LATEST FRONTIERS of Hemodynamics, Imaging and Treatment of OBSTRUCTIVE VENOUS DISEASE

Alessia Giaquinta • Byung-Boong Lee • Carlo Setacci Pierfrancesco Veroux • Paolo Zamboni

With the collaboration of Massimiliano Veroux • Sonia Ronchey

EDIZIONI MINERVA MEDICA

00_Romane.indd III 03/01/18 10:24 This book has been supported by an unrestricted educationl grant from

ISBN: 978-88-7711-929-2

Th e publisher declares himself fully available to resolve any eventuality related to the reproduction of the cover image, for which the source was not found.

00_Romane.indd IV 03/01/18 10:24 Preface

Th is new book, “Latest Frontiers of Hemo- high fi elds. Lastly, MRI can also be used to map dynamics, Imaging and Treatment of Obstruc- CSF fl ow and diff usion over time. All of these tive Venous Disease”, is a welcome addition to features help to promote a fundamental under- the literature espousing the importance of the standing of the role of the venous system. role of the venous system in human physiology Th is book is composed of two main parts. and the treatment of venous abnormalities. Th e Th e fi rst part contains the study and treatment many authors of this text are leaders in the fi eld of large veins. Vein anatomy and function are and provide a prescient outlook to both cur- presented as introductory concepts in Chapters rent and future technology. Th e International 1 to 4. Th ese fi rst four chapters provide the read- Society for Neurovascular Disease (ISNVD) er with the background required to appreciate recognizes the importance of the coupled vas- the fl ow and hemodynamics associated with the cular and cerebro-spinal fl uid (CSF) system in major veins in the body. Diff erent diseases and the brain and looks to new advances in these treatments are then covered in Chapters 5 to 22. areas. Th is book off ers the insight necessary to Th e second part focuses on venous outfl ow and help promote future developments in this area. its dysfunction in several diseases, such as multi- Th e last century focused predominantly on ple sclerosis and Meniere’s disease (Chapters 23 the importance of the arterial system and of to 28). Th is same group of chapters also discuss- the detection of obstruction and prevention of es the new condition of chronic cerebrospinal the delivery of oxygen to the tissue. However, venous insuffi ciency and brings the eld fi up to the venous system plays multiple roles: 1) the date with new fi ndings from ongoing studies. delivery of the deoxygenated blood back to the Th ese fundamental advances are presented in heart; 2) an interface with the CSF via arach- terms of modern imaging methods including noid granulations, and 3) the role of carrying MRI, ultrasound, computed tomography, ple- out macromolecules delivered by the CSF that thysmography, and catheter venography. are transported through the venous endothe- In summary, over and above the current lium. Imaging, and in particular magnetic reso- modern treatments of venous disease discussed nance imaging (MRI), off ers the potential to in this book, the ability to quantify venous quantify the levels of oxygen in veins, and uses structure and function in a way that can impact the sensitivity of the MRI signal to the presence treatment is the main focus of this book, which of oxygenation and its changes to measure brain has been designed to provide the reader with a function. MRI can also monitor blood fl ow at a well-rounded and exciting outlook for the fu- very high resolution as a function of the cardiac ture of venous disease understanding and treat- cycle, and map out the entire venous system ment. down to the resolutions of 50 microns using E. Mark Haacke, Ph.D.

00_Romane.indd V 03/01/18 10:24 Foreword

Th e Editors have written a thorough great part as noted in the United States. Th is current review of diagnosis and management has changed in the past twenty-fi ve years with of the challenges associated with and multiple new eff orts through the American focusing on the large veins of the body. Th e Phebological Society and the American chapters cover a wide variety of subjects Venous Forum increasing and complimenting and the accompanying references off er the similar well-established activities in similar opportunity for further review and study. societies throughout the whole world. Th e accompanying graphic illustrations add Th e Vietnam Vascular Registry established additional information and clarifi cation to in 1966 at Walter Reed General Hospital the written material. Th e chapter titles allow in Washington, D.C., USA provided an rapid access to specifi c areas of interest in early emphasis on the repair of large veins, the venous system. Th e contributors are particularly in the lower extremities, rather established physicians and surgeons with than the traditionally accepted ligation. Th e extensive experience in managing problems statistics to support the absence of increased in the venous system including clinical thrombophlebitis and of pulmonary research. Th is is a most timely contribution embolism with long-term patency assured with increasing world-wide appreciation have resulted in an increased acceptance of of the importance of the venous system in this approach. maintaining good health. A study published in 2017 Journal of William Harvey, an Englishman who Vascular Surgery: Venous and Lymphatic studied in Italy at Padua University with Disorders from Johns Hopkins Hospital in Fabricius where he earned his Doctor of Baltimore, Maryland draws attention to the Medicine in 1602 taught us about circulation “perceived weakness in venous education in the seventeenth century emphasizing the in vascular surgery trainees” in the United important role of the venous system. His States. Th is book will contribute immensely classic book Motu Cordis was published in to educate the next generation of physicians 1628. Yet, and particularly in the twentieth and surgeons in the evaluation and treatment century, with the many exciting discoveries in of venous disorders. treating problems associated with the arterial system, the venous system was ignored in Norman M. Rich, MD, FACS

VII

00_Romane.indd VII 03/01/18 10:24 Authors

GLORIA ADAM JUDY S. BLEBEA Clinic of Cardiology and Angiology, Acibadem Department of Radiology, University of City Clinic, Sofi a, Bulgaria Oklahoma College of Medicine Oklahoma City, OK, USA GIUSEPPE ATTANASIO Head and Neck Department, Umberto I MATTEO BOSSI Polyclinc, Rome, Italy Vascular Surgery Unit, Vita-Salute University, San Raff aele Scientifi c Institute, Milan, Italy CLIVE B. BEGGS Institute for Sport, Physical Activity and Leisure, ALDO BRUNO School of Sport, Leeds Beckett University, Vascular Surgery Division, GEPOS Hospital Leeds, UK Telese T., Benevento, Italy

FILIPPO BENEDETTO SAGAR BUCH Department of Biomedical Sciences and Th e MRI Institute for Biomedical Research, Morphological and Functional Imaging, Detroit, MI, USA Policlinico G. Martino, University of Messina, Messina, Italy LUIGI CALIFANO Departmental Unit of Audiology and DOMENICO BENEVENTO Phoniatrics, A.O.G. Rummo (G. Rummo Vascular Surgery, Department of Medical Hospital Group), Benevento, Italy Surgical and Neurological Sciences, University of Siena, Italy ALESSANDRO CAPPELLANI Vascular Surgery and Organ Transplant Unit, BENDETTO BERNARDO Department of Surgery, University Hospital of Vascular Surgery Division, GEPOS Hospital Catania, Italy Telese T., Benevento, Italy PATRIZIO CASTELLI ROBERTO BERTINI Vascular Surgery, Department of Medicine and Urology Department, Vita-Salute University, San Surgery, Circolo University Teaching Hospital, Raff aele Scientifi c Institute, Milan, Italy University of Insubria School of Medicine, Varese, Italy JOHN BLEBEA Department of Surgery, Central Michigan PIER PAOLO CAVAZZUTI University College of Medicine, Saginaw, MI, ENT Department, Maggiore Hospital, Bologna, USA Italy

00_Romane.indd IX 03/01/18 10:24 AUTHORS

YONGSHENG CHEN SERGIO GIANESINI Th e MRI Institute for Biomedical Research, Department of Morphology, Surgery and Detroit, MI, USA Experimental Medicine and Vascular Diseases Center, University of Ferrara, Italy; Unit of ROBERTO CHIESA Translational Surgery and Vascular Diseases Vascular Surgery Unit, Vita-Salute University, Center, Azienda Ospedaliera Universitaria di San Raff aele Scientifi c Institute, Milan, Italy Ferrara, Italy

EFREM CIVILINI ALESSIA GIAQUINTA Vascular Surgery Unit, Humanitas Clinical and Vascular Surgery and Organ Transplant Unit, Research Hospital, Rozzano, Italy Department of Surgery, University Hospital of Catania, Italy GIUSEPPE D’ARRIGO Vascular Surgery and Organ Transplant Unit, VINCENZO GIUGLIANO Department of Surgery, University Hospital of Neuro Radiology Department, Gepos Hospital Catania, Italy Telese T., Benevento, Italy

MICHAEL D. DAKE PETER GLOVICZKI Stanford University School of Medicine, Joe M. and Ruth Roberts Professor of Surgery Department of Cardiothoracic Surgery, Falk and Chair, Emeritus, Division of Vascular and Cardiovascular Research Center, Stanford, CA, Endovascular Surgery, Mayo Clinic, Rochester, USA MN, USA

GIANMARCO DE DONATO ALESSANDRO GRANDI Vascular Surgery, Department of Medical Vascular Surgery Unit, Vita-Salute University, Surgical and Neurological Sciences, University of San Raff aele Scientifi c Institute, Milan, Italy Siena, Italy LACHEZAR GROZDINSKI ESTER DE MARCO Clinic of Cardiology and Angiology, Acibadem Vascular Surgery and Organ Transplant Unit, City Clinic, Sofi a, Bulgaria Department of Surgery, University Hospital of Catania, Italy E. MARK HAACKE Wayne State University, Detroit, MI, USA ROBERTA DE VIZIA Neuro Radiology Department, Gepos Hospital SIMON HARDY Telese T., Benevento, Italy Consultant Vascular Surgeon, East Lancashire Hospital NHS Trust, Blackburn, UK PETER D. DO Stanford University School of Medicine, DEJAN JAKIMOVSKI Department of Cardiothoracic Surgery, Falk Buff alo Neuroimaging Analysis Center, Cardiovascular Research Center, Stanford, CA, Department of Neurology, Jacobs School of USA Medicine and Biomedical Sciences, University at Buff alo, State University of New York, Buff alo, HECTOR FERRAL NY, USA Department of Radiology, NorthShore University HealthSystem, Evanston, IL , USA ARJUN JAYARAJ Th e RANE Center for Venous and Lymphatic CLAUDE FRANCESCHI Diseases, St. Dominic Hospital, Jackson, MS, Hôpital Paris Saint-Joseph, Paris, France USA

ROBERTO GALEOTTI JAMES LAREDO Unit of Interventional Radiology, Azienda Department of Surgery, George Washington Ospedaliera Universitaria di Ferrara, Italy University, Washington DC, USA

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BYUNG-BOONG LEE SESHADRI RAJU Department of Surgery, George Washington Th e RANE Center for Venous and Lymphatic University, Washington DC, USA Diseases, St. Dominic Hospital, Jackson, MS, USA NICOLA MANGIALARDI Vascular Surgery Department, San Camillo SONIA RONCHEY Forlanini Hospital, Rome, Italy Vascular Surgery Unit, San Filippo Neri Hospital, Rome, Italy KAREN MARR Buff alo Neuroimaging Analysis Center, FABRIZIO SALVI Department of Neurology, Jacobs School of IRCCS of Neurosciences, Bellaria Hospital, Medicine and Biomedical Sciences, University at Bologna, Italy Buff alo, State University of New York, Buff alo, SALVATORE J.A. SCLAFANI NY, USA Radiology Unit, SUNY Downstate Medical DANIELE MASCIA Center; Fresenius Vascular Care, Brooklyn, Vascular Surgery Unit, Vita-Salute University, NY, USA San Raff aele Scientifi c Institute, Milan, Italy CARLO SETACCI Vascular Surgery, Department of Medical DIEGO MASTRANGELO Vascular Surgery Division, Gepos Hospital Telese Surgical and Neurological Sciences, University T., Benevento, Italy of Siena, Italy FRANCESCO SETACCI ERICA MENEGATTI Department of Vascular Surgery IRCCS Department of Morphology, Surgery and Multimedica, Milan, Italy Experimental Medicine and Vascular Diseases Center, University of Ferrara, Italy; Unit of FRANCESCO SISINI Translational Surgery and Vascular Diseases Section of Medical Physics, Department of Physics Center, Azienda Ospedaliera Universitaria di and Earth Sciences, University of Ferrara, Italy Ferrara, Italy DOMENICO SPINELLI ANTONIO MINNI Department of Biomedical Sciences and Head and Neck Department, Umberto I Morphological and Functional Imaging, Polyclinc, Rome, Italy Policlinico G. Martino, University of Messina, Messina, Italy DOVILE MOCISKYTE Vascular Surgery and Organ Transplant Unit, STEFAN STEFANOV Department of Surgery, University Hospital of Clinic of Cardiology and Angiology, Acibadem Catania, Italy City Clinic, Sofi a, Bulgaria

GIANCARLO PALASCIANO MARCO TADIELLO Vascular Surgery, Department of Medical Vascular Surgery, Department of Medical Surgical and Neurological Sciences, University of Surgical and Neurological Sciences, University of Siena, Italy Siena, Italy

IVO PETROV MIRKO TESSARI Clinic of Cardiology and Angiology, Acibadem Department of Morphology, Surgery and City Clinic, Sofi a, Bulgaria Experimental Medicine and Vascular Diseases Center, University of Ferrara, Italy; Unit of GIORGIO LUCA POLETTO Translational Surgery and Vascular Diseases Vascular Surgery Unit, Humanitas Clinical and Center, Azienda Ospedaliera Universitaria di Research Hospital, Rozzano, Italy Ferrara, Italy

00_Romane.indd XI 03/01/18 10:24 AUTHORS

MATTEO TOZZI PAOLO ZAMBONI Vascular Surgery, Department of Medicine and Department of Morphology, Surgery and Surgery, Circolo University Teaching Hospital, Experimental Medicine and Vascular Diseases University of Insubria School of Medicine, Varese, Center, University of Ferrara, Italy; Unit of Italy Translational Surgery and Vascular Diseases Center, Azienda Ospedaliera Universitaria di SANTI TRIMARCHI Th oracic Aortic Research Center, Policlinico Ferrara, Italy San Donato IRCCS, University of Milan, San MATILDE ZAMBONI Donato Milanese, Italy Post graduated School in Vascular Surgery, DAVID UTRIAINEN University of Padua, Italy Th e MRI Institute for Biomedical Research, Detroit, MI, USA ANTONIO ZANGHI Vascular Surgery and Organ Transplant Unit, MASSIMILIANO VEROUX Department of Surgery, University Hospital of Vascular Surgery and Organ Transplant Unit, Catania, Italy Department of Surgery, University Hospital of Catania, Italy ROBERT ZIVADINOV PIERFRANCESCO VEROUX Buff alo Neuroimaging Analysis Center, Vascular Surgery and Organ Transplant Unit, Department of Neurology, Jacobs School of Department of Surgery, University Hospital of Medicine and Biomedical Sciences, University at Catania, Italy Buff alo, State University of New York, Buff alo, CARLA VIRGILIO NY, USA; Center for Biomedical Imaging Vascular Surgery and Organ Transplant Unit, at Clinical Translational Science Institute, Department of Surgery, University Hospital University at Buff alo, State University of New of Catania, Italy York, Buff alo, NY, USA

XII

00_Romane.indd XII 03/01/18 10:24 Contents

PART ONE: THE LARGE VEINS

1. From anatomy to function of large vein ...... 3 B.B.Lee, J. Laredo

2. Hemodynamics and volume changes of the venous system ...... 11 P. Zamboni, M. Tessari

3. Compliance properties of the vein: a forgotten concept ...... 19 P. Zamboni, F. Sisini

4. Obstructive truncular venous malformations: general overview ...... 28 B.B.Lee, J. Laredo

5. Secondary occlusive disease of the great veins ...... 37 A. Jayaraj, P. Gloviczki

6. Primary venous aneurysms ...... 48 P. Zamboni

7. ECD of large veins ...... 53 E. Menegatti, M. Zamboni, C. Franceschi

8. New devices for the treatment of large veins ...... 68 S. Ronchey

9. Indications and potential benefi ts of endovascular treatment of occlusive venous disease ...... 74 A. Jayaraj, S. Raju

XIII

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10. Venous thoracic outlet syndrome ...... 83 J. Blebea, J.S. Blebea

11. Clinical presentation and treatment of secondary venous occlusive disease of the thorax ...... 97 P.D. Do, M.D. Dake

12. Open surgery techniques for reconstruction of vena cava ...... 110 R. Chiesa, D. Mascia, M. Bossi, A. Grandi, R. Bertini, E. Civilini, G.L. Poletto

13. Treatment of large veins of the thorax in hemodialysis patients with arm swelling 132 M. Veroux, G. D’Arrigo, D. Mociskyte, A. Giaquinta, A.Zanghi, P. Veroux

14. Endovascular treatment of obstructive diseases of inferior vena cava ...... 142 I. Petrov, L. Grozdinski, G. Adam, S. Stefanov

15. Inferior vena cava syndrome and malignancy ...... 156 S. Trimarchi, D. Spinelli, F. Benedetto

16. Renal vein compression syndromes: embryology, physiology, diagnosis, clinical manifestations and treatment ...... 165 S.J.A. Sclafani

17. Endovascular management of mesenteric vein occlusion ...... 178 H. Ferral

18. Primary Budd-Chiari syndrome: suprahepatic inferior vena cava occlusive disease 184 B.B. Lee

19. May-Th urner syndrome and chronic iliofemoral vein occlusions ...... 194 A. Jayaraj, S. Raju

20. Th romboaspiration device in the treatment of acute deep vein thrombosis and pulmonary embolism ...... 206 C. Setacci, M. Tadiello, F. Setacci, G. de Donato, M. Tozzi, D. Benevento, P. Castelli, G. Palasciano

21. Deep vein valves incompetence and treatment implications ...... 216 S. Hardy

22. Treatment of iliac refl ux in duplicated femoral venous segments ...... 230 P. Zamboni, S. Gianesini

XIV

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PART TWO: CEREBRAL OUTFLOW

23. MR imaging of intracranial and extracranial veins ...... 237 E.M. Haacke, D. Utriainen, S. Buch, Y. Chen

24. Imaging of extracranial obstructive venous disease ...... 251 D. Jakimovski, K. Marr, R. Zivadinov

25. Chronic cerebrospinal venous insuffi ciency ...... 269 P. Zamboni, E. Menegatti, R. Galeotti, F. Salvi

26. Catheter venous angiography for the evaluation of cerebral venous outfl ow ...... 280 A. Giaquinta, C.B. Beggs, M. Veroux, A. Cappellani, E. De Marco, P. Veroux

27. Chronic cerebrospinal venous insuffi ciency and Meniere disease ...... 284 A. Bruno, S. Ronchey, L. Califano, G. Attanasio, A. Minni, P.P. Cavazzuti, V. Giugliano, R. De Vizia, D. Mastrangelo, B. Bernardo, N. Mangialardi

28. Novel compliant scaff old with specifi c design for venous system ...... 295 P. Veroux, A.Giaquinta, C. Virgilio, M.Veroux

00_Romane.indd XV 03/01/18 10:24 Part one The large veins

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B.B. Lee, J. Laredo

MACROSCOPIC TO MICROSCOPIC dothelium (up to 40-50 μm diameter) sur- ASPECTS OF VENOUS ANATOMY rounded by pericytes, contractile cells, to control blood fl ows through the microvascu- Veins are defi ned as a transportation conduit lature while large venules (50-100 μm diam- to carry back the blood toward the heart from eter) are surrounded further by one or two tissue, starting from the venules in peripheral layers of smooth muscle cells, and a thin layer tissues and organs to converge to create various of connective tissue beyond the pericytes and sizes of small and then larger veins. Th e ulti- the smooth muscle cells. mate “large” veins to deliver the blood to the Hence, the venular endothelium is able to right atrium of the heart is the vena cava, supe- keep a unique anatomical structure of labile rior and inferior, the largest veins in the human junctions/gaps between the cells to “open” body. Th ese two large veins deliver the blood under the infl uence of serotonin, histamine, to the right atrium of the heart from above and bradykinin and other agents through infl am- below; the superior vena cava (SVC) from the matory reactions resulting in increased per- upper extremities and head and neck, the infe- meability and subsequent local swelling. rior vena cava (IVC) from the lower extremities On the contrary, the veins belonging to and abdomen/torso to the heart.1-4 macrovasculature in general are structurally However, the microvasculature, so called diff erent from venules; they stay ‘collapsible’ “venule”, which is composed of blood vessels since they do not encounter high systolic that are smaller than 100 microns only visible pressure like arteries but low pressure based through the microscope, is separately grouped on “vis-a-tergo” (i.e. pushing force acting as part of the tissue it is connected to, in view from behind), the residual arterial pressure of a regulatory function controlling vascular transmitted through the capillaries for the ve- permeability and myogenic responses that nous return. can adapt blood fl ow.5-7 Only those veins of Such collapsible nature of the conduit is the macrovasculature, visible with the naked physiologically as well as hemodynamically eye, are considered as independent anatomi- more ideal for complex venous fl ow patterns cal entities of venous system.8, 9 Although they in intermittent nature, varying from high both belong to the basic functional unit of velocity to no fl ow, and also for the role as the cardiovascular system, they are diff erent “capacitance vessels” containing most (60- structurally and functionally from each other 70%) of the blood volume as the ‘reservoir’ of in their architecture and cellular components. the venous system in addition to its primary Indeed, small venules are the tubes of en- function as transport system.5, 10-12

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Th e venous volume/fl ow will be con- in the iliac veins and inferior vena cava while trolled by the delicate balance among trans- venous valves are found in the deep and super- mural pressure, active tone of the muscular fi cial veins and most perforating veins.5, 10 media layer and passive compliance of the However, to meet the special functional adventitial layer. Large diameter veins with a needs in certain organs with unique ana- high passive compliance and variable venous tomical conditions there are variations in the tone are capable to store blood and also mo- structure of blood vessels. Pulmonary arteries, bilize quite easily by increasing the tone of the for example, have thin walls with a signifi cant venous wall with a low variation of transmu- reduction in both muscular and elastic ele- ral pressure whenever needed.5, 10 ments, while the veins have a well-developed To meet such natural mandate as illustrat- media of smooth muscle cells. Umbilical ves- ed above, they have made of much thinner sels are another example, to show the vein smooth muscle cell layers in tunica media, the with a thick muscular wall with two to three middle layer among three layers of vein wall – muscle layers while the arteries with two lay- tunica interna, media, and externa – in com- ers of smooth muscle cells without a promi- parison to those of arteries while tunica ad- nent internal elastica or adventitia. ventitia/externa, the outer layer of vein wall is made of thick connective tissue. Indeed, veins in small and medium sizes contain only a few FUNCTIONAL ASPECTS OF layers of smooth muscle cells to compose a VENOUS ANATOMY thin media although these groups of veins have a much thicker adventitia composed of Primary function of venous system is to de- collagen and some longitudinal smooth mus- liver deoxygenated blood from the tissue to cle fi bers occasionally. the right atrium of the heart for systemic cir- Veins of larger diameter have thinner walls culation. For the return of blood to the heart, than arteries but the tunica adventitia makes the action of the (calf) muscle pump and up the bigger part of the venous wall so that the thoracic pump action of breathing dur- large veins are considerably thicker in the tu- ing respiration is essential in addition to the nica adventitia than the tunica media in gen- residual arterial pressure transmitted through eral. Extreme example is IVC which presents the capillaries for the venous return, so called with much reduced or absent tunica media “vis-a-tergo” (i.e. pushing force acting from and an adventitia with large bundles of longi- behind).5, 10 tudinally disposed smooth muscle. However, not all veins take deoxygenated Veins are, therefore, less muscular than blood back to the heart; there is an exception, arteries in general, suffi cient to carry blood the pulmonary and umbilical veins, both of back from the tissue to the heart, in contrast which carry oxygenated blood to the heart. to arteries but a new additional structure of Th e venous blood delivered to the right atri- one way “valves” evolved in most veins to um is further transferred to the right ventricle prevent refl ux/backfl ow throughout systemic so that it is pumped through the pulmonary venous system in various extents depending arteries to the lungs to get the necessary re- upon the location. Valves are usually bicuspid oxygenation through pulmonary circulation. with the leafl ets centrally directed of venous In pulmonary circulation, oxygenated blood fl ow.13, 14 blood returns from the lungs to the left atri- Venous valves are present in nearly all of the um through the pulmonary veins and then veins of the lower extremities; in general, the into the left ventricle, completing the cycle further away from the central circulation, the of blood circulation. Indeed, the systemic cir- more frequent a venous valve is present in the culation is by far the larger of the two, which venous system. Venous valves are often absent transports oxygen from the heart to the tis-

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sues of the body, but proper pulmonary circu- enormous amount of new information on lation, that is, deoxygenated blood from the the venous system including its neglected re- heart to the lungs by the pulmonary arteries lationship with the lymphatic system. Now, and return blood from the lungs to the heart a new concept on the venous system is es- by pulmonary veins remains essential for tablished as one of dual drainage system to- complete cycle of systemic circulation. gether with the lymphatic system 19 with a In addition, the hepatic-portal veins cir- new prospect. And it further warrants a new culation carry the blood between capillary interpretation of the venous system with fresh beds from the capillary beds in the digestive insights based on hemodynamic aspect 10 as tract to the capillary beds in the liver, where well as embryological aspect.20 it is taken up by the hepatic veins before it is Indeed, proper understanding of the anat- taken back to the heart. omy of the vena cava as ultimate ‘large veins’ Blood fl ow through the venous system is warrants correct embryological interpretation under neuromuscular control and is aff ected of their complex structure from functional by gravity and muscular contractions. Com- point of view. Because, a defective develop- petent venous valves warrant for this normal ment of this ‘large’ vein would accompany venous function. Normal valve function can with much profound clinical impacts (e.g. provide a water-tight closure against a retro- suprahepatic inferior vena cava occlusive dis- grade pressure gradient opposite to the di- ease,1, 2 known as primary Budd-Chiari syn- rection of the leafl ets. Th is function ensures drome). unidirectional fl ow for physiologic drainage Four pairs of the cardinal veins should go of venous compartments emptying the ve- through complicated evolutional/maturation nous blood/fl ow from superfi cial to deep process to interconnect among a total of eight venous system of lower extremity, regardless diff erent segments to form one new vena cava of posture or changes in intra-abdominal or system in right side of the body cavity in the intrathoracic pressures. Th e valve leafl ets re- later stage of embryogenesis. Some parts of main passively open when the pressure gradi- the cardinal veins would disappear through ent is antegrade in the same direction as the this due process of natural involution, while leafl ets.15-18 some would become incorporated into new- Normal valve closure also produces dy- ly formed inferior vena cava (IVC)-bilateral namic fracturing of the gravitational hy- iliac vein system as well as superior vena cava drostatic pressure and is essential for proper (SVC)-innominate-jugular vein system com- function of the peripheral muscle pumps. bined with azygos-hemiazygos system. Muscular activity such as walking can reduce Naturally, such complex process to form the hydrostatic pressure from 90 mmHg to the large veins (e.g. inferior and superior vena 30 mmHg only by competent venous valves cava) would accompany with substantial risk that fractionate the pressure column during of developmental defects.1-4, 20, 21 Hence, a lower extremity muscular contraction (sys- precise understanding of this unique embryo- tole) and relaxation (diastole).5, 10, 15-18 logical aspect of ‘large’ vein, that is, vena cava is warranted. EMBRYOLOGICAL ASPECTS OF VENOUS ANATOMY CARDINAL VEINS: EMBRYOLOGICAL VEINS Th roughout the last century, advanced di- agnostic technology led by Duplex ultra- Th e development of the axial/truncal venous sonography, magnetic resonance imaging, system is preceded by the complex capillary/ and computerized tomography has provided reticular plexuses in early embryonic stage;

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the primitive circulation system develops from the mesoderm as early as 15 to 16 days of gestation to form heart and blood vessels, starting as isolated masses and cords of mes- enchymal cells.1-4, 20 An extensive network of blood vessels has formed from the clusters of angiogenetic cells/mesenchyme throughout the embryonic body by the beginning of the fourth week, to establish a communica- tion with extra-embryonic vessels to create a “primitive vascular system”: vitelline-umbili- FIGURE 1.2. Embryonic veins at the 7th week: vitelline/umbilical veins de- th 1-4 velopmental process. Till the 7 week of embryonal development, the entire cal-cardinal vein system (Figures 1.1, 1.2). right umbilical vein and proximal left umbilical vein regress; the distal left Th e primitive vascular complex in structure umbilical vein subsequently anastomoses with the hepatic sinuses to form of capillary and reticular plexuses is soon re- ductus venosus. Ductus venosus allows venous blood from the umbilical vein and the portal vein directly to the inferior vena cava (IVC); distal/up- placed by the newly developed four paired car- per most segment of the right vitelline vein remains as the most proximal dinal veins in the early embryonic stage as an segment of IVC reaching to the heart tube via paired sinus venosus while all axial, truncal venous system: anterior cardinal, other parts of the vitelline veins regress/involute completely (adapted from: 20 posterior cardinal, supracardinal and subcar- Lee BB ). dinal veins. Th ese cardinal veins subsequently go through complicated evolutional process to draining centrally into the sinus venosus (sinus form two ultimate large veins: SVC and IVC. horns) and also receiving the paired ‘vitelline’ Paired anterior and posterior cardinal veins vessels from the yolk sac to develop into the merge to become the ‘common cardinal veins,’ hepatic portal system and also the paired ‘umbilical’ veins from the chorion and body stalk to form the ductus venosus (Figure 1.1). Th e paired umbilical veins return blood from the placenta to capillary networks in the liver at 4 weeks. During the fi fth week of development, the right umbilical vein regresses/ involutes together with the proximal portion of the left umbilical veins, leaving only the distal part of the left umbilical vein to return/ carry blood from the placenta to the embryo as a single vein. At 8 weeks when left umbilical vein loses its original connection with left sinus horn, the distal left umbilical vein anastomoses with the hepatic sinuses and to the newly formed ductus venosus (direct venous shunt of oxygenated blood from placenta to heart), which allows venous blood from the umbilical vein FIGURE 1.1. Embryonic veins at the 5th week: anterior/posterior/common and the portal vein to bypass the liver and cardinal veins and vitelline/umbilical veins developmental process. The embryo demonstrates the development of paired sets of the ‘vitelline’ and fl ow directly to the IVC and fi nally to reach ‘umbilical’ veins in its 5th week, which initially drain the yolk sac and allantois the heart via the paired sinus venosus. Ductus but later drain the intestines and the placenta, respectively and also paired venosus is a single oblique channel among in- sets of anterior and posterior cardinal veins join to form the “common cardinal veins”, draining centrally into the sinus venosus. The common cardinal trahepatic anastomoses, draining directly into veins also receive “vitelline” and “umbilical” veins, as depicted (adapted from: nascent IVC as crucial shunt to right atrium Lee BB 20). from umbilical system (Figure 1.2).

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When regression of left vitelline vein is completed, its drainage is shunted to right vitelline vein through new intrahepatic anastomoses. And superior portion of right vitelline vein (portion between liver and heart) becomes the terminal portion of IVC. Such complicated vascular changes on vitelline vein and umbilical vein system in- volving ductus venosus development and eventual regression through the obliterating process will add more risk of developmental FIGURE 1.3. A, B) Precardinal/anterior cardinal vein-involved devel- anomalies. Since superior portion of right vi- opmental process. Paired anterior cardinal veins form common cardinal veins with paired posterior cardinal veins, draining centrally into the sinus telline vein (portion between liver and heart) venosus (sinus horns) as depicted. Paired anterior cardinals soon form an becomes terminal portion of inferior vena anastomosis between them; the connection grows from the left to the right cava, IVC and hepatic veins has high risk dur- anterior cardinal vein to form the left brachiocephalic (innominate) vein. The left anterior cardinal vein distal (cranial) to the anastomosis becomes the ing the fusion process of umbilical vein and “left internal jugular vein” while left anterior cardinal vein proximal to the vitelline vein besides the risk of overextension brachiocephalic anastomosis regresses to become the base of the “coronary into hepatic vein-IVC system.3 sinus” of the heart as displayed. Right anterior cardinal vein proximal to the right brachiocephalic vein forms SVC with common cardinal, and terminal/ proximal segment of posterior cardinal vein (adapted from: Lee BB 20). SUPERIOR VENA CAVA (SVC): EVOLUTION OF ANTERIOR CARDINAL VEINS Meanwhile, the proximal (caudal) portion of left anterior cardinal vein to the anasto- Initially, “bilateral anterior cardinal veins”, mosis regresses to form the great cardiac vein also known as the precardinal veins, drains the with the terminal segment of the left poste- body portion cephalad to the developing heart rior cardinal vein. Th e oblique vein of the left (head, neck, upper torso and upper limbs), atrium (vein of Marshall) on the back of left while “bilateral posterior cardinal veins”, also atrium and the “coronary sinus” of the heart known as the postcardinal veins, drains the comprise the great cardiac vein. On the right caudal portion of the body (torso and lower side, the proximal part of right anterior cardi- limb).20-23 But, soon, major evolutional pro- nal vein forms the SVC with the right com- cess is evolved along the anterior cardinal mon cardinal vein in conjunction with right veins; paired anterior cardinal veins form an horn of the Sinus Venosus (Figure 1.3). anastomosis fi rst through newly formed left SVC is therefore made up of three diff er- brachiocephalic (innominate) vein to let the ent segments: blood drain from the ‘left anterior cardinal 1. right anterior cardinal vein proximal to vein’ into the “right anterior cardinal vein”. the brachiocephalic anastomosis; Th e distal (cephalad) portion of the left 2. right common cardinal vein; anterior cardinal vein to the brachiocephalic 3. right horn of the Sinus Venosus. anastomosis becomes the ‘left internal jugular Hence, the anterior cardinal veins remain vein’ and subsequently joins the ‘left subcla- largely intact through such complicated evo- vian vein’ from the developing upper limb. lution to become the veins of the heart and Accordingly, the distal (cephalad) portion of SVC and its tributaries together with com- bilateral anterior cardinal veins become the mon cardinal and terminal/proximal pos- bilateral internal jugular veins and the blood terior cardinal veins. Indeed, these veins are from the left internal jugular vein passes further involved in the formation of the arch through the left brachiocephalic veins drain- of azygos vein together with the proximal seg- ing directly into the SVC 24, 25 (Figure 1.3). ment of the right posterior cardinal vein. Th e

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FIGURE 1.4. A,B) Three sets/pairs of cardinal veins: precardinal, postcardinal, and supracardinal, are evolved to azygos vein system. Azygos venous system is initially derived from the paired supracardinal vein; proximal segment of right supracardinal vein forms the arch of azygos vein together with the cranial part of the right posterior cardinal vein while (cranial part of) left supracardinal vein becomes the hemiazygos and also accessory azygos veins. The hemiazygos vein on the left side drains into the azygos vein located in the right side before it is drained into SVC; ‘accessory’ hemiazygos vein along the course of the involuted left common cardinal vein, drains into the hemiazygos vein before it crosses over the midline to the azygos vein (adapted from: Lee BB 20).

FIGURE 1.5. A-C) Developmental process of inferior vena cava involved by posterior cardinal, supracardinal and subcardinal veins. Three pairs of the posterior-/ sub-/supra-cardinal veins go through much more extensive evolution as well as involution process to form the IVC as well as hepatic veins together with bilateral vitelline and umbilical veins. The role of posterior veins, the fi rst pair of embryological vein for the caudal body venous drainage, is soon taken over by subsequently developing pairs of subcardinal and supracardinal veins, to fi nish the formation of the IVC as shown (adapted from: Lee BB20 ).

termination of the left posterior cardinal vein before it drains into SVC. Th e “accessory” transforms into great cardiac vein draining hemiazygos vein along the course of the in- into left atrium as illustrated as above. voluted left common cardinal vein, drains Azygos venous system is initially derived into the hemiazygos vein before it crosses the from the paired supracardinal venous system, midline to fl ow into the azygos vein (Figures one of three cardinal veins that drain caudal 1.4, 1.5). portion of the body, together with the posterior cardinal veins.26, 27 Another word, the right supracardinal vein forms “azygos vein” together INFERIOR VENA CAVA (IVC): with the cephalad part of the right posterior EVOLUTION OF POSTERIOR, cardinal vein fi nally to the arch of azygos vein. SUPRA AND SUB-CARDINAL VEINS And the left supracardinal vein becomes the hemiazygos vein and also accessory azygos vein. Th e posterior cardinal (postcardinal) veins Th e hemiazygos vein located on the left are the fi rst pair of embryonic veins among drains into the azygos vein on the right side three cardinal veins to drain caudal body, but

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its leading role is soon taken over by subse- Th e IVC is therefore, an embryologically quently developed two additional pairs of compound vessel as the outcome of a com- subcardinal and supracardinal veins. Th e shift plicated fusion process among multiple seg- of systemic venous return to right side to line ments of diff erent embryonic veins: vitelline, up with right atrium initiates the radical re- supracardinal, subcardinal, and posterior car- modeling of these three pairs of cardinal ve- dinal, and their anastomosis among them and nous systems through the fi nal vascular trunk also between own sub- and supra-cardinals. maturation stage of embryogenesis.20, 28-30 Naturally there exists a high risk of develop- Th ese three pairs of posterior cardinal, mental anomalies occurring during this com- subcardinal, and supracardinal veins go plicated IVC formation process.31, 32 through extensive evolution as well as involu- Depending upon the location as well as tion to form the IVC to drain the trunk and the extent of anatomical variation caused by lower extremities.18, 19 anomalous development of vena cava, its clin- Th is complicated process for the comple- ical impact to the target organs/tissues will tion of vena cava development involves an in- vary heavily by the collaterals developed as tricate series of new development, regression, compensatory route of venous drainage.33-35 and anastomosis to compose multi-segments of vena cava from diff erent origins for the -fi nal replacement of three cardinal veins alto- REFERENCES gether.20, 28-30 Eventually, the IVC is formed through the following embryonic structures: 1. Lee BB, Villavicencio L, Kim YW, Do YS, Koh 1. suprahepatic segment of the IVC: it is the KC, Lim HK et al. Primary Budd-Chiari Syn- most proximal segment of the IVC devel- drome: Outcome of Endovascular Management oped from the persistent proximal portion for Suprahepatic Venous Obstruction. J Vasc Surg of the right vitelline vein which is the pre- 2006;43:101-8. cursor of the common hepatic vein; 2. Lee BB, Laredo J, Neville R. Embryological back- 2. new hepatic segment: it develops from ground of truncular venous malformation in the an anastomosis between the segments of extracranial venous pathways as the cause of chron- right vitelline vein and the right subcar- ic cerebrospinal venous insuffi ciency. Intern Angiol 2010;29:95-108. dinal vein distal to the developing liver 3. Warwick R, Williams PL, editors. Gray’s anatomy. to connect this proximal-most (suprahe- 35th ed. Philadelphia: WB Saunders; 1973. p. 164-7. patic) segment to the distally located right 4. McClure CFW, Butler EG. Th e development of vena subcardinal vein while allowing the drain- cava inferior in man. AmJ Anat 1925;35:331-83. age of the hepatic veins/liver; 5. Laredo J, Lee BB. Venous physiology and patho- 3. renal/mesenteric segment: it is represent- physiology. In: Chaar CIO, editor. Current man- ed by a preserved segment of the right agement of venous diseases. Berlin: Springer-Ver- subcardinal vein; lag; 2017. 4. new junctional segment of the IVC: it is 6. Curry FR, Adamson RH. Vascular permeability formed through the anastomosis between modulation at the cell, microvessel, or whole organ the right subcardinal vein and the more level: towards closing gaps in our knowledge. Car- distally located right supracardinal vein; diovasc Res 2010;87:218-29. 5. infrarenal segment: it is represented by the 7. Pober JS, Sessa WC. Infl ammation and the blood microvascular system. Cold Spring Harb Perspect preserved segment of the right supracardi- Biol 2014;7:a016345. nal vein; 8. Krentz AJ, Clough G, Byrne CD. Interactions be- 6. last caudal segment of the IVC: it is tween microvascular and macrovascular disease in formed as a new segment to connect the diabetes: Pathophysiology and therapeutic implica- right supracardinal and most distal part of tions. Diabetes Obes Metab 2007;9:781-91. the bilateral posterior cardinal veins. 9. Al-Wakeel JS, Hammad D, Al Suwaida A, Mitwalli

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