Draft:George Mchedlishvili

GEORGE I. MCHEDLISHVILI გიორგი იოსების ძე მჭედლიშვილი Георгий Иосифович Мчедлишвили George Mchedlishvili George I. Mchedlishvili გიორგი იოსების ძე მჭედლიშვილი (June 16, 1921 - April 14, 2014) was a prominent Georgian and Soviet scientist who made significant contributions in the field of normal and pathological physiology. His research primarily focused on blood flow, specifically microcirculation, and the adjacent arterioles and venules in living organisms, including cerebral circulation. Early Life and Career George I. Mchedlishvili was born on June 16, 1921, in Tbilisi, the capital of Georgia (Southern Caucasus), which was then part of the Soviet Union. He came from a family of medical professionals. His father, Joseph Mchedlishvili (1891-1932), was a gastroenterologist who unfortunately passed away when George was just 11 years old. His mother, Ann Greenberg (1894-1978), was a clinical hematologist and bacteriologist. In 1952, George married Marina Adamia (1924-2003), a piano teacher working in a music school. The couple had two children: Joseph (born in 1953), who later became a screenwriter, and Nina (born in 1955), a music school teacher. George received a comprehensive education during his childhood, becoming proficient in basic European languages. He attended a special German school for eight years and then a Russian school in Tbilisi for three years. During his university years, he learned French and subsequently English. In 1939, after completing his secondary education, George Mchedlishvili enrolled in the Tbilisi Medical State Institute (University), where he excelled and received a special stipend for his outstanding achievements. He graduated with honors in 1944, earning a medical doctor diploma. In 1947, he defended his dissertation and obtained the scientific degree of Candidate of Medical Sciences. Later, in 1956, he earned the prestigious title of Doctor of Medical Sciences from the Scientific Council at the Presidium of the Soviet Academy of Medical Sciences in Moscow. While studying medicine at the Tbilisi Medical Institute, Mchedlishvili became increasingly convinced that his true passion lay not in patient treatment, but rather in research ‒ specifically, understanding the mechanisms of physiological and pathological processes in living organisms. As a result, he dedicated his subsequent professional career to the field of normal and pathological physiology. In 1942, while still a student at the Medical Institute in Tbilisi, Georgia, Mchedlishvili began working at the [|Institute of Physiology of the Georgian Academy of Sciences]. This institute, founded and initially led by the renowned Georgian physiologist Prof. Ivane Beritashvili, became his scientific home until 2014. Following the passing of his scientific mentor, Prof. Vladimir Voronin (1870-1960), in 1960, Mchedlishvili assumed leadership of the institute’s scientific subdivision, which evolved from a department to a laboratory and eventually a research center. Professional Activity For over 60 years after graduating from the university, Mchedlishvili served as a dedicated researcher at the I. Beritashvili Institute of Physiology within the [|Georgian Academy of Sciences in Tbilisi]. His expertise lay in the field of normal and pathological physiology, with a specific focus on blood microcirculation and clinical hemorheology. Throughout his career, he maintained a consistent approach to research. He pursued specific topics relentlessly until he uncovered novel insights into physiological processes or regularities. As a result, he discovered numerous phenomena and patterns ‒ previously unknown, undescribed, or unexplained ‒ in the specialized scientific literature. Mchedlishvili consistently aimed to publish his findings in reputable, peer-reviewed journals recognized worldwide. George I. Mchedlishvili’s groundbreaking research led to the publication of physiological and pathological phenomena that were previously unknown in the world of biomedical science. His pedagogical activities were relatively modest within the universities of Tbilisi. Initially, he worked at the Medical Institute, later transitioning to the Postgraduate Medical Academy and the I. Pipia Medical Institute in Tbilisi. Over a span of more than 50 years, during which he headed scientific subdivisions at the I. Beritashvili Institute of Physiology, Mchedlishvili trained numerous scientists who now contribute to institutions worldwide, including those in the United States. He was also an invited lecturer at foreign universities, including Poland (Warsaw, Wroclaw) in the 1960s, Sweden (Lund, Gothenburg) in 1963, and Germany (Cologne, Marburg, Hamburg, Tubingen) in 1967-1969. Additionally, he delivered lectures in the United States (Philadelphia, Baltimore, San Diego, Los Angeles, Iowa) in 1990. Mchedlishvili’s expertise extended to peripheral blood flow and microcirculation disorders, as evidenced by the chapters he authored in the popular Russian Textbook of Pathological Physiology compiled by A.D. Ado and published in 1980, 1994, 2000, and 2001. Despite the limitations faced by Soviet citizens during certain periods of his life, Mchedlishvili actively participated in international and regional scientific conferences. His presentations were well-received, with over 150 delivered at both Soviet and foreign conferences. Notably, he was invited to deliver a plenary lecture at the 30th International Congress of Physiological Sciences in Vancouver, Canada, in 1986. George I. Mchedlishvili’s active participation in international scientific meetings during recent years is evident through the increasing number of papers presented by the laboratory he headed at various Congresses on Biorheology and Clinical Hemorheology. Notably, these contributions were significant in Lisbon, Portugal (1997, 9 papers), Pecs, Hungary (1999, 12 papers), and Antalya, Turkey (2002, 11 papers). Despite maintaining close and friendly relationships with outstanding specialists worldwide, Mchedlishvili engaged in only a limited number of joint experimental research projects with them. This tendency can be attributed to his pronounced independence of thought and his commitment to conducting biomedical research in areas that were autonomous and free from external influence. Mchedlishvili’s prolific scientific output spans the years from 1947 to 2001, encompassing over 700 titles. His contributions include: •	7 scientific books (monographs) •	13 books compiled and edited by him •	350 papers in scientific periodicals and collections of scientific works •	12 chapters in handbooks and textbooks •	25 entries in encyclopedias •	Nearly 300 abstracts of presentations A comprehensive list of Mchedlishvili’s scientific publications up to his 80th anniversary was compiled in a booklet titled “Microcirculation, Hemorheology, Cerebral Circulation: Scientific Publications by George Mchedlishvili (1947-2001)” and published in Tbilisi, Georgia, in 2002 by “Megobari” Publishers. Microcirculation Research Bold text At the outset of his scientific career, George I. Mchedlishvili delved into the intricacies of regional blood flow, specifically focusing on microcirculation within living tissues. His investigations centered on the peripheral microvascular networks that permeate all tissues. These networks consist of the narrowest blood vessels ‒ the capillaries ‒ along with their feeding arterioles and draining venules. Remarkably, these vessels have diameters approximately 1/100 of a millimeter, making them comparable in size to red and white [|blood cells] (erythrocytes and leukocytes). Mchedlishvili’s groundbreaking contributions include: 1.	Principles of Blood Distribution in Capillary Networks (1951): He elucidated the fundamental principles governing blood flow within capillary networks. His work shed light on how blood is distributed across these intricate networks. 2.	Role of Plasmatic Capillaries in Microvessel Derecruitment (1957): Mchedlishvili discovered that plasmatic capillaries serve as intermediaries between active capillaries (with normal blood flow) and those that are switched off (with a closed lumen). This insight significantly advanced our understanding of microvascular dynamics. 3.	Irregular Distribution of Red Cells and Plasma in Arteries (1980, 1986): His investigations extended beyond capillaries to larger arteries, including branches of the aortic arch supplying blood to the brain and hands. Surprisingly, even in these major arteries, irregular distributions of red cells and plasma were observed. This phenomenon challenged conventional assumptions about blood composition and hematocrit. In recognition of his groundbreaking discoveries, the State expertise of the former Soviet Union awarded Mchedlishvili a special Diploma of Discovery in 1954.

 Blood Fluidity in Microvessels  Understanding blood flow dynamics within microvessels ‒ particularly capillaries and adjacent arterioles and venules ‒ has been essential for comprehending microcirculation changes under both normal and pathological conditions. For decades, specialists grappled with the notion that blood behaves differently in these tiny vessels, where red and white blood cells are nearly commensurate with the microvascular lumina (typically less than 10-15 μm in diameter). George I. Mchedlishvili dedicated significant attention to factors influencing blood fluidity and disturbances within microvessels. Notably, he observed that under normal conditions, red blood cells move in a structured manner, rather than chaotically. Their interactions play a crucial role in shaping microvascular flow. Gradually, Mchedlishvili concluded that this specific structuring is the key determinant of blood flow resistance in microvessels. His extensive research, spanning several decades, culminated in monographs published in 1958, 1986, and 1989, as well as a comprehensive review article in a specialist periodical in 1991. Mchedlishvili’s investigations also focused on disturbances in blood flow structuring within microvessels and their impact on flow resistance. Notably, he identified erythrocyte aggregation — the clumping together of red blood cells ‒ as a major contributor to flow resistance disruption in microvessel lumina (1958, 1991). This discovery laid the groundwork for the development of the “Georgian technique,” a reliable method used to investigate RBC aggregability in patients with various diseases (1993). In subsequent studies, it was demonstrated that blood rheological disorders related to enhanced red blood cell (RBC) aggregability significantly increase within the capillary lumina during various significant diseases. These conditions include essential hypertension, lacunar brain infarcts, malignant tumors, and diabetes mellitus. The blood rheological disorders associated with enhanced RBC aggregation play an active role in the pathogenesis of these pathologies.

Physiology of The Cerebral Blood Flow George I. Mchedlishvili made several scientific discoveries concerning the normal and pathological physiology of cerebral circulation. One of the most crucial findings was related to the functional organization of the cerebral vascular bed. Unlike other organs in the body, the brain’s blood supply is uniquely controlled not only by the smallest arterioles (precapillary vessels) but also by all arterial branches, including the larger ones such as the internal carotid and vertebral arteries. Mchedlishvili’s discovery revealed that this vascular mechanism ensures a constant blood supply to the entire cerebral vascular bed, even when systemic arterial pressure undergoes significant fluctuations. This phenomenon, known as autoregulation, maintains stable blood flow to cerebral tissue. The date of this discovery is fixed as 1960, and it was subsequently approved by the State Expertise of the former Soviet Union. This discovery significantly advanced scientific knowledge about the physiological mechanism of cerebral blood flow regulation. Additionally, the author identified the major arteries of the brain as the vascular mechanism responsible for actively damping pulsatile oscillations of systemic arterial pressure (1977). This regulation is particularly crucial for the brain, which is encased within the cranial cavity. Without such control, fluctuations in intracranial blood pressure could lead to abnormal conditions. The author also uncovered distinctive functional peculiarities in the smaller cerebral arteries distributed on the brain surface (known as pial arteries). These vessels give rise to smaller branches that enter the brain, supplying it with oxygen and other necessary materials. The rich anastomosis of pial arteries creates arterial circles on the brain surface. Notably, the size of these circles correlates with the level of development in different animal species, providing evidence that this peculiarity evolved during vertebrate development (1984). The intricate system of ramifying and anastomosing pial arteries, with high vasomotor activity, serves as an adjustment mechanism akin to taps. These arteries provide adequate blood supply to cerebral tissue in accordance with the metabolic needs of brain tissue elements. In 1967, Mchedlishvili further discovered that the previously denied neurogenic vasomotor activity of pial arterial branches is most pronounced, ensuring that smaller portions of brain tissue receive sufficient blood supply. Additionally, the even smaller arteriolar branches distributed within the cerebral cortex (distinct from other organs in the body) were found to possess minimal vasomotor activity, protecting the cerebral tissue from mechanical effects. These smaller branches play a lesser role in controlling blood flow within the feeding capillary networks of cerebral tissue. Contrary to the dominant doctrine of the 19th century, which conjectured that blood volume and flow remained constant within the hermetically sealed cranium, Mchedlishvili’s studies conclusively demonstrated that microcirculation in cerebral tissue is precisely regulated by the physiological control system. This conceptual shift was primarily due to his anatomical and physiological findings, which convincingly established that neurogenic control by adrenergic and cholinergic nerves is perfectly adjusted (1965, 1970). Since then, this concept has not been doubted in the world of biomedical science. Cerebrovascular Spasm: Understanding Pathological Constriction in Brain Arteries When any obstruction occurs within an artery, disrupting blood flow to specific tissues, it poses a significant threat ‒ especially to the brain. Brain tissue is exceptionally sensitive to disturbances in blood supply. Alongside obstructions caused by thrombi (blood clots), another critical factor is the excessive constriction of muscles within arterial walls. This phenomenon is known as arterial spasm or vasospasm. Previously, there were debates about whether vasospasm could occur in larger brain arteries. Unfortunately, direct investigation of these arteries was challenging due to their limited accessibility. However, George I. Mchedlishvili’s groundbreaking work shed light on the functional peculiarities of various parts of the cerebral vascular bed, providing insights into why vasospasm predominantly affects larger cerebral arteries (1975). Mchedlishvili and his associates meticulously gathered direct evidence regarding the essence and typical features of pathological constriction ‒ the arterial spasm. They developed experimental techniques that allowed precise analysis of the physio-pathological processes within arterial smooth muscles. Here are the key findings: 1.	Pronounced Constriction: Vasospasm involves a pronounced constriction of the affected artery. This constriction persists, and subsequent dilation is disrupted. As a result, the artery remains constricted with a considerably narrowed lumen for an extended period. 2.	Pathophysiological Insights: Detailed analysis of the pathophysiological processes within arterial muscle (1977) deepened our understanding of the spasm-like pathological constriction. This constriction ultimately leads to the development of arterial spasm, causing disturbances in blood supply to specific brain tissue areas. Brain Edema: Understanding Pathological Swelling in the Brain George I. Mchedlishvili conducted a series of experimental studies aimed at better understanding the development of brain edema ‒ a highly significant pathological process. While edema can occur in various parts of the body, it poses the greatest danger within the brain. The brain is encased in a rigid skull, and any edema inevitably disrupts its blood supply, often leading to the patient’s death. In 1961, Mchedlishvili analyzed these mechanisms in experimental studies. He specified the changes in brain tissue during edema development, identifying factors that could either promote or prevent this dangerous pathological event. Additionally, he was the first to investigate specific changes in the mechanical properties of cerebral tissue during brain edema. These alterations may play both a pathogenic and a compensatory role in brain edema development (1989). In summary, Mchedlishvili’s research significantly advanced our understanding of brain edema, shedding light on the delicate balance between swelling and blood supply within the brain.

SELECTED PUBLICATIONS 1. G.I.Mchedlishvili. Capillary Circulation. Publishers of Georgian Academy of Sciences, Tbilisi, 1958, 188 pp. (in Russian). 2. G.Mchedlishvili, D.Baramidze, L.Nicolaishvili. Functional behaviour of pial and cortical arteries in conditions of increased metabolic demand from the cerebral cortex. Nature, 1967, v. 213, 506-507. 3. G.Mchedlishvili, L.Nicolaishvili. Evidence of a cholinergic nervous mechanism mediating the autoregulatory dilatation of the cerebral blood vessels. Pflügers Archiv, 1970, v. 315, 27-37. 4. G.Mchedlishvili. Vascular Mechanisms of the Brain. Plenum Publishing Corporation. New York and London, 1972, 120 pp. 5. G.Mchedlishvili, N.Mitagvaria, L.Ormotsadze. Vascular mechanisms controlling a constant blood supply to the brain (“autoregulation”). Stroke, 1973, v. 4, 742-750. 6. G.I.Mchedlishvili. Cerebral Arterial Spasm. Publishers “Metsniereba”, Tbilisi, 1977, 183 pp. (in Russian). 7. G.Mchedlishvili, M.Y.Purves, A.G.B.Kovách (Eds.). Regulation of Cerebral Circulation. Proceedings of the 4th Tbilisi Symposium. Publ. “Akadémiai Kiadó”, Budapest, 1979, 268 pp. 8. G.Mchedlishvili. Physiological mechanisms controlling cerebral blood flow. Stroke, 1980, v. 11, 240-248. 9. G.Mchedlishvili. The nature of cerebral vasospasm. Blood Vessels, 1981, v. 18, 311-330. 10. G.Mchedlishvili. Arterial Behavior and Blood Circulation of the Brain. Plenum Press. New York and London, 1986, 338 pp. 11. G.Mchedlishvili, M.Varazashvili. Systemic hemorheological phenomenon accounting for advantageous oxygen supply to, and asymmetry of, the brain. Brain Res., v. 386, 64-68. 12. G.I.Mchedlishvili Blood Microcirculation: General Principles of Control and Disturbances. Publishers “Nauka”, Leningrad, 1989, 288 pp. (in Russian). 13. G.Mchedlishvili. Dynamic structure of blood flow in microvessels. Microcirc. Endothelium Lymphatics, 1991, v. 7 (1-3), pp. 3-49. 14. G.Mchedlishvili, M.Tomita, R.Tuma (Eds). Microcirculation of the Brain. A Synoptic View by World Experts. NOVA Science Publishers, New York, 1992, 268 pp. 15. G.Mchedlishvili, R.Shakarishvili, M.Aloeva, N.Momtselidze, Elaborated – “Georgian index” of erythrocyte aggregability characterizing the microrheological disorders associated with brain infarct. Clin. Hemorheol., 1995, v. 15, pp. 783-793. 16. G.Mchedlishvili, M. Varazashvili, A.Mamaladze, N.Momtselidze. Blood flow structuring and its alteration in capillaries of the cerebral cortex. Microvasc. Res., 1997, v. 53, 201-210. 17. G.Mchedlishvili, L.Gobejishvili, A.Mamaladze, N.Momtselidze. Microcirculatory stasis induced by hemorheological disorders: further evidence. Microcirculation, 1999, v. 5, 97 – 106. 18. G.Mchedlishvili (Editor-Compiler) “Hemorheology in Microcirculation: Pathological Changes” (Proceedings of the 7th Tbilisi Symposium). Ed. by M.Tomita and G.W.Schmid-Schonbein (Eds.). Suppl. of “Keio J. Med.”. Tokyo, 2000, 82 pp. 19. G.Mchedlishvili, N.Maeda. Blood flow structure related to red cell flow: a determinant of blood fluidity in narrow microvessels. Japan. J. Physiol., 2001, v. 51, 19-30. 20. G.Mchedlishvili, M.Mantskava, N.Pargalava. Arteriolar resistance and hemorheological disorders related to Raynaud’s phenomenon. Microvasc. Res. 2001, v.62, 190-195.