Biochemical markers of hypertensive retinopathy: Summary of doctoral thesis in medical sciences: 315.01. Medical biochemistry

Abstract

THE RESEARCH CONCEPTUAL FRAMEWORK The relevance and importance of the researched problem. High blood pressure (HBP), the most common cardiovascular disease, is a major public health problem, its prevalence ranging from 5-10% in underdeveloped countries till 20-30% in industrialized countries, with a worldwide impairment of approx. 40% of people over the age of 25 [1]. Extensive population-based epidemiological studies have indicated that 3-14% of non-diabetic adults > 40 years of age have characteristic hypertensive retinopathy (HR) changes, with a higher prevalence in the 40-60 age group, with men being more predisposed to develop retinopathy, according to studies in India, while in Europe there is a greater affectation of the female [2]. Called the "silent killer", hypertension is a risk factor for a number of eye conditions, but HR, in which the retinal vessels undergo a series of changes, is the most common. The danger of the condition is due to the unawareness of the presence of the disease, because of non-existence of premonitory signs, the symptoms usually developing in the late stages [3]. In the latest articles, researchers use and consider HR a marker for a number of vascular diseases, as well as a harbinger of the risk of stroke, cardiovascular disease, microalbuminuria, chronic kidney disease and even death. However, for the moment, the evaluation of hypertensive signs of retinopathy appears only in the clinical guidelines for the management of patients with hypertension [4]. HR has a complex vascular phenotype, including three separate pathophysiological stages, which creates a broad spectrum of retinal vascular changes, reflecting the severity and duration of BP amplification. These changes are explained by the specific ability of self-regulation of the retinal vessels in response to changes in BP that allows a stable retinal vascular flow to be maintained by active arterial vasoconstriction. Self-regulatory mechanisms explain arterial vasoconstriction, as well as the specificity of "soft" exudates and deep haemorrhages associated with arteriolar occlusions [5]. In addition to self-regulation, the second characteristic of retinal circulation is the presence of a blood-retinal barrier (BRB), the lesion of which is responsible for superficial retinal bleeding, retinal oedema and hard exudates ("dry exudates") [2]. There is an interrelation between the development of microvascular and macrovascular hypertensive complications and the lesions generated by the presence of free radicals. Several biochemical pathways have been associated with the amplification of free radical formation in patients with HTN, which could be considered one of the pathogenic mechanisms of HTN itself and, probably, of the mechanisms of HR development [6]. Oxidative and nitrosative stress have been directly involved in the mechanisms of development of vascular rigidity and endothelial dysfunction in correlation with HTN [7]. The role of oxidative (OS) and nitrosative stress (NS) in the development of HTN and HR is unanimously recognized. At the same time, the number of studies on the mechanisms by which this process is involved in retinal damage remain to be incompletely elucidated. The role of OS and NS in the development of HR has been indirectly demonstrated by identifying the amplification of gamma-glutamyl transferase activity and ferritin levels in the blood of patients with HR, the correlation of changes in GSH/GSSG and LDL-Col with retinal vessel dynamics in patients with HTN [8]. However, it is still controversial whether OS and NS have a causative effect on the development of HR or are a consequence of tissue damage [9]. The existing data are insufficient to ascertain with certainty the role of various factors (OS, NS, antioxidant system, inflammation, etc.) in the chain of pathogenic links of HR, as well as the use of specific markers in diagnosis, prognosis and monitoring. Previous studies of HR-associated metabolic changes and assessment of the usefulness of markers in the diagnosis of pathological condition have been performed in patients' blood serum. At the same time, the eye is an organ with a certain degree of structural, functional and metabolic autonomy, the blood modifications not being a faithful reflection of the ocular changes. The tear film is a polycomponent biological fluid, the composition of which is directly correlated with the ocular structures (their integrity and functionality) and primarily reflecting local physiological and pathological changes. Being conventionally accessible, the tear is a valuable biological material for visual apparatus research [10]. The investigation of different representative tear markers in various ocular pathologies could be a useful tool in their diagnosis due to the significant variety and the presence in different compartments of the eye of multiple chemical compounds [10]. However, so far, the diagnosis of HR is mainly based on ophthalmological evaluation of patients. The uniqueness of the retinal vessels is related to the easy accessibility for a physical examination, but the physical consult depends on the dexterity and experience of the ophthalmologist and is largely subjective. In this context, biochemical markers could be useful not only in understanding of the HR pathogenic mechanisms and fully estimation of pathological metabolic changes in the retina caused by HTN, but also in objectifying and quantifying these changes at the level of HR diagnosis and in establishing an accurate, personalized treatment tactic, as well as in monitoring the effectiveness of treatment and the evolution of retinopathy. Following the above, it is imperative to identify objective markers of ocular damage in hypertension, which should be outlined as promising explanatory indices and laboratory markers of metabolic disorders. The aim of the research was to study the role of oxidative stress, antioxidant system (AOS) and renin-angiotensin system in the pathogenesis of hypertensive retinopathy and the identification of laboratory markers for the diagnosis and monitoring of the pathology. Research objectives: 1. The study of changes in OS and antioxidant system indices in serum and tear of patients with primary hypertension with varying degrees of HR. 2. The evaluation of serum and tear RAS markers in patients with primary hypertension with varying degrees of HR. 3. The correlations identification of biochemical changes with the severity of HR. 4. The establishment of biochemical markers for early diagnosis and prognosis of HR evolution. Scientific research methodology. An analytical, observational study was performed on a representative sample of patients with primary HTN with HR without specific antihypertensive treatment, divided into study subgroups according to the severity of HR, respecting all scientific requirements and ethical principles of institutional, national and international research. In order to achieve the objectives of the thesis, tears and blood serum were investigated to assess the metabolic indices of OS, antioxidant and RAS systems and ischemia. The Research Ethics Committee positive decision was obtained on 08.02.2018 (no. 35/34). The novelty and scientific originality of the obtained results. The research complemented the current knowledge on the pathogenesis of HR, analyzing biochemical changes and their reflection in blood and tears. Markers of OS, antioxidant protection, ischemic damage and RAS were measured in both fluids, with the appreciation of the presence of tear–blood serum correlation of the evaluated indices. It has been shown that the eye is structurally autonomous, with specific defensive systems, which later allows it to withstand the effects of OS. The idea of the lack of a single reliable index, relevant for all HR stages was suggested, the appreciation of clinical manifestations tending to remain a priority. Approval of scientific results. The research results were presented, discussed and approved at several national and international scientific forums: Annual Scientific Conference of Institute of Emergency Medicine Specialists “News and controversies in medical-surgical emergency management”, Chisinau, Moldova, November 10, 2017; 7th International Medical Congress for Students and Young Doctors MedEspera, “Nicolae Testemitanu” SUMPh, Chisinau, Moldova, May 3-5, 2018; Annual scientific conference of young specialists within IMSP IMU "Performances and perspectives in medical and surgical emergencies", Chisinau, Moldova, May 18, 2018; Annual Scientific Conference of Institute of Emergency Medicine "News and controversies in the management of medical and surgical emergencies", Chisinau, Moldova, December 7, 2018; VII Bukovinian International Medical Congress, BIMCO 2020, Bukovinian State Medical University, Chernivtsi, Ukraine, April 7-10, 2020. Congress dedicated to the 75th anniversary of the founding of “Nicolae Testemitanu” SUMPh, Chisinau, Moldova, October 20- 23, 2020; XXIst International Scientific and Practical Conference International Trends in Science and Technology, Warsaw, Poland, January 31, 2020; 7th Lublin International Medical Congress, LIMC 2020, Medical University of Lublin, Lublin, Poland, 26-28 November 2020; VIIIth Bukovinian International Medical Congress, BIMCO 2021, Bukovinian State Medical University, Chernivtsi, Ukraine, April 6-9, 2021; International Scientific Conference on Medicine 2021, University of Latvia, Riga, Latvia, 23-24 April 2021; EURETINA 2021 Virtual, 9-12 September 2021.