cm proximally from bifurcation) of the leading edge of the intima surface and the leading edge of the adventitia surface followed by multiple measurements between pairs of pixels located on both traces. Mean IMT was calculated as the average of the left and right IMT .
In all patients medical history was collected including concomitant diseases, smoking and drinking habits and the use of medications. Laboratory tests: serum concentrations of uric acid, creatinine, total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and hs-CRP were also obtained at the initial visit.
All performed examinations and laboratory tests were then repeated after 6 months of follow-up.
Data are presented as means and standard deviations (SD) and medians and interquartile ranges in cases where nonparametric tests were used. To determine the study sample, we chose as optimal parameter the IMT because of the association with atherosclerosis, BP and potential reversibility during ULT. The analysis showed that to determine a 0.1 mm difference in IMT with mean value of 0.9 and SD of 0.16 mm [27, 28] with a power of 80% and with a significance of p=0.05, using the two-tailed test, the population of 42 people in each group is required. Normality of variables distribution was tested and, if confirmed, parametric tests were used. When studied variables did not have normal distribution nonparametric tests were used. Between group differences were evaluated using Student’s t-test, Mann-Whitney U test or chi-squared test, as appropriate. To assess the effects of the therapy the repeated-measures t-test, Wilcoxon signed-rank test, ANCOVA and the association between variables using the Spearman rank correlation were used. Univariate and multivariate regression analyses were used to determine the influence of independent factors on IMT. P-values <0.05 were considered statistically significant for all tests. Statistical analyses were performed using STATISTICA software (StatSoft, Poland), version 13.1.