New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation

New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation

Editors

Ion C. Ţintoiu

Adrian Ursulescu

John A. Elefteriades

Malcolm John Underwood

Ionel Droc

Table of Contents

Cover image

Title page

Dedication

Copyright

List of Contributors

Preface

Part I. Overview

Chapter 1. Aging Aorta—Cellular Mechanisms

Aging and Stiffness Aorta

Intima–Endothelial Senescence

Intima and Media—Apoptosis

Intima–Extracellular Matrix and MMPs Roles

Media–VSMCs

Media–Elastin/Collagen Ratio

Media Inflammation

Telomere Length—A Biomarker of Aorta Aging

Atherogenesis

Conclusions

Chapter 2. Endothelial Dysfunction in Aortic Aneurysm

Overview

Oxidative Stress

Graft Endothelialization

Conclusions

Chapter 3. Histology of Aortic Disease and Progression of Aortic Dissection From Acute to Chronic

Introduction

Normal Histology of the Aorta

Histology of Aortic Aneurysm and Dissection

Histology of the Transition From Acute to Chronic Dissection

Macroscopic Changes of the Transition From Acute to Chronic Dissection

Chapter 4. The Pathogenesis of Aortic Valvular Disease

Pathogenesis of Aortic Stenosis

Aortic Regurgitation

Chapter 5. Aortic Root Pathologies

Introduction

Functional Anatomy

Histopathologic Changes

Aortic Root Pathologies

Chapter 6. Cellular Mechanisms of Ascending Aortic Aneurysms

Structure, Size, and Location of Aorta

Diagnosis and Risk Factors of Ascending Aortic Aneurysm

Characterization of Ascending Aortic Aneurysms

Cellular Mechanisms of Ascending Aortic Aneurysm

Additional Factors Involved in Ascending Aortic Aneurysm

Potential Drug Treatments for Ascending Aortic Aneurysm

Summary

Chapter 7. Mathematical Modeling of Aortic Aneurysm Progression

Introduction

Mathematical Modeling and Systems Analysis of Biological Phenomena

Petri Net–Based Model of Aortic Aneurysm Progression

Chapter 8. Genetic Basis of Aortic Disease

Syndromic Thoracic Aortic Aneurysms and Dissections

Nonsyndromic Thoracic Aortic Aneurysms and Dissections

Conclusions

Chapter 9. Congenital Malformations (Bicuspid, Right Aortic Arch, Coarctation)

Introduction

Bicuspid Aortic Valve and Associated Aortopathy

Right Aortic Arch

Coarctation

Conclusion

Chapter 10. Guilt by Association: Paradigm for Detection of Silent Aortic Aneurysms

Introduction

Intracranial Aneurysm

Aortic Arch Anomalies

Abdominal Aortic Aneurysm

Bicuspid Aortic Valve

A Positive Thumb–Palm Sign

Family History of Aortic Disease

Simple Renal Cysts

Giant Cell Arteritis (and Other Autoimmune Disorders)

Chapter 11. Inflammatory Diseases (Takayasu, Giant Cell Arteritis, Behçet Disease)

Vascular Inflammation—Central Role in the Pathogenesis of Takayasu’s Arteritis, Giant Cell Arteritis, and Behçet Disease

Biomarkers in Inflammatory Vasculitis

Diagnostic Imaging and Assessment of Aortic Inflammation

Pleiotropic Therapy of Inflammatory Vasculitis

Part II. Diagnostic Evaluation Methods

Chapter 12. Chest X-Ray in Aortic Disease

Introduction

Capabilities of the Plain Chest X-Ray

Diagnosis of Acute Aortic Syndrome

Conclusions

Chapter 13. Echocardiography in Aortic Valve Stenosis

Degenerative Aortic Stenosis

Rheumatic Aortic Stenosis

Congenital Aortic Stenosis

Quantification of Aortic Stenosis

Calculating the Jet Velocity and the Transaortic Pressure Gradient

Aortic Valve Area

Special Varieties of Valvular Aortic Stenosis

Low-Flow, Low-Gradient Aortic Stenosis With Reduced Left Ventricular Ejection Fraction

Paradoxical Low-Flow, Low-Gradient Aortic Stenosis

Aortic Stenosis Associated With a Noncompliant Left Ventricle, With Reduced Ejection Fraction

Aortic Stenosis Associated With Systolic Aortic Regurgitation

Stress Echocardiography in Asymptomatic Aortic Stenosis

Conclusions

Chapter 14. Echocardiographic Assessment of the Aorta

Introduction

Echography for the Assessment of Normal Thoracic Aorta

Echography for the Assessment of Pathology of Thoracic Aorta

Duplex Ultrasound and Other Echographic Techniques for the Assessment of Abdominal Aorta

Conclusion

Chapter 15. Echocardiography in Acute Aortic Syndromes

Acute Aortic Syndromes: Classification, Clinical Manifestation, and Management

Role of Echocardiography in Diagnosis of Acute Aortic Syndrome

Perioperative Echocardiographic Assessment

Summary

Chapter 16. Transesophageal Echocardiography in the Assessment of Aortic Valve and Aortic Root Disease

Introduction

Technical and Practical Considerations

Transesophageal Echocardiography Role in the Morphological Assessment of Aortic Valve Disease

Transesophageal Echocardiography Role in Evaluation of Aortic Stenosis

Transesophageal Echocardiography Role in Evaluation of Aortic Regurgitation

Transesophageal Echocardiography Role in the Morphological Assessment of Aortic Root Disease

Conclusions

Chapter 17. 3D Virtual Intravascular Endoscopy of Aortic Disease

Introduction

Virtual Intravascular Endoscopy

Virtual Intravascular Endoscopy of Aortic Aneurysm

Virtual Intravascular Endoscopy of Aortic Dissection

Virtual Intravascular Endoscopy of Endovascular Stent Grafts

Summary

Chapter 18. CT Angiography

Introduction

CT Angiography of the Aorta

Abnormalities of the Aorta

Summary

Chapter 19. Magnetic Resonance Angiography

Introduction

Patient Preparation, Imaging Technique, and Data Postprocessing

Normal Aorta

Aortic Aneurysm

Acute Aortic Syndromes

Aortitis

Aortic Stenosis

Aortic Coarctation

Follow-up Examinations

Conclusions

Chapter 20. CT and MRI in Acute Aortic Syndrome

Introduction

Choice of Imaging Modality

Computed Tomography Angiography of the Aorta

Magnetic Resonance Angiography of the Aorta

Aortic Dissection

Intramural Hematoma

Penetrating Aortic Ulcer

Conclusion

Chapter 21. Dual-Energy CT of Aortic Disease

Introduction

Principles of DECT

DECT Techniques

Image Weighting Factor

Virtual Noncontrast Images

Virtual Monochromatic Imaging

Iterative Reconstruction

Contrast Medium Dose

Applications of DECTA in Aortic Disease

Radiation Dose

Conclusion

Part III. Treatment

Chapter 22. Current Status of Medical Therapy of Thoracic Aortic Aneurysm and Dissection

Introduction

Medical Therapy Overview

β-Blockers

Angiotensin Receptor Blockers

Matrix Metalloproteinase Inhibitors

Statins

Medical Management of Acute Aortic Event

Conclusions

Chapter 23. Organ Preservation During Open Thoracoabdominal Reconstruction

Background

Surgical Approach and Protection Techniques

Two-Staged Approach in Distal Aortic and TAAA Aneurysms

Cerebrospinal Fluid Drainage

Profound Hypothermic Circulatory Arrest

Major Drawback With Deep Hypothermia

Motor- and Somatosensory-Evoked Potentials

Left Heart Bypass Approach

Celiac Trunk and Superior Mesenteric Artery Perfusion

Renal Protection

Aortic Reconstruction With the Aim of Minimizing Organ Ischemia

Extracorporeal Membrane Oxygenator

Conclusion

Chapter 24. Conventional Aortic Valve Surgery (Open Surgical Approaches)

Introduction

Historical Perspective

Indications

Conventional Aortic Valve Replacement

Outcomes

Future

Chapter 25. Reconstructive Surgery of the Aortic Valve

Introduction: A Need to Preserve Native Valve

Anatomy and Pathophysiology—Crucial Considerations

Patient Selection—A Key of Surgical Success

Techniques for Aortic Valve Repair

Early and Long-Term Outcomes

Conclusions

Chapter 26. Aortic Root Replacement

Historical Perspective

Indications for Aortic Root Surgery

Initial Stages

Operative Techniques

Outcomes

Future

Chapter 27. Current Status of Open Surgery in Aortic Arch Surgery

Introduction

Brain Protection

Surgical Considerations

Future Directions

Abbreviations

Chapter 28. Dissection of the Ascending Aorta and Aortic Arch

Introduction

Open Surgery in ATAAD—Supportive Techniques

The Elephant Trunk Procedure

Hybrid Procedures

Total Thoracic Endovascular Aortic Repair for Acute Thoracic and Ascending Aorta Dissection

Chapter 29. Dissection of Thoracoabdominal Aorta

Introduction, Epidemiology, and Pathophysiology

Etiology and Natural History

Classification

Clinical Presentation

Diagnosis

Biomarkers

Management

Conclusion

Chapter 30. Open Repair of Thoracic and Thoracoabdominal Aortic Aneurysms

Introduction

Intraoperative Techniques

Spinal Cord Protection

Renal–Visceral Protection

Postoperative Management

Special Situations

Conclusion

Chapter 31. Subtotal and Total Aortic Replacement

Introduction

Revolutionary Discovery of Heart–Lung Machine

Evolution of Graft Tube

Subtotal and Total Aortic Arch Replacement

Total Aortic Arch Replacement Technique

Complications of and Results of Aortic Arch Surgery

Results of Aortic Arch Surgery

Chapter 32. Hybrid Techniques for Complex Aortic Surgery

Introduction

Division

Conclusions

Chapter 33. Minimally Invasive Aortic Surgery: Mini-Bentall Procedure and Beyond

Introduction

Etiology of Thoracic Aortic Aneurysm

Marfan Syndrome

Nonsyndromal Familial Thoracic Aortic Aneurysm

Bicuspid Aortic Valve

Pathophysiology of Thoracic Aortic Aneurysm

Indications for Surgery

Evolution of Proximal Thoracic Aortic Surgery

Evolution of Minimally Invasive Cardiac Surgery

Mini-Bentall and Hemiarch Procedure

Preparation

Mini-sternotomy

Cannulation and Cardiopulmonary Bypass

Preparation of the Aortic Root

Aortic Root Replacement

Hemiarch Replacement

Graft-to-Graft Anastomosis

Completion of Procedure

Discussion

Conclusions and Future Directions

Chapter 34. Abdominal Aortic Aneurysms (AAA): Actual Approach

Introduction

Open Repair of AAA

The Endovascular Repair

Follow-Up of EVAR

Anesthetic Considerations for AAA

Therapeutic Strategies for rAAA

Complications After Ruptured AAA Treated Endovascularly

Conclusions

Chapter 35. Surveillance After Elective EVAR

Introduction

Postoperative Surveillance

EVAR Surveillance Protocol

Chapter 36. Dissection of the Abdominal Aorta

Introduction

Symptoms and Signs

Diagnosis

Management Strategies

Chapter 37. The Various Types of Endovascular Stent Grafts for EVAR: How Do They Compare?

Introduction

Technical Characteristics of Commercially Available Endografts

Anatomic Suitability of Different Endografts in AAA

Comparing the Clinical Efficacy Between Various Endografts

Mechanical Differences Between Endografts

Discussion

Chapter 38. Endovascular Stent-Graft Repair of Abdominal Aortic Aneurysms

Background

Indications for EVAR

Anatomic Criteria for EVAR Device Eligibility

Preoperative Imaging

Vascular Access

The EVAR Device

Stent-Graft Deployment

Endoleaks

Post-EVAR Surveillance Imaging

Chapter 39. Risk of Thrombosis in Downstream Flow of Mechanical Aortic Valves: A Computational Approach

Background on Computational Approach

Comparison of the Effects of Bileaflet and Trileaflet Mechanical Aortic Valve Design on Downstream Flow Patterns and Blood Shear

Effect of Implantation Angles of Mechanical Aortic Valves on Flow Patterns and Blood Shear

Summary

Chapter 40. Thoracic Endovascular Aortic Repair

Introduction

Developing a TEVAR Program

TEVAR for TAD

TEVAR for TAA

TEVAR for Traumatic Aortic Injury and Connective Tissue Disorder

Current Technical Aspects of TEVAR

Complications

Conclusion

Abbreviations

Chapter 41. Transcatheter Aortic Valve Implantation

Historical Development

Patient Selection

Indications for TAVI

Surgical Techniques and Access Sites

Prosthesis

Complications

Updates and Future Developments

Chapter 42. Transcatheter Aortic Valve Implantation in Aortic Valve Regurgitation

Introduction

Current Valves in Use

Discussion

Conclusion

Chapter 43. David Procedure—Reconstruction of the Native Insufficient Valve

Background

Premise of Functioning AV After Aortic Valve–Sparing Repair

Indications for Reimplantation of Aortic Valve

Choosing the Right Prosthesis (Measure or Guess?)

Reimplantation of Normal Aortic Valve

FAQ

Reimplantation of the Tricuspid Aortic Valve (Structurally Abnormal)

Reimplantation of the Bicuspid Aortic Valve

FAQ

Abbreviations

Chapter 44. Acute Aortic Syndrome: Current Understandings

Introduction

Epidemiology

Management of Penetrating Aortic Ulcer and Differentiation from Ulcerlike Projections

Conclusion

Chapter 45. Surgical Treatment of Acute Aortic Syndrome

Introduction

Surgical Treatment

Follow-Up

Chapter 46. Minimally Invasive Surgery for Aortic Aneurysms

Introduction

Definition, Etiology, and Classification

Indications for Surgical Treatment

Surgical Approach and Surgical Technique

Results and Discussion

Conclusion

Chapter 47. Minimally Invasive Ross Procedure

Introduction

Ross Procedure, Definition

Minimally Invasive Ross Procedure—Operative Strategy and Initial Steps

Summary

Chapter 48. Complex Reoperative Thoracic Aortic Surgery: Tactics and Techniques

Introduction

Indication for Reoperative Thoracic Aortic Surgery

Perioperative Strategies and Techniques

Conclusions

Abbreviations

Chapter 49. Endoleak Treatment—Real Clinical Challenge

Introduction

Endoleaks Classification

Conclusions

Chapter 50. Traumatic Aortic Injury

Definition and Injury Classifications

Epidemiology

Pathogenesis

Pathology

Diagnosis

Choice of Optimal Treatment

Interventional Treatment of Traumatic Aortic Injury

Results

Conclusions

Chapter 51. Mesenteric Ischemia in Aortic Aneurysm/Dissection

Introduction

Anatomical Consideration

Pathophysiology

Clinical Manifestation

Diagnostic Evaluation

Treatment

Chapter 52. Guidelines on the Diagnostic and Treatment of Aortic Valve

Aortic Stenosis

Medical Therapy: Recommendations

Timing of Intervention: Recommendations

Chapter 53. Guidelines and Aortic Diseases

Introduction

Acute Aortic Syndromes

Aortic Aneurysm

Genetic Causes of the Aortic Diseases

Aortic Diseases Associated With Atherosclerotic Lesions

Tumors of the Aorta

Follow-Up Imaging and Management Recommendations

Summary

Index

Dedication

I dedicate this monograph to my teachers Vasile Candea, Victor Voicu, Ioan Pop D. Popa, and Matei Iliescu who guided me to be a part of the team and helped me in research.

Thanks to my wife Olga and my daughter Raluca for their patience during the writing of this monograph.

Ion C. Ţintoiu

Copyright

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List of Contributors

Aamer Abbas,     Texas Tech University Health Sciences Center, El Paso, TX, United States

Marc Albert,     Robert Bosch Hospital, Stuttgart, Germany

Abdulrahman Almutairi

Curtin University, Perth, WA, Australia

King Fahad Specialist Hospital, Dammam, Saudi Arabia

Cătălina Arsenescu-Georgescu

Prof. Dr. George I.M. Georgescu Institute of Cardiovascular Diseases, Iasi, Romania

Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania

Hardy Baumbach,     Robert Bosch Hospital, Stuttgart, Germany

Jaroslav Benedik,     University Hospital Essen, Essen, Germany

Romi Bolohan,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Ecaterina Bontas,     Prof. Dr. C. C. Iliescu Emergency Institute of Cardiovascular Diseases, Bucharest, Romania

Radim Brat

University Hospital Ostrava, Ostrava, Czech Republic

University of Ostrava, Ostrava, Czech Republic

Cosmin Buzila,     Army’s Center for Cardiovascular diseases, Bucharest, Romania

Blanca Călinescu

Army’s Clinical Emergency Center for Cardiovascular Diseases, Bucharest, Romania

Vasile Goldiş Western University of Arad, Arad, Romania

Francisca Blanca Calinescu,     University of Medicine Vasile Goldis, Arad, Romania

Carlos Capuñay,     Diagnóstico Maipú, Vicente López, Bs As, Argentina

Patricia Carrascosa,     Diagnóstico Maipú, Vicente López, Bs As, Argentina

Liviu Chiriac,     Central Military Hospital, Bucharest, Romania

Simon C.Y. Chow,     The Chinese University of Hong Kong, Shatin, Hong Kong SAR

Celia Georgiana Ciobanu,     C. C. Iliescu Institute of Cardiovascular Disease, Bucharest, Romania

Daniel Cochior

Titu Maiorescu University of Bucharest, Bucharest, Romania

Hospital SANADOR, Bucharest, Romania

Anneke Damberg,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Rolf Dammrau,     Praxis für Gefäß- und Thoraxschirurgie Rolf Dammrau, Düren, Germany

Roxana O. Darabont

University and Emergency Hospital of Bucharest, Bucharest, Romania

University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Debabrata Dash

Thumbay Hospital, Ajman, United Arab Emirates

Beijing Tiantan Hospital, Beijing, China

Tan Tao Medical School, Long An Province, Vietnam

Kamen Dimitrov,     Medical University of Vienna, Vienna, Austria

Bogdan Mihail Dorobantu,     Fundeni Clinical Institute, Dan Setlacec Center of General Surgery and Liver Transplantation, Bucharest, Romania

Lucian Florin Dorobantu,     Monza Hospital, Bucharest, Romania

Gabriela Droc,     University of Medicine Carol Davila, Bucharest, Romania

Ionel Droc,     Army’s Center for Cardiovascular diseases, Bucharest, Romania

Silviu I. Dumitrescu

Titu Maiorescu University of Bucharest, Bucharest, Romania

Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Marek Ehrlich,     Medical University of Vienna, Vienna, Austria

Mohamad El Gabry,     University Hospital Essen, Essen, Germany

John A. Elefteriades,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Ross Findlay,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Tatjana Fleck,     Medical University of Vienna, Vienna, Austria

Maria Florescu

University and Emergency Hospital of Bucharest, Bucharest, Romania

University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Campbell D. Flynn,     University of Sydney, Sydney, NSW, Australia

Dorota Formanowicz,     Poznan University of Medical Sciences, Poznan, Poland

Piotr Formanowicz

Poznan University of Technology, Poznan, Poland

Polish Academy of Sciences, Poznan, Poland

Ulrich F.W. Franke,     Robert Bosch Hospital, Stuttgart, Germany

Cristian Gabriel,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Edmo A. Gabriel,     Cardiovascular Surgery of Heart Hospital, São José do Rio Preto, Brazil

Marian Gaspar,     Institute of Cardiovascular Medicine, Timisoara, Romania

Mario Gaudino,     New York Presbyterian/Weill Cornell Medical Center, New York, NY, United States

Efstratios Georgakarakos,     Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece

Leonard N. Girardi,     New York Presbyterian/Weill Cornell Medical Center, New York, NY, United States

Nora Goebel,     Robert Bosch Hospital, Stuttgart, Germany

Deniz Göksedef,     Istanbul University, Istanbul, Turkey

Viorel Goleanu,     Central Military Hospital, Bucharest, Romania

Maria-Magdalena Gurzun

Euroecolab, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Army’s Center for Cardio-Vascular Disease, Bucharest, Romania

Mina Hanna,     UT Southwestern Medical Center, Dallas, TX, United States

Jacky Y.K. Ho,     The Chinese University of Hong Kong, Shatin, Hong Kong SAR

Doris Hutschala,     Medical University of Vienna, Vienna, Austria

Mircea Ifrim,     Romanian Academy of Medicine, Bucharest, Romania

Heinz Jakob,     University Hospital Essen, Essen, Germany

Mariana Jinga

Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Carol Davila Emergency Central Military Hospital, Bucharest, Romania

Robert Juszkat,     University of Medical Sciences, Poznan, Poland

Kaan Kırali,     Koşuyolu Heart and Research Hospital, Istanbul, Turkey

Foad Kabinejadian,     University of Michigan, Ann Arbor, MI, United States

Gökhan Kahveci,     Koşuyolu Heart and Research Hospital, Istanbul, Turkey

Asha Kandathil,     UT Southwestern Medical Center, Dallas, TX, United States

Ambrose Kibos,     Center Hospitalier Coutances, Coutances, France

Horst Kinkel,     Düren County Hospital, Düren, Germany

Yee Han Kuan,     National University of Singapore, Singapore, Singapore

Ioana Smarandita Lacau,     Regina Maria Ponderas Academic Hospital, Bucharest, Romania

Joel A. Lardizabal,     Bakersfield Heart Hospital, Bakersfield, CA, United States

Christopher Lau,     New York Presbyterian/Weill Cornell Medical Center, New York, NY, United States

Günther Laufer,     Medical University of Vienna, Vienna, Austria

Hwa Liang Leo,     National University of Singapore, Singapore, Singapore

Liviu Macovei

Prof. Dr. George I.M. Georgescu Institute of Cardiovascular Diseases, Iasi, Romania

Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania

Stephane Mahr,     Medical University of Vienna, Vienna, Austria

Aurel Mironiuc,     Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania

Iancu Mocanu,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Horatiu Moldovan

Titu Maiorescu University of Bucharest, Bucharest, Romania

Romanian Academy of Medical Sciences, Bucharest, Romania

SANADOR Hospital, Bucharest, Romania

Fanar Mourad,     University Hospital Essen, Essen, Germany

Sandip K. Mukherjee,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Alice Munteanu,     Central Military Hospital, Bucharest, Romania

Vasile Murgu,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Ioan Tiberiu Nanea

University of Medicine and Pharmacy Carol Davila Bucharest, Romania

Prof. Dr. Th. Burghele University Hospital, Bucharest, Romania

Vinh-Tan Nguyen,     Institute of High Performance Computing, A∗STAR, Singapore, Singapore

Daniel Nita

Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Carol Davila Emergency Central Military Hospital, Bucharest, Romania

Michał Nowicki,     Poznan University of Medical Sciences, Poznan, Poland

Letícia Oliveira,     União das Faculdades dos Grandes Lagos, São José do Rio Preto, Brazil

Irinel Parepa,     Sf. Apostol Andrei County Clinical Emergency Hospital, Constanta, Romania

Andrew G. Percy,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Bartłomiej Perek,     University of Medical Sciences, Poznan, Poland

Sven Peterss,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Aruna Poduri,     Stanford University, Palo Alto, CA, United States

Bogdan Alexandru Popescu

Euroecolab, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Emergency Institute for Cardio-Vascular Diseases CC Iliescu, Bucharest, Romania

Mateusz Puślecki,     University of Medical Sciences, Poznan, Poland

Florentina Radu-Ionita

Titu Maiorescu University of Bucharest, Bucharest, Romania

Carol Davila Emergency Central Military Hospital, Bucharest, Romania

Shahzad G. Raja,     Harefield Hospital, London, United Kingdom

Prabhakar Rajiah,     UT Southwestern Medical Center, Dallas, TX, United States

John Mark Redmond,     Our Lady’s Children’s Hospital Crumlin, Mater Misericordiae University Hospital, Dublin, Ireland

Dan Riga

Academy of Romanian Scientists, Bucharest, Romania

ARS Medical Sciences Section, Bucharest, Romania

European Academy of Sciences and Arts, Bucharest, Romania

Clinical Psychiatric Hospital Prof. Dr. Obregia, Bucharest, Romania

Sorin Riga

European Academy of Sciences and Arts, Bucharest, Romania

Clinical Psychiatric Hospital Prof. Dr. Obregia, Bucharest, Romania

Romanian Medical Sciences Academy, Bucharest, Romania

Andrei Rosu

Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Razvan Rosulescu,     Central Military Hospital, Bucharest, Romania

Magdalena Rufa,     Robert Bosch Hospital, Stuttgart, Germany

Christian Rustenbach,     Robert Bosch Hospital, Stuttgart, Germany

Sabit Sarıkaya,     Koşuyolu Heart and Research Hospital, Istanbul, Turkey

Dragos Savoiu,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Nikolaos Schoretsanitis,     Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece

Sanjiv S. Sharma,     Bakersfield Heart Hospital, Bakersfield, CA, United States

Sharaf-Eldin Shehada,     University Hospital Essen, Essen, Germany

Constantin Silvestru,     Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Dorota Sobczyk,     John Paul II Hospital, Cracow, Poland

Alina Stan,     Robert Bosch Hospital, Stuttgart, Germany

Sebastian Stefaniak,     University of Medical Sciences, Poznan, Poland

Marlies Stelzmüller,     Medical University of Vienna, Vienna, Austria

Zhonghua Sun,     Curtin University, Perth, WA, Australia

Mohamed Teleb,     Texas Tech University Health Sciences Center, El Paso, TX, United States

Matthias Thielmann,     University Hospital Essen, Essen, Germany

Oliver Thompson,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

David H. Tian

Royal North Shore Hospital, Sydney, NSW, Australia

Macquarie University, Sydney, NSW, Australia

Ion C. Ţintoiu

Titu Maiorescu University of Bucharest, Bucharest, Romania

Vasile Candea Army’s Center for Cardiovascular Diseases, Bucharest, Romania

Carol Davila Emergency Central Military Hospital, Bucharest, Romania

Prof. Dr. C. C. Iliescu Emergency Institute of Cardiovascular Diseases, Bucharest, Romania

Konstantinos Tsagakis,     University Hospital Essen, Essen, Germany

Malcolm J. Underwood,     The Chinese University of Hong Kong, Shatin, Hong Kong SAR

Adrian Ursulescu,     Robert Bosch Hospital, Stuttgart, Germany

Dragos Vinereanu

University and Emergency Hospital of Bucharest, Bucharest, Romania

University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Kristina Wachter,     Robert Bosch Hospital, Stuttgart, Germany

Daniel Wendt,     University Hospital Essen, Essen, Germany

Randolph H.L. Wong,     The Chinese University of Hong Kong, Shatin, Hong Kong SAR

Tristan D. Yan

Macquarie University, Sydney, NSW, Australia

University of Sydney, Sydney, NSW, Australia

Özge Altaş Yerlikhan,     Koşuyolu Heart and Research Hospital, Istanbul, Turkey

Mohammad A. Zafar,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Bulat A. Ziganshin,     Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States

Preface

The pathology of the aorta is a complex phenomenon, which is becoming more frequent in the last decades probably due to population aging and the inefficient control of the atherogenetic and prevention phenomenon.

This monograph provides information on innovative elements that unitarily comprise the aorta from valves to iliac bifurcation. We have explained the physiopathological mechanisms, histological basis, genetics, segmentary or whole concern of the aorta in aneurysmal process as well as mathematical models of this process.

The diagnosis of this pathology contains data obtained from both classical and modern techniques.

Therapeutic solutions have been described through the prism of applying each technique depending on particular pathological interests of the aorta. Thus, there are surgical techniques, interventional and hybrid depending on the process itself, as well as long-term point of view.

Therefore, this pathology is assessed in its complexity from all points of view.

The subject of this monograph is very vast and we could not approach this pathology from all directions and thus selected the most important subjects.

We hope this book is useful for specialists as well as doctors.

Finally, we express our gratitude to Elsevier for the opportunity to publish this book, Stacy Masucci and Samuel Young for the support that they have given us in writing this monograph.

Ion C Ţintoiu

Adrian Ursulescu

John A Elefteriades

Malcom John Underwood

Ionel Droc

Part I

Overview

Outline

Chapter 1. Aging Aorta—Cellular Mechanisms

Chapter 2. Endothelial Dysfunction in Aortic Aneurysm

Chapter 3. Histology of Aortic Disease and Progression of Aortic Dissection From Acute to Chronic

Chapter 4. The Pathogenesis of Aortic Valvular Disease

Chapter 5. Aortic Root Pathologies

Chapter 6. Cellular Mechanisms of Ascending Aortic Aneurysms

Chapter 7. Mathematical Modeling of Aortic Aneurysm Progression

Chapter 8. Genetic Basis of Aortic Disease

Chapter 9. Congenital Malformations (Bicuspid, Right Aortic Arch, Coarctation)

Chapter 10. Guilt by Association: Paradigm for Detection of Silent Aortic Aneurysms

Chapter 11. Inflammatory Diseases (Takayasu, Giant Cell Arteritis, Behçet Disease)

Chapter 1

Aging Aorta—Cellular Mechanisms

Florentina Radu-Ionita¹,², Ion C. Ţintoiu¹,³, Andrei Rosu³,⁴, Ecaterina Bontas⁵, Daniel Cochior¹,⁶, Romi Bolohan³, Constantin Silvestru³, Mircea Ifrim⁷, Iancu Mocanu³, Dan Riga⁸,⁹,¹⁰,¹¹, Vasile Murgu³, Sorin Riga¹⁰,¹¹,¹², Dragos Savoiu³, and Ambrose Kibos¹³     ¹Titu Maiorescu University of Bucharest, Bucharest, Romania     ²Carol Davila Emergency Central Military Hospital, Bucharest, Romania     ³Vasile Candea Army's Center for Cardiovascular Diseases, Bucharest, Romania     ⁴Carol Davila University of Medicine and Pharmacy, Bucharest, Romania     ⁵Prof. Dr. C. C. Iliescu Emergency Institute of Cardiovascular Diseases, Bucharest, Romania     ⁶Hospital SANADOR, Bucharest, Romania     ⁷Romanian Academy of Medicine, Bucharest, Romania     ⁸Academy of Romanian Scientists, Bucharest, Romania     ⁹ARS Medical Sciences Section, Bucharest, Romania     ¹⁰European Academy of Sciences and Arts, Bucharest, Romania     ¹¹Clinical Psychiatric Hospital Prof. Dr. Obregia, Bucharest, Romania     ¹²Romanian Medical Sciences Academy, Bucharest, Romania     ¹³Center Hospitalier Coutances, Coutances, France

Abstract

A significant risk factor for cardiovascular diseases is aging; an independent prediction factor for cardiovascular death is arterial stiffness. To reiterate, aged aorta is defined by endothelial dysfunction with the alteration of contraction and migration of vascular smooth muscle cells, production and contention of extracellular matrix, with its proliferation and senescence. As widely validated, the cellular mechanisms that caused alteration in the aged vessels have the same significance for the development of cardiovascular disorders such as hypertension or atherosclerosis. For that reason, the National Institute of Aging stress on molecular, genetic, cellular, and enzymatic research approaches for studying about aging aorta and aorta stiffness. As a result, amplified arterial stiffness should be regarded as a biomarker of aging and cardiovascular disease.

Keywords

Aging aorta; Aorta stiffness; Apoptosis; Arterial stiffness; Extracellular matrix; Inflammation; Senescence; Telomere shortening; Vascular smooth muscle cells

Chapter Outline

Aging and Stiffness Aorta

Intima–Endothelial Senescence

Intima and Media—Apoptosis

Intima–Extracellular Matrix and MMPs Roles

Media–VSMCs

Media–Elastin/Collagen Ratio

Media Inflammation

Telomere Length—A Biomarker of Aorta Aging

Atherogenesis

Conclusions

References

Further Reading

A man is as old as his arteries.

Thomas Sydenham (1624–1689)

Aging and Stiffness Aorta

Initially, increasing data support that arterial stiffness is an excellent and obvious biomarker for cardiovascular disease (CVD) and its related risks [1–14]. With respect to their basic architecture, arteries are usually described as cross-sectional arrangements of cells and extracellular matrix (ECM). As a standard, ECM within the media comprises lamellae of elastic material, layers of vascular smooth muscle cells (VSMCs), and collagen fibers [15]. Collagen is two times more stiffer than elastin and VSMC [16] but predominates in peripheral arteries. As a side note, structures such as VSMCs from young arteries of the arterial wall give elasticity through the protein components such as ECM, elastin, fibrillin, collagen, glycoproteins, and proteoglycans [17]. As a consequence, there is a progressive increase in vessel stiffness from the proximal to distal arterial compartments. With advancing age, the human aorta dilates and becomes stiffer with physiological pressures [18–22]. Specifically, the dominant element of arterial aging is the stiffening and dilation of the proximal aorta, known as senile arteriosclerosis as already explained by Osler [23]. In fact, elastic arteries have two alterations with age [24]: (1) dilation and (2) stiffening are the most evident in the proximal aorta with its major branches [24–27]. As previously reported, it is worthy to note that pure arterial aging was observed frequently in Chinese populations without atherosclerosis [25,26].

In summary, there are multiple cellular and intracellular mechanisms that further determine the loss of elasticity of the aorta. Of these, the most significant mechanisms mentioned earlier are (1) apoptosis of tunica media; (2) migration, proliferation, and infiltration by VSMCs of the subendothelial layer; (3) changes with proliferation of ECM in intima (tunica interna); (4) infiltration with inflammatory cells; (5) fragmentation of elastin and collagen tissue initially replaced in tunica media and then expanding in the underlying and overlying layers; (6) telomere shortening, decrease of the line in stem cell number and their function, atherogenesis, calcification, and so on. Altogether these mechanisms and others are implied in the stiffness of the aorta wall. The information is presented in Table 1.1.

Table 1.1

Mechanisms of Changes in Aging Aorta Wall

AGEs, advanced glycation end-products; Ang II, angiotensin II; ↓decrease; ECM, extracellular matrix; ↑increase; ICAM, intracellular adhesion molecule; MMPs, matrix metalloproteinases; VSMC, vascular smooth muscle cell.

Figure 1.1  Fibrosis of the adventitia in Hutchinson–Gilford progeria syndrome (HGPS). Hematoxylin and eosin (H&E) staining of selected tissues from patients HG001 (A) and HG120 (B and C). (A) Aorta with thickened adventitia ( arrow ). (B) Mid-right coronary characterized by an enlarged and highly fibrotic adventitia ( arrow ). The media is markedly thinned in the area with adventitial fibrosis. (C) High-power image of the adventitia ( arrow ) shown in (B). (D) A 16-year-old non-HGPS aorta with nondiseased adventitia ( arrow ). (E) A 16-year-old non-HGPS left anterior descending (LAD). (F) A 93-year-old LAD with advanced atherosclerosis. Arrowhead points to the adventitia. ad indicates adventitia; m , media. (Scale bars: A, C, and D, 50   μm; B, E, and F, 500   μm.) From Olive M, Harten I, Mitchell R, Beers JK, Djabali, K, Cao, K, Erdos, MR, Blair, C, Funke, B, Smoot, L, Gerhard-Herman, M, Machan, JT, Kutys, R, Virmani, R, Collins, FS, Wight, TN, Nabel, EG, Gordon, LB. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol November 2010;30(11):2301–09 with permission.

Intima–Endothelial Senescence

Senescence should not be confounded with the death of senescent cells that can progress on long periods of time [45]. The first description of halting of cell division was studied by Hayflick and Moorhead in normal human fibroblasts culture [46]. In particular, endothelial senescence is an irreversible increase unresponsive to numerous stressors [47,48]. In this way, Olive et al. (2010) evaluated genetically diagnosed children with Hutchinson–Gilford progeria syndrome, which revealed extremely increased CVD, with important mortality from myocardial infarction or stroke for the age group between 7 and 20  years (Fig. 1.1) [49]

Basically, cellular senescence is the hallmark of an aging organism characterized by irremediable development of blockage cell morphology, growth of DNA oxidative stress, decreasing of telomere length, amplified representation of senescence-related β-galactosidase (SA-β-gal), and a greater elevation of cyclin-dependent kinase inhibitors affiliated to tumor suppressor pathways, specifically (p16/p19/p21) [50–53]. Another characteristic of cellular senescence is the Senescence Associated Secretory Phenotype (SASP) with the secretion of proinflammatory cytokines that function together within inflammation process [54]. Furthermore, one more finding of senescence is related to the epigenome [55]. As a result, DNA methylation is decreasing during senescence with the disequilibrium of chromosomal activity. Aneuploidy or polyploidy is often seen in aging cells being associated with the decay of DNA restoration [56].

Senescent endothelial phenotypes are described by increasing inflammatory markers such as inflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1), decreased nitric oxide (NO) formation with raised oxidative stress triggered by endothelial NO synthase (eNOS) uncoupling, and raised expression of aging oxidative stress markers [47,57–61]. Consistent with a growing evidence, eNOS uncoupling is a major process of oxidative stress associated with reduced NO bioavailability in endothelial senescence, with vascular aging and age-related CVD [42,62,63]. Another important regulator of organism aging is mTOR (mammalian target of rapamycin)/S6K1 [64,65], implicated in regulation of many cellular functions [64]. Essentially, senescent human endothelial cells exhibit raised amounts of VCAM1 and ICAM1 in comparison with young cells (nonsenescent cells) [61].

As already described by evidence, microribonucleic acid (miRNA) especially miR-34a is correlated with endothelial senescence by its increased expression in murine and humans with age [66–69]. For instance, increased miR-34a exists during the culturing of endothelial and endothelial progenitor cells and may speed up the phenotype of senescence via direct downregulation of one of its target genes, Sirtuin-1 (SIRT1) [67,69]. Therefore, it is important to underline that SIRT1 can cancel out the processes of senescence mediated by VSMCs of atherogenesis and vascular calcification [70,71] (Fig. 1.2).

In conclusion, endothelial senescence is the main feature of vascular aging and supports the progress of atherosclerosis. As well, reduced SIRT1 expression facilitates the occurrence of senescence in endothelial cells [74–78] and atherosclerosis [78].

Intima and Media—Apoptosis

All cells contain responsible structures for apoptosis. This process is the most significant in the vessel wall remodeling even if at one moment it causes negative remodeling with a destructive role. In this regard, Mallat et al. (2000) described four stages in the completion of apoptosis: (1) the initiation or signaling phase; (2) the control and the effectors phase; (3) the DNA alterations phase; and (4) detection of apoptotic cells and removal of apoptotic bodies [79] (Fig. 1.3).

Figure 1.2  Sirtuin-6 (SIRT6) prevents endothelial senescence. Over-replication of endothelial cells (ECs) leads to decreased expression of SIRT6, which in turn results in a proinflammatory phenotype, p21 upregulation, DNA damage, telomere dysfunction, cell cycle arrest, and impaired angiogenesis. All are indications of EC senescence, but their cause–effect relationship is unknown [72] . From Shen J, Ma W, Liu Y. Deacetylase SIRT6 deaccelerates endothelial senescence. Cardiovasc Res March 1, 2013;97(3):391–2 with permission.

Figure 1.3  Schematic representation of main apoptotic pathways. Activation of caspase-8 (and subsequent activation of the caspase cascade) occurs following ligation of death-signal-transmitting receptors. Caspase-9 activates cell disassembly in response to agents or insults that trigger the release of cytochrome c from the mitochondria and is activated when complexed with deoxy-adenosine triphosphate, Apaf-1, and extramitochondrial cytochrome c to form the multiprotein apoptosome ensemble. Caspase-8 and caspase-9 can activate caspase-3 by proteolytic cleavage, and caspase-3 amplifies caspase-8 and caspase-9 signals into fully fledged commitment to disassembly, therefore, propagating the caspase cascade. Ligation of the death-signal-transmitting receptor TNFR (tumor necrosis factor receptor) may also generate signal transduction pathways leading to the activation of the nuclear transcription factor (NF)-κB and to the induction of cytoprotective genes. From Mallat Z, Tedgui A. Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol July 2000;130(5):947–62 with permission.

In summary, the apoptosis of endothelial cells includes mechanisms for vascular injury and atherosclerosis [80–82]. Also, endothelial cell apoptosis is carried out by the way of activation of caspases–cysteine protease family [83,84]. Further, nitric oxide (NO) disturbes the apoptosis signal-transduction pathway [85,86]. It must be underlined that the apoptosis is inhibited by restraining caspases by the way of S-nitrosylation of the basic cysteine remnants [84,87–89]. Regardless of this, it is already acknowledged that the telomere damage has a major task in apoptosis and stress-caused senescence [90].

Intima–Extracellular Matrix and MMPs Roles

Stiffness of the large arteries is induced by several factors, mainly by the ECM proteins of the vessel wall named elastin and collagen. Further, these structural proteins can be produced de novo in adults and are enzymatically degraded by elastases and matrix metalloproteinases [91]. For instance, the elastin is a very stationary protein that permits blood vessels to return to their shape after contracting or stretching [24,92]. VSMCs mostly produce the aorta elastin [93,94]. Also, it is important to underline that the vessel tissue lacking fibrillin 1 microfibrils discharge MMPs, which further damage the vessel wall with its dilatation. In fact, normal deterioration of the ECM has an onset during early adulthood for all mammalian species [95]. The study of Fritze et al. (2010) [96] with multiphoton laser scanning microscopy of human aorta revealed a dramatic decrease of these interlaminar elastic fibers with age and increase of spaces incompletely filled with proteoglycans within the aortic media [97]. As a consequence, the aortic wall thickened [98].

MMPs represent a major function in the aortic disease [99] and are a large family of proteases [100,101]. They are recognized as the main proteolytic enzyme group involved in the remodeling of ECM by modifying cell–cell and cell–matrix interactions [102] (Fig. 1.4).

Various human MMPs have been documented [100]; they are separated into six groups: collagenases (MMP-1, -8, -13, and -18), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -10, -11, and -17), matrilysins (MMP-7 and -26), membrane-type MMPs (MT-MMPs: MMP-14, -15, -16, -17, -24, and -25), and other MMPs (MMP-12, -19, -20, -21, -22, -23, -28, and -29) [103]. After MMP synthesis, most of them are either secreted freely into the extracellular space or fixed to the surface of cell membranes [104,105]. As expected, there is a precise control of MMP expression and function [103].

Conventionally, MMP-2 and MMP-9 have a significant task in vascular remodeling [106–108]. Increased human MMP-2 and MMP-9 levels correlate with elastic laminae artery damage and aneurysm formation [109]. Moreover, MMP-1, -2, -3, -8, and -9 are implicated in the increase in vascular remodeling by matrix damage with the splitting of intima from the media [110]. Importantly, increased MMP2 activity coexists with VSMC apoptosis in the aorta, as well as bicuspid aortic valve, in patients with Marfan syndrome [111]. Further, the interaction of AngII, monocyte chemoattractant protein-1 (MCP-1), calpain, transforming growth factor (TGF)-β1, tumor necrosis factor-α, and interleukin-1 with young VSMCs boosts MMP-2 [112–118]. Taken together normal human aortic wall progresses with proinflammatory markers and is marked by increased activation of MMPs [98].

Figure 1.4  Matrix metalloprotein (MMP) influences the vascular smooth muscle cell (VSMC) migration. MMPs can remodel basement membrane components, including laminin and type IV collagen, and help free cells to migrate. Loss of basement membranes promotes the phenotypic modulation of VSMC. This leads to synthesis, among other things, of new integrin subunits and new matrix components that include glycoprotein ligands for these integrins, for example, vitronectin, osteopontin, and tenascin. MMPs also fragment existing membrane components such as type I collagen and this can create new integrin-binding sites. By acting through integrins and focal adhesion kinase (FAK), ECM components influence intracellular pathways that regulate the cytoskeletal changes necessary for motion. MMPs could shed cadherins and could thereby relieve constraints on movement caused by adherens junctions. From Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res February 15, 2006;69(3):614–24 with permission.

Media–VSMCs

In fact, VSMCs represent the major stromal cells of the vessel wall that is constantly exposed to biochemical mechanisms and mechanical indicators of flow blood. Without doubt, VSMCs are implicated in all physiological and pathological processes of the vascular wall. To start with, VSMCs generate ECM during arterial wall growth that further confers the ability to the arterial wall to resist high blood pressures. Moreover, VSMCs fix the injuries of the arterial wall [119]. Also, the media is physiologically available to leucocytes [120,121], and it is allowing access to soluble plasma systems too [122].

The influence of aging on VSMCs is not debatable. Arterial aging alterations include the activation of the renin–angiotensin–aldosterone system, modifications of VSMCs findings, altered regeneration of endothelial cells with increased expansion, and movement of VSMCs with further aged vessel remodeling [123,124]. Also, consistent with the actual evidence, VSMCs obtained from human atherosclerotic lesions senescence more rapidly in comparison with VSMCs from normal vessels [125].

A noteworthy summary explanation looking at the influence of aging on VSMCs is shown in Fig. 1.5. In particular, the age-associated disproportion with the dominant prooxidant state supports the inflammatory reaction; further with AngII-signaling molecule formation by VSMCs, principally TGF-β1, MCP-1, and MMPs.

Figure 1.5  Schematic diagram illustrating some of the common and specific molecular pathways controlling vascular smooth muscle cell (VSMC) phenotypic modulation in hypertension and aging. The CArG–SRF–myocardin axis plays a central role in maintaining the contractile state of VSMCs. Its activity is modulated by Notch, Wnt, platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-b signaling through the action of the repressor factors, Herp1, Kruppel-like factor (KLF)4/5, and Elk1. A VSMC synthetic phenotype may result from increases in Ang II, intracellular Ca ²+ , or stretch under the regulation of these specific transcriptional pathways. Arterial distensibility decreases with age but not in hypertension, which is associated with the maintenance of arterial function. From Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovasc Res July 15, 2012;95(2):194–204 with permission.

To sum up, the age-related irremediable cellular senescence process leads to a gradual diminishing of the VSMCs plasticity acting as a corresponding signaling process and with the increase in arterial stiffness [119]. Of importance, these destructions are controlled by time alterations of telomeres due to the degenerative processes.

Media–Elastin/Collagen Ratio

The main etiology for aortic wall stiffness is the changes of the ratio elastin versus collagen with increase in collagen proportion. Therefore, the collagen replaces elastin from tunica medie (thickest layer with elastic fibers and smooth muscle fibers) and penetrates overlying and underlying layers with the decrease in arterial elasticity. Undoubtedly, the highest increasing proportion of collagen causes premature senescence [126]. Furthermore, multiple studies corroborate this hypothesis [127,128] and it was not surprising that studies on intima–media thickness show progressive thickening with age [4,5,127,129].

Therefore, during the arterial wall stiffness process, the most important significant changes are the changing of ratio between elastin and collagen that is done by the disorganization of VSMCs, modification of EMC, elastin fragmentation (Fig. 1.6) induced by MMP-2, MMP-1, MMP-9, and falling display of the tissue inhibitors of MMPs (TIMPs) [114,131]. Importantly, histological studies proved that there was destruction of the medial elastin of the proximal aorta with little aging alteration in distal muscular arteries [4,123,128,132–134].

Figure 1.6  High magnification of Masson trichrome/smooth muscle actin (SMA) staining in very young and very old aortic media. Aorta of the 3-year-old child (left) shows a parallel and dense distribution of SMC between elastic fibers. In the aorta of 83-year-old man (right), there is a reduced number of SMC and thick sporadic elastic fibers in an abundant connective tissue (SMA with Masson’s trichrome contrast staining, 400×). From Zarkovic K, Larroque-Cardoso P, Pucelle M, Salvayre R, Waeg G, Nègre-Salvayre A, Zarkovic N. Elastin aging and lipid oxidation products in human aorta. Redox Biol 2015;2015(4):109–17 It is an open access article.

And, the association of elastin and collagen with VSMCs speeds up the stiffness of the aortic arterial wall. Moreover, Boon et al. and Ott et al. showed recently that elastin degeneration is controlled by the combination of AngII and micro-RNA29 [135,136].

Media Inflammation

Arterial stiffening is correlated in different conditions with inflammation [137], even if inflammation does not have a clear association with atherosclerosis [138]. However, severe inflammation is sufficient to trigger vascular inflammation [139]. Furthermore, previous work has been shown that aged vessels are correlated with eNOS uncoupling [63]. Besides, as mentioned earlier, there is a SASP represented by the secretion of proinflammatory biomarkers such as proteases, cytokines, chemokines, growth factors, and soluble receptors that act via paracrine and/or autocrine way [50,140]. Senescent VSMCs are associated with SASP and may cause a chronic low-grade inflammation for aging vessels [3,141].

Moreover, proinflammatory stimuli and high-fat diet inhibit miR-181b expression in murine tissues, such as aorta [142,143]. Of note, circulating miR-181b levels are also reduced in the elderly [144], suggesting that aging alters atheroprotective miRNA expression in humans. Also, activation and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) support vascular inflammation, atherosclerosis, and metabolic syndrome [145]. In contrast, activation of SIRT1 restrains vascular inflammation [146–148].

Telomere Length—A Biomarker of Aorta Aging

Telomeres are one of the several key elements required for genomic stability [149,150]. An important feature is that telomeres have a protective role for chromosomes by avoiding enzymatic attrition, nonhomologous recombination, and end–end fusion of chromosomal DNA. Telomeres are set as duplex loops, which include a double-stranded telomere loop (T-loop) and a single-stranded (D-loop) (Fig. 1.7) [151,154,155].

Figure 1.7  The duplex structure of a telomere consisting of DNA forming a T-loop and D-loop. Several shelterin proteins bind specifically to the telomeric DNA and facilitate telomere end protection and length control [151] . Shelterin complex core proteins—TRF1, 2—telomeric repeat-binding factors; RAP1—human repressor activator protein 1; TIN2-TRF1—interacting protein; accessory binding proteins—Ku-the Ku70/Ku86 heterodimer, tank-1, tank-2—tankyrase; MRE11/RAD50/NBS1-MRN DNA detection and repair complex, hnRNPs—heterogeneous nuclear ribonucleoprotein [152] . From Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg July 2010;40(1):17–26 with permission.

In summary, telomeres are protein structures represented by multiplying of the sequential nucleotides TTAGGG, which are located at the distal end of the eukaryotic chromosomes to have a protective role in maintaining chromosome function by preventing their structural degradation in the mitogenesis [149,156]. As a result, there is a consecutive shortening of telomeres with each cell division [157]. Consequently, short telomeres may generate the cellular senescence [158]. Tchirkov and Lansdorp proposed the importance of both sufficient telomerase activity and maintenance of telomere length for aging in primary human fibroblast [159]. Therefore, telomere integrity is controlled by telomerase that is composed from a functional subunit of RNA and reverse transcriptase catalytic subunit [160], which by their activity maintains the balance between telomeres length and telomeres shorten [161,162]. Shortening of telomeres due to different degenerative processes is proved by human and experimental studies as being implied in the aging–cardiovascular disorders [163].

It must be underlined that in vessel wall, the telomeres length shortening is faster due to permanent stress produced by contraction and relaxation of the aorta and other specific components. Furthermore, Benetos et al. (2001) have been shown in a study population of 193 patients (120 men, 73 women) with a mean age of 56  ±  11  years, that in both genders, shortening of telomere was associated with age (P  <  .01) [164]. On the other hand, Mather et al. (2011) [165] examined over 3830 studies in which included was the main search criteria age and mortality in correlation with telomeres length by a question: Is Telomere Length a Biomarker of Aging? (Table 1.2). Their conclusion was that telomere length as a biomarker of age is equivocal and more studies are compulsory.

Numerous studies increasingly sustain a correlation between shorten telomere and raised tendency to cardiovascular morbidity. On the other hand, only some studies confirm a direct correlation between shorten telomeres with vascular surgical disorders such as carotid stenosis, aortic aneurysm, and PVD (Table 1.3).

It has to be mentioned that the results of some studies from Table 1.3 [153] are debatable because they included only patient cohorts over 85  years old. In this context, the decay of telomeres may additionally increase the vascular disease risk alongside the abovementioned risk factors [180].

Despite the earlier evidence, multiple studies approached the corroboration between the significance of shorten telomeres with life span and mortality, for which the American Federation of Aging Research [182,183] has been introduced that short telomeres are aging biomarkers, considering that telomere length is more faithful than chronological age.

Other mentioned mechanisms correlating the telomere decay with vascular disease comprise [47,184–187] the following: (1) fast cellular senescence may connect the telomere decay with disease development based upon the fact that the senescent tissue is correlated with endothelial dysfunction and plaque instability; (2) high oxidative stress such as smoking and hypertension causes oxidative DNA; (3) atherosclerotic disease is associated with entire inflammatory process that causes telomere decay because of higher rates of leukocyte production; (4) decreased telomerase activity; and (5) increased blood homocysteine that is linked with shorten telomeres.

Table 1.2

Telomere Length and Mortality/Life Span Studies

Studies used peripheral blood samples for TL estimation. CVD, cardiovascular disease; n.s., not significant; Q-PCR, quantitative real-time polymerase chain reaction; TL, telomere length; TRF, terminal/telomere restriction fragment analyses. ∗P  <  .05; ∗∗P  <  .01; ∗∗∗P  <  .001.

From Mather KA, Jorm AF, Parslow RA, Christensen H. Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci February 2011;66(2):202–13 with permission.

Table 1.3

Summary of Telomere Length Dynamic Studies in Vascular Surgical Disease and Healthy Vascular Tissue

From Butt HZ, Atturu G, London NJ, Sayers, RD, Bown, MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg July 2010;40(1):17–26 with permission.

Certainly, prospective longitudinal studies looking for the correct explanation of shortening of telomere length are required. Telomere increase by telomerase oversecretion does not influence stress-induced senescence [188] but restrains replicative senescence [189–191]. Last, telomere shortening is strongly related with severe atherosclerosis [185].

Atherogenesis

The theory of cellular aging was first used by Hayflick during the 1960s [46,192] and assumes decreasing or stopping of cell division from the structure of arterial wall. In these conditions, VSMCs and elastin are replaced by connective tissue (collagen) that because of its reduced elasticity causes stiffness of aortic wall, conditions in which atherogenesis and calcification are favored and occur frequently in the arteries of elderly patients. The Russell Ross hypothesis on atherosclerosis development has been modified three times and established as being a response to injury hypothesis [193–195]. This theory states that reactive oxygen species has a significant task in the initiation and progression of atherosclerosis [196].

Figure 1.8  Atherosclerosis in the aged artery.

Aged endothelial cells express various adhesion molecules (AM), which facilitate the binding as well as transportation of various inflammatory cells, including monocytes (M) and lymphocytes (L) into the intima. OxLDL plays a major role in the formation of foam cells (F). The foam cells secrete several growth factors (GF) and cytokines (C) that lead to increased proliferation of vascular smooth muscle cells (VSMCs). Increased expression of endothelin-1 facilitates atherosclerosis through ET-A receptor activation. The lymphocytes also play a critical role in causing inflammation in the endothelium. Altogether, these changes facilitate the plaque formation in the blood vessels of aged populations [198]. It is an open access chapter under Attribution 3.0 Unported (CC BY 3.0).

Cellular senescence is involved in vascular disorders, mainly atherosclerosis. It is also established that the initiation of premature senescence through the p53/p21-dependent pathway in human VSMCs [197]. Aging alterations of aortic wall are the result of the concomitantly or sequentially degenerative process, which comprise endothelium, intima, tunica media, and tunica adventitia, and produce: stiffness, calcifications, atheroma, and deformation. The main factor of aging aorta is that atherosclerosis undoubtedly starts with endothelium alteration by the adhesion of the molecules that attract inflammatory cells (lymphocytes, monocytes) and penetrate both the tunica media and intima. As a consequence, oxidized low density lipoproteins by (OxLDL) arise from the foam cells (F). Conversely, these foam cells produce growth factors (GFs) and cytokines (C). Further, these determine the proliferation of VSMCs, activation of endothelin, and lymphocyte infiltration [198,199] (Fig. 1.8).

As already described, atherosclerosis development is reduced by NO [200] that also has an antioxidant effect [201]. The basal NO secretion was examined with NO synthase inhibitor such as N(G)-monomethyl L-arginine and superoxide dismutase [202]. Also, the expression of p22phox is an important element of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, when atherosclerosis is increased [203]. To summarize, NO works by numerous processes to stop the development of atherosclerosis [204].

Senescent endothelial cells exist in human atherosclerosis but not in nonatherosclerotic pathology [205] and support that cellular senescence causes atherogenesis [206]. MMP9 (gelatinase B) is expressed in atherosclerotic lesions [207]. Further, Blankenberg et al. (2003) [208] showed that the C−1562T polymorphism increased promoter activity, adjusted plasma MMP9 levels in patients with CVD, and prognosticated CV events. Finally, vascular inflammation is coordinated by multiple cytokines and chemokines secreted by a plethora of vascular cells and immune cells [209].

Increasing evidence suggests an important role of miRNAs as epigenetic regulators of age-related diseases, including vascular and metabolic diseases [210,211]. Gene expression, cell-type–specific function, and cell–cell communication are regulated by miRNAs, which emerge as important regulators of the cardiovascular system. Because miRNA controls the fate of many genes modulating signaling networks and cell function, targeting a miRNA might be a promising strategy to treat atherosclerotic disease (Fig. 1.9).

Conclusions

Strategies to prevent the premature senescence of VSMCs could be an effective approach for reducing vascular disease. Therefore, the prevention of arterial aging and its side effects could be made by regular exercise, drugs therapy, or the debatable newly benefits effects of nutraceuticals.

Figure 1.9  miRNAs implicated in atherosclerotic processes. Positive/atheroprotective (in green frame ) or negative/atherogenic (in red frame ) effects of miRNAs on the atherosclerotic process are shown. Question marks next to miRNAs indicate controversial or contradictory evidence. miRNAs in bold are those reported to be regulated by blood flow/shear stress. Low-density lipoprotein (LDL) diffuses from the blood into the intima and undergoes oxidative modification. Oxidized LDL triggers the expression of leukocyte adhesion molecules by endothelial cells. The initial steps of atherosclerosis include adhesion of blood monocytes to the activated endothelium, their migration into the intima, their maturation into macrophages (or dendritic cells), and their uptake of lipid yielding foam cells. Although fewer in number than macrophages, other leukocyte subsets, such as T cells, also enter the intima and regulate cellular and humoral immune responses. Lesion progression involves the proliferation and migration of SMCs into the intima, as well as increased extracellular matrix protein synthesis, including collagen. Advanced lesions also exhibit intraplaque neovascularization and outward remodeling. Abbreviations: LDL, low-density lipoprotein; SMC, smooth muscle cell. From Andreou I, Sun X, Stone PH, Edelman ER, Feinberg MW. miRNAs in atherosclerotic plaque initiation, progression, and rupture. Trends Mol Med May 2015;21(5):307–18 with permission.

Exercise enhances endothelial function in muscular arteries [213] and decreases the magnitude of reflected waves that come back to the heart [214].

In case of drugs administration for aging prevention, the proportion of elastin fracture could be decreased by therapy with beta-blockers. In monogenic disorders such as Marfan’s syndrome, beta-blockers efficiently decreased arterial stiffness [215]. Moreover, the use of statins improves endothelial function, raises NO systemic availability, and raises antioxidant and antiinflammatory outcomes [216–218].

Understanding of new molecular therapies that influence the vascular aging mechanisms has important scientific consideration. miRNAs are emerging as new therapeutic targets [219]. As already described, miR-34a is defined as p53-regulated tumor suppressor miRNA, effective in regulating cell cycle ending, apoptosis, and senescence [220–222].

Moreover, NO decreases atherosclerosis. Therefore, eNOS may have an important function in the control of endothelial cells senescence, being an important aim for a new therapeutic strategy of vascular aging disorders [223].

Phosphodiesterase 1 (PDE1) inhibitors may represent novel therapeutic agents for treating CVDs [224]. Recent studies also identify nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) as underlying an aging suppression pathway in smooth muscle cells, with potential relevance to controlling atherosclerosis and possibly other diseases of aging [225,226]. Moreover, the beginning of endothelial senescence can be anticipated or stopped by some growth factors, as well as PF/VEGF, TGF-β, IGF, or IL-1α [227–229].

During this decade, nutraceuticals received significant consideration from the part of researchers in aging prevention. Resveratrol (3,5,4′-trihydroxystilbene), a polyphenol from red wine has antiaging abilities (preservation of telomere length) could be a helpful nutraceutical therapy in CVD [226]. Furthermore, from the same group of polyphenol, the plant flavonoids [230–232] showed antiaging properties. For instance, grape seed proanthocyanidin extracts have higher antioxidant properties in comparison with vitamin C, vitamin E, or any other antioxidant [233] and decreases atherosclerosis too [234].

To summarize, CVD is the principal etiology of worldwide mortality and early arterial stiffening is a major promoter to this risk. Increased data of studies underline that arterial stiffness is an independent predictor of cardiovascular disorders. Unfortunately, the accurate molecular pathways managing stiffness are unsuccessfully comprehended and further studies are obviously required.

References

[1] Najjar S.S, Scuteri A, Lakatta E.G. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension. September 2005;46(3):454–462.

[2] Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. May 2001;37(5):1236–1241.

[3] Wang M, Jiang L, Monticone R.E, Lakatta E.G. Proinflammation: the key to arterial aging. Trends Endocrinol Metab. February 2014;25(2):72–79.

[4] Lakatta E.G, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a ‘set up’ for vascular disease. Circulation. 2003;107:139–146.

[5] Lakatta E.G, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease. Circulation. 2003;107:346–354.

[6] Nichols W, O’Rourke M. Principles of measurement, preventing and treating arterial stiffness. In: Safar M.E, O’Rourke M.F, eds. Arterial stiffness. Handbook of hypertension. vol. 23. Elsevier; 2006:137–160 503–16.

[7] Sehgel N.L, Vatner S.F, Meininger G.A. Smooth muscle cell stiffness syndrome-revisiting the structural basis of arterial stiffness. Front Physiol. November 2015;18(6):335.

[8] Vogel R.A, Benitez R.M. Noninvasive assessment of cardiovascular risk: from Framingham to the future. Rev Cardiovasc Med. Summer 2000;1(1):34–42.

[9] Anderson T.J. Arterial stiffness or endothelial dysfunction as a surrogate marker of vascular risk. Can J Cardiol. February 2006;22(Suppl. B):72B–80B.

[10] Franklin S.S. Arterial stiffness: is it ready for prime time? Curr Cardiol Rep. November 2007;9(6):462–469.

[11] Martin C, Cameron J, McGrath B. Mechanical and circulating biomarkers in isolated clinic hypertension. Clin Exp Pharmacol Physiol. April 2008;35(4):402–408.

[12] Wang X, Keith Jr. J.C, Struthers A.D, Feuerstein G.Z. Assessment of arterial stiffness, a translational medicine biomarker system for evaluation of vascular risk. Cardiovasc Ther. Fall 2008;26(3):214–223.

[13] Laurent S, Boutouyrie P, Vascular Mechanism Collaboration. Dose-dependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Hypertension. October 2014;64(4):709–716.

[14] Laurent S, Briet M, Boutouyrie P. Arterial stiffness as surrogate end point: needed clinical trials. Hypertension. August 2012;60(2):518–522.

[15] Benetos A, Bouaziz H, Albaladejo P, Guez D, Safar M.E. Carotid artery mechanical properties of Dahl salt-sensitive rats. Hypertension. February 1995;25(2):272–277.

[16] Li J.K.J. The arterial circulation: physical principles and clinical applications. Totowa (NJ): Humana Press; 2000:271.

[17] Bank A.J, Wang H, Holte J.E, Mullen K, Shammas R, Kubo S.H. Contribution of collagen, elastin, and smooth muscle to in vivo human brachial artery wall stress and elastic modulus. Circulation. December 15, 1996;94(12):3263–3270.

[18] Hallock P, Benson I.C. Studies on the elastic properties of human isolated aorta. J Clin Invest. July 1937;16(4):595–602.

[19] Wellman W.E, Edwards J.E. Thickness of the media of the thoracic aorta in relation to age. Arch Pathol (Chic). August 1950;50(2):183–188.

[20] Simon E, Meyer W.W. The volume, volume extensibility and the pressure-length relationship of the total aortic expansion chamber in relation to age, hypertension and arteriosclerosis. Klin Wochenschr. May 1, 1958;36(9):424–432 [Article in German].

[21] Roach M.R, Burton A.C. The effect of age on the elasticity of human iliac arteries. Can J Biochem Physiol. April 1959;37(4):557–570.

[22] Learoyd B.M, Taylor M.G. Alterations with age in the viscoelastic properties of human arterial walls. Circ Res. March 1966;18(3):278–292.

[23] Osler W. The principles and practice of medicine. 3rd ed. Appleton; 1898.

[24] Nichols W.W, O’Rourke M.F. McDonald’s blood flow