Front Cover

Post-Genomic Cardiology

Copyright Page

Contents

Preface

I: Post-Genomic Cardiology

1 Introduction to the Molecular Biology of the Cell

Nucleic Acids, Genes, Chromatin, and Chromosomes

DNA Transacting Processes: Replication, Transcription, and Repair

DNA replication

Gene expression

Transcription

Pre-mRNA processing

Repair of DNA damage

Genetic Variability Associated with Human Diseases

Cell Cycle

References

2 Methodologies in the Era of Cardiovascular “Omics”

Introduction

Genomics Approaches: NGS and GWAS

Genome-wide association studies

Genome-wide analysis of cardiovascular disease

Transcriptomics

RNA sequencing

Chromatin immunoprecipitation-based transcriptomics

Transcriptomics of cardiovascular disease

Proteomics and Interactomics

MS-based proteomic technology

Quantitative MS-based proteomics

Proteomic analysis of posttranslational modifications

Interactomics: MS analysis of protein–protein interactions

Metabolomics

Approaches in metabolomic profiling: targeted and untargeted metabolomics

NMR techniques

MS-based technologies

Metabolomics in assessing cardiovascular disease

Cardiac Imaging

Super-resolution fluorescence microscopy

Fluorescent probes and fluorescence resonance energy transfer (FRET)

Translational Bioinformatics

Conclusions

Summary

References

3 Post-Genomics Cardiovascular Signaling Pathways

Introduction

Cardiac Signaling in Physiological Growth

Receptors

Toll-Like receptors

G Proteins

Effectors

Kinases and phosphatases

Ca2+-Mediated Signaling

Integrating responses

Transcription factors and translational control

Translation control

Signaling at the Plasma Membrane

Sarcolemmal KATP channel

Signaling at the Mitochondria

Reactive oxygen species generation and signaling

Negative effects of ROS

Cell-Cycle signaling, cell proliferation, and apoptosis

Stress, Survival, and Metabolic Signaling

Survival/Growth signals

Stress signals

Metabolic signals

Extracellular signals and matrix

Signaling in Cardiac Development and Aging

Conclusion

Summary

References

II: Pediatric Cardiology in the Post-Genomic Era

4 Molecular Determinants of Cardiac Development

Introduction

Overview of Cardiac Morphogenesis

Regulatory networks controlling cardiovascular development

Major signaling pathways regulating heart development

Transcription factor circuit regulating cardiac development

MicroRNAs in Cardiovascular Development

Conclusions

Summary

References

5 Molecular Determinants of Congenital Heart Disease

Introduction

Etiology of CHD: Interplay of Genetic and Environmental Factors

Molecular Mechanisms of CHD

CHD associated with aneuploidy and chromosomal structural abnormalities

CHD caused by single-gene mutations

Syndromic CHDs Caused by Point Mutations

RASopathies

Defects of NOTCH signaling associated with CHD

Nonsyndromic CHDs Caused by Point Mutations

Non-Syndromic CHD Caused by Impaired Signaling Pathways

Defects of the NOTCH signaling pathway in nonsyndromic CHD

Defects of the NODAL signaling pathway in nonsyndromic CHD

Nonsyndromic CHD Caused by Point Mutations in Transcription Factors

Nonsyndromic CHDs Caused by Point Mutations in Structural Proteins

Noncoding RNAs and CHD

Conclusions

Summary

References

III: Post-Genomic Assessment of Coronary Artery Disease, Angiogenesis,and Hypertension

6 Molecular Determinants of Atherosclerosis

Overview of Atherogenesis

Lipoproteins

Endothelial Dysfunction

Rho Kinases and Statins in Atherosclerosis

ROCKs

Statins

Tumor Necrosis Factor (TNF) in Atherogenesis

TNF and lipid metabolism

TNF effects on endothelial dysfunction

TNF and ROS generation

Monocytes and Macrophages

Progression of atherosclerosis: inflammation

Adhesion and migration

Antiinflammatory Factors

TGF β–signaling pathway

Peroxisome proliferator-activated receptors

Liver X receptor signaling

Atherosclerotic plaque formation and development

Thrombosis

Conclusion

Summary

References

7 Molecular Genetics of Coronary Artery Disease and Myocardial Infarction

Introduction

Animal Studies

Linkage and Genome-Wide Association Studies in Myocardial Ischemia

HapMap

Genome-wide association studies (GWAS)

Chromosome 9p21.3 region

Candidate Gene Identification Approach

Acute coronary syndrome

Genes and Inflammatory Signaling Pathways Involved in CAD/MI

Other molecular players in the inflammatory signaling pathways

Other Signaling Pathways in CAD/MI

Connexin and transforming growth factors signaling

NO signaling

Additional Gene LOCI Associated with MI

Sex Hormone and MI

Gene Profiling in Myocardial Ischemia/Infarct

Genetics and Ethnic Differences in Coronary Artery Disease

Beyond GWAS

MicroRNAs Markers in CAD/MI

Conclusions

Summary

References

8 Cellular and Molecular Aspects of Cardioprotection

Introduction

Cellular and Molecular Events in IPC

IPC and Potassium Channels

Signaling Pathways

Cell Death

Early and Late IPC Pathways

IPC and Cell Death

Mitochondrial Activity and ATP Levels in IPC

Mitochondria and Antioxidants

Gene Expression in Early IPC (Signaling Book)

Second window of protection/delayed preconditioning

Postconditioning and Cardioprotection

Remote Conditioning

Application in Humans

microRNAs in Cardioprotection

Conclusions and Future Perspective

Summary

References

9 Molecular Determinants of Cardiac Neovascularization

Introduction

Vasculogenesis

Angiogenesis

Arteriogenesis

Molecular Mechanisms of Neovascularization

Vascular endothelial growth factor

Platelet-derived growth factor

Fibroblast growth factors

Neurotrophins

Tumor growth factor β

CD151

Hypoxia-inducible factors

Notch

MicroRNAs

Therapy

Pharmacological approaches

Gene therapy

Cell therapy

Conclusions and Future Perspectives

Summary

References

10 Post-Genomics Appraisal of Systemic and Pulmonary Hypertension

Introduction

Animal Models of Hypertension

Evidence of genetic contributions to hypertension

Genomic assessment of primary systemic hypertension

Identification of primary risk genes and candidate genes

Gene Expression and Profiling in Primary Systemic Hypertension

Global and specific analysis

Signaling pathways in primary systemic hypertension

Primary pulmonary hypertension

Genetics of PPH

Gene expression profiling in pulmonary hypertension

Conclusions and Future Directions

Summary

References

IV: Post-Genomic Analysis of the Myocardium

11 Post-Genomic Appraisal of Myocarditis

Introduction

Pathogenesis of Autoimmune Myocarditis

Viral phase

Signaling Pathways of Innate and Acquired Immunity

Innate immunity

Virus-mediated myocardial injury

Virus-mediated pathways involved in acquired immunity

Gene expression profiling in myocarditis

Genetic polymorphisms in myocarditis

The chromosomal factor

Mutations associated with myocarditis and dilated cardiomyopathy

Epigenetics factors in myocarditis

DNA methylation

Histone modifications

miRNAs

Selenium

Viral genetic variations and myocarditis

Diagnosis of autoimmune myocarditis

Animal models

Treatment

Conclusions

Summary

References

12 Cardiomyopathies: A Comparative Analysis of Phenotypes and Genotypes

Introduction

Hypertrophic Cardiomyopathy

Clinical manifestations

Potential promoters of maladaptive hypertrophic response

Myocardial energetics

Effectors of LVH

Genetics of HCM

β-myosin heavy chain

Myosin-binding protein C

Cardiac troponins

Regulatory and essential myosin-light-chain genes

Cardiac actin

Z disc proteins: titin gene (TTN, MLB, and T-Cap)

Nonsarcomeric genes

Animal Models of Genetic HCM

Sarcomeric mutations

Cardiac troponin T-gene mutations

Cardiac troponin I gene

α-tropomyosin

Myosin light chain

Other nonsarcomeric models of HCM

Dilated Cardiomyopathy

Clinical manifestations

Genetics of FDCM

Chromosomal loci

Cardiac actin gene

Myosin-heavy-chain genes

MyBPC3 gene

Cardiac troponin T and tropomyosin genes

Involvement of the titin gene in DCM

Desmin gene

δ-sarcoglycan gene

Metavinculin gene

Lamin A/C gene and emerin

Dystrophin gene

Tafazzin gene

Identification of additional genes

Transgenic Models of Dilated Cardiomyopathy

Mechanistic Hypotheses of DCM

Abnormal gene expression in advanced DCM

Restrictive Cardiomyopathy

Clinical manifestations

Chromosomal loci and disease genes

Arrhythmogenic Right Ventricular Dysplasia

Clinical manifestations

Genetics of ARVD

Unclassified Cardiomyopathies

Mitochondrial cardiomyopathy

Clinical evidence of nuclear mutations in mitochondrial components

Transgenic models of mitochondrial cardiomyopathy

Mitochondrial DNA and cardiomyopathy in transgenic mice

Cardiomyopathy and Diabetes Mellitus

Genetics in Diabetes

Conclusion

Summary

References

V: Heart Failure, Cell Death, and Mitochondria Dynamics

13 Gene Profiling, Energy Metabolism, and Remodeling of the Failing Heart

Introduction

The Profiling of Gene Expression in Heart Failure

Global and Specific Analysis of Gene Expression

Susceptibility/modifier genes/RNAi in heart failure

RNA interference

MicroRNAs and HF

Epigenetics and HF

Histone/Chromatin Modifications; Epigenetic Control of Gene Expression

Critical role of histone acetylation/chromatin remodeling in the triggering/progression of cardiac hypertrophy

Other regulators of chromatin remodeling have been recently identified that may be operative in the heart

DNA modification/methylation

Transcriptional Coactivator p300 and Cardiac Hypertrophy

Energy Metabolism Profiling

Intracellular Calcium-Cycling Profiling

The Genetics of Human HF

Bioenergetics and Metabolic Changes in the Failing Heart

Mitochondria in cardiac bioenergetics

Oxidative stress and apoptosis

Nitric oxide and HF

Mitochondrial DNA Integrity and HF in Transgenic Mice

Peroxisome proliferator activated receptor gamma coactivator 1 (PGC1)

Peroxisome proliferator activated receptor (PPAR)

Mitochondrial Gene Profiling

Implication of Metabolic Genes in HF

From Cardiac Remodeling to Overt HF

The Extracellular Matrix

Metabolic remodeling

Conclusion

Summary

References

14 Oxidative Stress and Cell Death in Cardiovascular Disease: A Post-Genomic Appraisal

Introduction

Oxidative Stress

Sources of ROS/RNS

Mitochondria-derived ROS

Cytosolic sources of ROS

Cell Death

Apoptosis

Extrinsic pathway

Intrinsic pathway

Necrosis

Autophagy

Cell death and CVD

Conclusions

Summary

References

15 The Emerging Role of Mitochondrial Dynamics in Cardiovascular Disease

Introduction

Mechanisms of Mitochondrial Fusion and Fission

Mitochondrial fusion

Mitochondrial fission

Mitochondrial trafficking

Regulation of mitochondrial dynamics

Physiological Roles of Mitochondrial Dynamics

Mitochondrial DNA stability

Respiratory capacities

Stress responses, apoptosis and mitophagy

Mitochondrial Dynamics in the Normal and Diseased Heart

Conclusions

Summary

References

VI: Molecular and Genetic Analysis of Metabolic Disorders

16 Post-Genomic Analysis of Fatty Acid and Glucose Metabolism in Cardiovascular Disease

Introduction

Metabolism of Fatty Acids and Glucose in Normal Cardiomyocytes

Transportation of fatty acids

Glucose carriers

Oxidation of fatty acids and glucose

Compartmentalization of FAO and glucose oxidation machinery

Regulatory Elements of Cardiac Bioenergy Molecules Metabolism

FAO regulation by peroxisome proliferator-activated receptors

Peroxisome proliferator-activated receptor gamma coactivator 1

GATA6 as a “Partner” transcription factor of PPAR

Other nuclear factors

Metabolic Dysfunction and Cardiovascular Disease Phenotypes

Heart failure

Cardiomyopathy

Dysrhythmias

Diabetes and hyperglycemia

Metabolic syndrome and insulin resistance

Metabolic Therapies: Current Status and Perspectives

Summary

References

VII: Molecular Genetics of Dysrhythmias

17 Post-Genomic Analysis of Dysrhythmias and Sudden Death

Introduction

Etiology of Cardiac Dysrhythmias

Ventricular Action Potential and Ion Currents

Cardiac Ion Channels

Properties of Ion Channels

Na+ channels

K+ channels

Hyperpolarization-activated cyclic nucleotide-gated channels

Cl− channels

Inherited Cardiac Dysrhythmias

Long QT syndrome

Short QT syndrome

Brugada syndrome

Catecholaminergic polymorphic ventricular tachycardia

Familial atrial fibrillation

Cardiac conduction defects

Sudden infant death syndrome

Wolff-Parkinson-White syndrome

Acquired Dysrhythmias

Atrial fibrillation and cardiac structural defects

Mitochondria and Heart Rhythm Disorders

The role of sarcolemmal KATP channels in dysrhythmia

Metabolic alterations

MPTP and IMAC

Animals Models for Cardiac Dysrhythmias

Post-Genomic Approaches to Rhythm Disorders

Genetic screening and risk stratification of dysrhythmias/cardiac events

Pharmacogenomics/pharmacogenetics and other therapeutic options in cardiac dysrhythmias

Gene- and cell-based therapies

Conclusions and Future Prospects

Summary

References

VIII: Genes, Gender, and Epigenetics

18 Gender and Cardiovascular Disease in the Post-Genomic Era

Introduction

Sex Steroid Hormones

Estrogen and its receptors

Androgens

Role of Gonadal Hormones in Cardiac Pathology

Animal and In Vitro Studies

Studies in Humans

Sex differences on cardiovascular phenotype development

Gender-Related Gene Regulation and Cardiovascular Disease

Epigenetic and Environmental Factors of Sex-Related Specifics of Cardiovascular Disease

Conclusion

Summary

References

IX: Aging and the Cardiovascular System

19 The Aging Heart: A Post-Genomic Appraisal

Introduction

Telomere Analysis

Telomeres and CV Aging

Signaling Pathways in the Aging Heart

Animal studies

Signaling in the Endothelium in Aging

Cellular Damage/Cell Loss, Mitochondria, and CV Aging

Reactive Oxidative Species Generation and Aging in the Heart

Inflammation and CV Aging

Neurohormonal Signaling in CV Aging

Prodeath and Prosurvival Signaling Pathways in Aging

Signaling factors in cell regeneration of the aging heart

Genetic Makeup of the Aging Heart

Age-related changes in Drosophila melanogaster

Epigenetic and Environmental Factors in Cardiac Aging

Gene Transfer in Cardiovascular Tissue

Knockout Transgenic Animal Models of Aging

Gene Profiling: Transcriptome and Proteomic Analysis

Proteomic Analysis

DNA Damage and Mutations in Aging

Types of DNA damage

Conclusion

Summary

References

20 Targeted Strategies to Fight Cardiac Aging

Introduction

Attenuating Cell Death and Remodeling

Initiating Prosurvival Pathways

Modulation of cardioprotection pathways as a potential strategy

Targeting oxidative stress and ROS in aging

Targeting mitochondrial dysfunction and mitochondrial structural defects

Transfection of mtDNA

Removing “Biological Garbage” in Aging: Targeting Lysosomes, Proteasomes and Other Approaches to Enhance Catabolic Gain

Targeting the nucleus

Genomic Instability

Targeting transcription

Targeting the sarcomere and the sarcoplasmic reticulum

Conclusion

Summary

References

21 Aging and the Cardiovascular System: The Road Ahead

Introduction

Genetic Analysis in Aging Research

Animal models: can simpler models of aging be translated to humans?

Systems biology of cardiac aging

Advances in Human Genotyping and Human Gene Analysis

Longevity and frailty genes

Methods of genetic analysis

Mitochondrial DNA and aging

Search for Biomarkers of Human Aging

Reversing Aging and/or Dysfunction of Age-Associated Diseases

Targeting cellular atrophy and depletion in aging

Stem cells as both primary targets of aging and a potential treatment plan

Targeting Specific Organelles in Aging: Mitochondria/Lysosome

Diastolic Dysfunction in Aging

Pharmacogenomics and Nutrigenomics

Conclusions and Future Perspective

Summary

References

X: Genetics, Epigenetics, and New Approaches to Treatment

22 Epigenetics and Cardiovascular Disease

Introduction

Basic Epigenetic Mechanisms

Chromatin structure

DNA methylation

Chromatin modifications

Histones modifications

Polycomb group and trithorax group protein chromatin regulatory complexes

ATP-dependent chromatin remodeling

Noncoding RNAs and epigenetics

Cardiovascular Epigenetics

DNA methylation in CVD

Conclusions

Summary

References

23 Gene- and Cell-Based Therapy for Cardiovascular Disease

Introduction

Gene Therapy

General considerations

Vectors and techniques for cardiac gene delivery

Gene delivery techniques

Potential Molecular Targets

Targeting the β-adrenergic system

β-AR overexpression

GRK2 inhibition: βARKct

Activation of adenylyl cyclase (AC) VI

Targeting Ca2+ cycling

SERCA2a overexpression

Inhibition of phospholamban (PLN) and protein phosphatase 1 (PP1)

Targeting S100A1

Targeting cell death

Targeting cardiac electrical dysfunction

Other targets

MicroRNA Therapeutics for CVD

miRNA targeting cardiac hypertrophy and fibrosis

miRNA targeting extracellular matrix deposition and aneurysm formation

miRNA targeting pathological cardiac remodeling and obesity

miRNA targeting dysrhythmias

miRNA targeting cardiomyocyte apoptosis

miRNA targeting atherosclerosis and vascular disease

Cell-Based Therapy

Cell Sources

Noncardiac stem cells

Skeletal myoblasts

Bone marrow-derived cells

Umbilical cord–derived stem cells

Pluripotent stem cells

Embryonic stem cells (ESCs)

Induced pluripotent stem cells (iPSCs)

Cardiac Progenitor Cells

Side population cells

c-kit+ CPCs

Sca-1+ CPCs

Isl1+ CPCs

Cardiospheres

Epicardial Progenitor Cells

Strategies for Cell Purification, Delivery, and Engrafting

Mechanisms of Heart Regeneration

Heart regeneration in mammals

Regulation of the CPC niche

Empowering Human Heart Regeneration

Conclusions

Summary

References

XI: Looking to the Future

24 The Path to Personalized Cardiovascular Medicine

Introduction

Genomic and Epigenomic Analysis

Transcriptomics

Proteomics and Metabolomics

Cardiovascular Pharmacogenetics and Pharmacogenomics

Clopidogrel pharmacogenomics

Warfarin pharmacogenomics

Statin pharmacogenomics

Integrating “Omics”: Systems Biology and Network Medicine

Conclusions

Summary

References

Glossary

Index