Front Cover

Genetics of Cardiovascular Disease

Copyright

Contents

Contributors

Preface

Chapter One: Genetic Experimental Preparations for Studying Atherosclerosis

1. Introduction

2. Why We Need More and Better Ways to Study Atherosclerosis

2.1. Gene-targeted mouse models of atherosclerosis

2.2. Gender effects on experimental preparations of atherosclerosis

3. Apolipoprotein E Knockout Mice for Study of Atherosclerosis Biology

4. Low-Density Lipoprotein Knockout (LDLR-/-) Mice for Study of the Biology of Atherosclerosis

5. Mixed Gene-Targeted Manipulations for the Study of Atherosclerosis

5.1. Bone marrow transplantation as a tool for the study of atherosclerosis

6. Methods Used to Study Atherosclerotic Preparations

7. Zebrafish Preparations for the Study of Atherosclerosis

8. Genetically Targeted Rat Preparations for the Study of Atherosclerosis

9. Genetically Targeted Porcine Preparations for the Study of Atherosclerosis

10. What Have We Learned About the Biology of Atherosclerosis from Genetic Experimental Preparations So Far?

11. Has the Information Learned About the Biology of Atherosclerosis from Mouse Preparations Been Translated to the Clinic?

12. Future Perspectives

Acknowledgments

References

Chapter Two: Genetics of Cardiovascular Development

1. Early Morphogenesis of the Mammalian Heart

1.1. The second heart field

2. Development of the Ventricular Wall

3. Atrial Development and Septation

4. Atrial Venous Connections

4.1. The atrioventricular canal

5. Outflow Tract Septation and the Neural Crest

6. The Conduction System

7. Cardiovascular Defects in the Context of Syndromes

8. Conclusions

Acknowledgments

References

Chapter Three: MicroRNA in Pulmonary Vascular Disease

1. Introduction

1.1. Pulmonary arterial hypertension

1.2. Animals models of PAH

1.3. MicroRNA

2. miRNA Biogenesis and Function

2.1. Regulation of miRNA expression

2.2. MicroRNA/mRNA interaction and target prediction

2.3. Cellular localization of miRNA

3. miRNA in PAH

3.1. miRNA in animal models of PAH

3.2. Ex vivo human pulmonary artery smooth muscle cells: miR-204 and STAT target signaling

3.3. miRNA in human plasma: miR-150 as a biomarker of PAH

3.4. Pathway-based investigation of miRNA in PAH

3.5. miR-424/503 mediate secondary effects of the Apelin-Apelin receptor axis

3.6. Hypoxia miR-210 and HIF1α

3.7. miRNA, inflammation, and BMPR2 signaling

4. Conclusions and Future Directions

Acknowledgments

References

Chapter Four: Zebrafish as a Model of Cardiac Disease

1. Introduction

2. Zebrafish Heart Development

2.1. Early patterning

2.2. Larval heart development and growth

3. Function and Electrophysiology of the Zebrafish Heart

4. Disease Models 1—Congenital Heart Defects

5. Disease Models 2—Hypertrophic and Dilated Cardiomyopathy

6. Disease Models 3—Arrhythmias

7. Heart Regeneration

8. Concluding Remarks

Acknowledgments

References

Chapter Five: The Zebrafish as a Model of Vascular Development and Disease

1. Introduction

2. Origins of the Vasculature in Zebrafish

3. Zebrafish Vasculogenesis

3.1. Regulation of initial angioblast migration

3.2. Regulation of endothelial cord formation and arterial-venous specification

4. Angiogenesis in Zebrafish

5. Lymphangiogenesis in Zebrafish

6. Vascular Myogenesis

7. Zebrafish as a Model for Vascular Disease

7.1. HHT/arteriovenous malformations

7.2. Klippel-Trenaunay syndrome

7.3. Cerebral cavernous malformations

7.4. von Hippel-Lindau disease

7.5. Zebrafish as a model to study arterial occlusion and collateral vessel formation

8. Summary

Acknowledgments

References

Chapter Six: Genetics of Response to Antiplatelet Therapy

1. Introduction

2. Aspirin

2.1. Polymorphisms that affect response to aspirin

2.2. GPIIIa receptor polymorphisms

2.3. COX-1 polymorphisms

2.4. Summary of the effect of genotype on response to aspirin

3. Clopidogrel

3.1. Metabolism of clopidogrel

3.2. Genetic polymorphisms and efficacy of clopidogrel

3.3. CYP2C19 loss-of-function alleles and pharmacokinetics of clopidogrel

3.4. CYP2C19 loss-of-function alleles and pharmacodynamic effect of clopidogrel

3.4.1. Summary of PK/PD effect of CYP2C19 loss-of-function polymorphisms

3.5. Effect of CYP2C19 loss-of-function alleles on clinical outcomes

3.5.1. Key observational studies of PCI and ACS patients

3.5.2. Key subgroup analyses of ACS clinical trials (see Tables6.1 and 6.2)

3.5.3. Meta-analysis and systematic review

3.5.4. Summary of the effect of CYP2C19 loss-of-function polymorphisms on clinical outcomes

3.6. CYP2C19 gain-of-function alleles

3.6.1. CYP2C19 gain-of-function alleles and the pharmacokinetic and pharmacodynamic response to clopidogrel

3.6.2. Summary of effect of CYP2C19*17 on pharmacodynamic effect of clopidogrel

3.6.3. Key observational studies investigating clinical outcomes

3.6.4. Genetic subgroup analyses of large ACS clinical trials

3.6.5. Systematic review and meta-analysis

3.7. ABCB1 genotype

3.7.1. ABCB1 genotype and PK/PD studies

3.7.2. Key observational studies investigating clinical outcomes

3.7.3. Key clinical trials

3.7.4. Meta-analysis

3.7.5. Summary of the effect of ABCB1 polymorphisms

3.8. Paraoxonase-1

3.9. Carboxylesterase

3.10. CYP3A4 genotype

3.11. PEAR1

4. Prasugrel

4.1. Introduction

4.2. Metabolism of prasugrel

4.3. Effect of CYP2C19 genotype on the effect of prasugrel

4.3.1. Observational studies investigating the effect of CYP2C19 genotype on PK/PD response to prasugrel in healthy volunt ...

4.3.2. Observational studies investigating the effect of CYP2C19 genotype on PK/PD response to prasugrel in patients with ...

4.3.3. Clinical trials investigating the effect of CYP2C19 genotype on pharmacodynamic effect of prasugrel

4.3.4. Key studies investigating the effect of CYP2C19 genotype on clinical outcomes of prasugrel-treated patients

4.3.5. Summary of the effect of CYP2C19 polymorphisms on prasugrel-treated patients

4.4. ABCB1

5. Ticagrelor

5.1. Influence of genetic polymorphisms on the effect of ticagrelor

6. GPIIb/IIIa Antagonists

6.1. PlA2 polymorphisms in healthy volunteer studies

6.2. PlA2 polymorphisms in ACS or post-PCI patients

6.2.1. Summary of the effect of PlA2 polymorphisms

7. Summary of the Genetics of Antiplatelet Drug Responses

References

Chapter Seven: The Role of the Transcription Factor KLF2 in Vascular Development and Disease

1. Introduction

2. The KLF Family of Transcription Factors

2.1. KLF2

2.1.1. KLF2 expression in human, mouse, and zebrafish

3. Mechanotransduction and KLF2 Expression

3.1. Flow-dependent regulation of KLF2

4. Non-Flow-Dependent Regulation of KLF2

4.1. Factors stimulating KLF2 expression

4.2. Factors inhibiting KLF2 expression

5. Functions of KLF2

5.1. Maintenance of endothelial homeostasis

5.1.1. Vasoregulation

5.1.2. Thromboprotection

5.1.3. Inflammation

5.1.4. Complement activation

5.1.5. Endothelial barrier function

5.1.6. Endothelial morphology and intercellular gap junctions

5.1.7. Oxidative stress

5.1.8. microRNA production

5.2. T-cell and B-cell biology

5.3. Monocyte and macrophage biology

5.4. Vasculogenesis and angiogenesis

5.5. Valvulogenesis

6. Summary

Acknowledgments

References

Index

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