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.

Impact of type 1 diabetes and its duration on wall-to-lumen ratio and blood flow in retinal arterioles.

BACKGROUND: Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. METHODS: Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12 months, group B with diabetes with 1-10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. RESULTS: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, mean BMI 22.9 ± 4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297 ± 121 arbitrary units [AU]) vs group B (236 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; p = 0.008) and comparable to that of the controls (p = 0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p = 0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. CONCLUSIONS: New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10 years.

Vascular Aging and Damage in Patients with Iron Metabolism Disorders.

Vascular aging is a physiological, multifactorial process that involves every type of vessel, from large arteries to microcirculation. This manifests itself as impaired vasomotor function, altered secretory phenotype, deteriorated intercellular transport function, structural remodeling, and aggravated barrier function between the blood and the vascular smooth muscle layer. Iron disorders, particularly iron overload, may lead to oxidative stress and, among other effects, vascular aging. The elevated transferrin saturation and serum iron levels observed in iron overload lead to the formation of a non-transferrin-bound iron (NTBI) fraction with high pro-oxidant activity. NTBI can induce the production of reactive oxygen species (ROS), which induce lipid peroxidation and mediate iron-related damage as the elements of oxidative stress in many tissues, including heart and vessels' mitochondria. However, the available data make it difficult to precisely determine the impact of iron metabolism disorders on vascular aging; therefore, the relationship requires further investigation. Our study aims to present the current state of knowledge on vascular aging in patients with deteriorated iron metabolism.

Subclinical macroangiopathic target organ damage in type 1 diabetes mellitus patients.

PURPOSE: We have summarized key studies regarding the assessment of subclinical macroangiopathic target organ damage (TOD) in type 1 diabetes mellitus (T1DM). RESULTS: Although chronic complications resulting from hyperglycemia, in particular macroangiopathies, are still the first cause of death in T1DM, there has been growing recognition of the role of hypoglycemia in cardiovascular morbidity and mortality. Subclinical TOD diagnosis ensures early implementation of the complex management aiming at either partial reversal of these complications or at least its downturn. To better identify patients with early TODs, several non-invasive diagnostic techniques are employed, including the ultrasonographic assessment of the intima-media thickness (IMT), computed tomography (CT) for coronary artery calcium (CAC) scores, and pulse wave velocity (PWV) measurement for arterial stiffness evaluation. Various studies reported that T1DM patients present an increased IMT. An increasing IMT fairly correlates with the cardiovascular (CV) events risk even after the adjustment to age, diabetes duration, quality of glucose control as well as the presence of hypertension, and chronic complications. Another, well established marker of the organ damage - CAC score is recommended by ACC/AHA guidelines to assess the overall CV risk in T1DM. Also, the arterial stiffness evaluation with PWV may further improve CV risk prediction, which has been reported in multiple studies including the Framingham Heart Study. CONCLUSIONS: There is shortage of data from prospective studies which could confirm the benefits of early treatment initiation based on the presence of the subclinical organ damage in T1DM. Most evidence comes from T2DM trials, where effective preventive measures were identified i.e.: smoking cessation, reasonable blood glucose control, efficacious hypertension treatment, and dyslipidemia management, as well as renoprotection. There is still a field for further research to see if routine assessment of asymptomatic vascular damage and early implementation of aggressive treatment would reduce mortality excess from CVD in T1DM.

Update of the position paper on arterial hypertension and erectile dysfunction.

: Sexual health is an integral part of overall health, and an active and healthy sexual life is an essential aspect of a good life quality. Cardiovascular disease and sexual health share common risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking) and common mediating mechanisms (endothelial dysfunction, subclinical inflammation, and atherosclerosis). This generated a shift of thinking about the pathophysiology and subsequently the management of sexual dysfunction. The introduction of phosphodiesterase type 5 inhibitors revolutionized the management of sexual dysfunction in men. This article will focus on erectile dysfunction and its association with arterial hypertension. This update of the position paper was created by the Working Group on Sexual Dysfunction and Arterial Hypertension of the European Society of Hypertension. This working group has been very active during the last years in promoting the familiarization of hypertension specialists and related physicians with erectile dysfunction, through numerous lectures in national and international meetings, a position paper, newsletters, guidelines, and a book specifically addressing erectile dysfunction in hypertensive patients. It was noted that erectile dysfunction precedes the development of coronary artery disease. The artery size hypothesis has been proposed as a potential explanation for this observation. This hypothesis seeks to explain the differing manifestation of the same vascular condition, based on the size of the vessels. Clinical presentations of the atherosclerotic and/or endothelium disease in the penile arteries might precede the corresponding manifestations from larger arteries. Treated hypertensive patients are more likely to have sexual dysfunction compared with untreated ones, suggesting a detrimental role of antihypertensive treatment on erectile function. The occurrence of erectile dysfunction seems to be related to undesirable effects of antihypertensive drugs on the penile tissue. Available information points toward divergent effects of antihypertensive drugs on erectile function, with diuretics and beta-blockers possessing the worst profile and angiotensin receptor blockers and nebivolol the best profile.

Insufficiency of the zona glomerulosa of the adrenal cortex and progressive kidney insufficiency following unilateral adrenalectomy - case report and discussion.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension and bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) seem to be the most common causes of PA. Unilateral adrenalectomy (UA) is the preferred treatment for APA, although the benefits are still difficult to assess. CASE REPORT: We present a case report of a 69-year old man with a 30 year history of hypertension and probably long-standing PA due to APA, with typical organ complications. Since repeated abdominal CT scans were equivocal, not showing radiological changes characteristic for PA, the diagnosis of APA was delayed and was only finally confirmed by adrenal venous sampling which demonstrated unilateral aldosteronism. The patient underwent UA, complicated by mineralocorticoid deficiency syndrome and increased creatinine and potassium levels. At 12 months follow-up the patient still had hyperkalemia and was fludrocortisone dependent. CONCLUSIONS: Older patients and patients with long-lasting PA who are treated with UA may demonstrate deterioration of renal function and develop transient or persistent insufficiency of the zona glomerulosa of the remaining adrenal gland necessitating fludrocortisone supplementation. Transient hyperkalemia may be observed following UA as a result of the prolonged effects of aldosterone antagonists and/or transient mineralocorticoid/glucocorticoid insufficiency. Additionally, the level of progression of chronic kidney disease after UA is difficult to predict. There likely exists a group of patients who might paradoxically have higher cardiovascular risk due to significant deterioration in kidney function not only resulting from the removal of the aldosterone induced glomerular hyperfiltration phenomenon. Identification of such a group requires further detailed investigation.

Single-pill combinations (SPCs) and treatment of arterial hypertension in Poland. Expert consensus statement of the Polish Society of Hypertension and Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy.

The reasons for the publication of current expert consensus statement after 4 years from the previous one are: the growing number of evidence on the benefits of the use of single-pill combinations (SPCs) in hypertension (also with concomitant dyslipidaemia), the extension of indications for their use in the hypertension management algorithm and the emergence in recent years after the publication of Polish Society of Hypertension experts' position statement in 2013 of new types of SPCs available to doctors in Poland, including triple-drug combinations of antihypertensives and the so-called "hybrids" SPCs containing not only antihypertensive drugs but also statins. The current position statement of experts summarizes the progress of knowledge and practical application of SPCs of antihy-pertensives in Poland. It seems that there will be a long gap in the introduction of new classes of antihypertensive drugs. The only noticeable progress in the pharmacotherapy of hypertension in the last 15 years, which may explain some increase in the effectiveness of blood pressure control in patients, is more common use of SPCs of antihypertensive drugs. Analysis of European Society of Hypertension (ESH) experts' lectures during this year's ESH 2017 Annual Meeting in Milan suggests that the next edition of the 2018 ESH Guidelines may include major changes in the antihypertensive therapy algorithm, suggesting the need for initiation of pharmacologic treatment with combination therapy, i.e. SPCs, in most patients with hypertension. Combination of an angiotensin converting enzyme (ACE) inhibitor + calcium antagonist should be considered optimal in patients with high and very high cardiovascular risk. Undoubtedly, the position of this combination is due to the ACCOM-PLISH trial in which such SPCs werefound to be more effective in reducing cardiovascular risk than SPCs composed of an ACE-inhibitor + thiazide diuretic. As a result of gradually increasing popularity of combined drugs, further SPCs that meet the criteria for optimal combination of antihypertensive drugs emerged in Poland between 2012 and 2017. Two of them provided the possibility of using SPCs in patients who do not need or should not use renin-angiotensin-aldosterone inhibitors. An interesting alternative is the SPC which contains antihypertensive agents along with other drugs used in cardiovascular prevention: statins and acetylsalicylic acid. This direction in the evolution of pharmacotherapy of hypertension is approaching the concept of "polypill". In the opinion of the authors, the use of SPCs in antihypertensive therapy will increase in Poland, which may contribute to further improvement of pressure control in our country. At present, almost all useful anti-hypertensive agents are available in the form of two-drug SPCs. The combination of a sartan with beta-blocker for hypertensive patients with cardiac hypertrophy who do not tolerate ACE inhibitors and a "hybrid" SPCs of an ACE inhibitor + statin are still expected. Three-drug combinations: ACE inhibitor + beta-blocker + calcium antagonist, for patients with hypertension and coronary artery disease requiring intensive therapy, and ACE inhibitor + beta-blocker + statin, which will enable SPCs therapy for most patients, would also be useful.

Modelling of subarachnoid space width changes in apnoea resulting as a function of blood flow parameters.

During apnoea, the pial artery is subjected to two opposite physiological processes: vasoconstriction due to elevated blood pressure and vasorelaxation driven by rising pH in the brain parenchyma. We hypothesized that the pial artery response to apnoea may vary, depending on which process dominate. Apnoea experiments were performed in a group of 19 healthy, non-smoking volunteers (9 men and 10 women). The following parameters were obtained for further analysis: blood pressure, the cardiac (from 0.5 to 5.0Hz) and slow (<0.5Hz) components of subarachnoid space width, heart rate, mean cerebral blood flow velocity in the internal carotid artery, pulsatility and resistivity index, internal carotid artery diameter, blood oxygen saturation and end-tidal carbon dioxide. The experiment consisted of three apnoeas, sequentially: 30s, 60s and maximal apnoea. The breath-hold was separated for 5minute rest. The control process is sophisticated, involving internal cross-couplings and cross-dependences. The aim of work was to find a mathematical dependence between data. Unexpectedly, the modelling revealed two different reactions, on the same experimental procedure. As a consequence, there are two subsets of cardiac subarachnoid space width responses to breath-hold in humans. A positive cardiac subarachnoid space width change to apnoea depends on changes in heart rate and cerebral blood flow velocity. A negative cardiac subarachnoid space width change to apnoea is driven by heart rate, mean arterial pressure and pulsatility index changes. The described above two different reactions to experimental breath-hold provides new insights into our understanding of the complex mechanisms governing the adaptation to apnoea in humans. We proposed a mathematical methodology that can be used in further clinical research.