Preface xxiii

1 Basic Concepts in Mass Spectrometry 1
Pietro Traldi and Gianluca Bartolucci

1.1 Introduction 1

1.2 Mass and Energy 2

1.3 Mass Spectrometry-Based Proteomic Analyses 4

1.4 Mass Spectrometry in Quantitative Protein/Peptide Analyses 23

1.5 Posttranslational Modifications Investigated by Mass Spectrometry 27

1.6 Outlook and Conclusion 28

References 28

2 Overview of Antibody-Based Technologies for Multiplexed Protein Detection and Quantification and Their Complementarity to Mass Spectrometry-Based Protein Profiling 31
Sonia Eligini, Erica Gianazza, and Alice Mallia

2.1 Introduction 31

2.2 Clinical Potentials of Mass Spectrometry-Based Proteomics 31

2.3 Mass Spectrometry-Based Proteomic Analysis Workflow: from Biomarker Discovery to Validation 32

2.4 Proteomic Analysis of Biological Samples: from Sample Preparation to Proteome Characterization for the Identification of Disease or Drug Candidates 34

2.5 Applications of the Emerging Mass Spectrometry-independent Targeted Proteomic Technologies in the Cardiovascular Field 42

2.6 Conclusions 57

References 58

3 General Features of the Cardiovascular System 65
Paul A. Iaizzo

3.1 Introduction 65

3.2 Components of the Cardiovascular System 65

3.3 Summary 77

References and Resources 77

4 Albumin and Cardiovascular Diseases 79
Cristina Banfi

4.1 Introduction 79

4.1.1 Structure and Functions of Human Albumin 79

4.2 Conclusion 98

References 99

5 Platelets: From Biomarker Discovery to Drug Target Identification by Proteomics 107
Cristina Banfi

5.1 Platelet Biology 107

5.2 Platelet Activation and Signaling 108

5.3 Platelets in Diseases 112

5.4 Role of Proteomics in Platelet Study 115

5.5 Post-translational Modifications of Platelet Proteins 124

5.6 Conclusions 130

References 131

6 The Role of Proteomics in Extracellular Vesicles Research in Cardiovascular Disease 139
Maísa García-Arguinzonis and Lina Badimon

6.1 History of EVs 139

6.2 Classification of EVs 140

6.3 Biogenesis of EVs 140

6.3.1 Exosomes 140

6.3.2 Microvesicles 141

6.3.3 Apoptotic Bodies 143

6.4 Other Extracellular Particles 143

6.5 Source of EVs in Cardiovascular Disease Studies 144

6.6 EV Isolation from Cell Cultures 144

6.7 Collection of EVs from Blood 144

6.8 Urine-EVs Separation 146

6.9 EVs from Solid Tissue 146

6.10 Storage of EVs 146

6.11 Isolation and Purification Methods 147

6.12 EV Separation Methods 147

6.13 Characterization of EVs 150

6.14 Proteomics 151

6.15 EVs in Cardiovascular Diseases 155

6.16 EVs in Atherosclerosis 155

6.17 EVs in Myocardial Infarction 157

6.18 EVs in Angiogenesis 159

6.19 EVs in Heart Failure 160

6.20 Engineered EVs 161

6.21 EV Databases 162

6.22 Conclusion 163

References 163

7 Proteomics of Human Lipoproteins in Cardiovascular Diseases 177
Cristina Banfi

7.1 Introduction 177

7.2 Chylomicrons Biogenesis and Metabolism 178

7.3 Very Low-Density Lipoprotein 183

7.4 Low-Density Lipoprotein 189

7.5 Lipoprotein(a) 193

7.6 High-Density Lipoprotein 196

7.7 Methodological Approaches for Isolating Lipoproteins 200

7.8 Multiplexing Analysis of Apolipoproteins in the Human Blood 202

7.9 Conclusions 203

References 204

8 Extracellular Matrix in Cardiovascular Pathophysiology: Proteomic Insights and Advancements to Mass Spectrometry-Based Characterization 215
Rachel Cahalane, Mandy E. Turner, Elena Aikawa, and Cassandra L. Clift

8.1 An Introduction to the Extracellular Matrix 215

8.2 Extracellular Matrix in Cardiovascular Pathobiology 219

8.3 Proteomic Targeting of the ECM 233

8.4 Conclusions and Future Directions 235

References 236

9 Pathogenesis of Atherosclerosis: What We are Learning from Proteomics 255
David del Rio-Aledo, Estefanía Núñez, Emilio Camafeita, Isabel Cerro-Pardo, Rafael Barrero, Ana Martínez del Val, Consuelo Marín, Luis Miguel Blanco-Colio, Jesús Vázquez, and Jose L. Martin-Ventura

9.1 Introduction 255

9.2 Fundamentals of Proteomics in Atherosclerosis 255

9.3 Mechanisms Involved in Atherosclerotic Plaque Development and Progression 260

9.4 Proteomic Biomarkers in Atherosclerosis 268

9.5 Future Perspectives and Challenges in Atherosclerosis Proteomics 270

9.6 Concluding Remarks 273

References 273

10 Emerging Insights into the Pathobiology of Acute Coronary Syndromes 283
Gabriele Nieddu, Marilena Formato, and Antonio J. Lepedda

10.1 Introduction 283

10.2 Searching for Circulating Biomarkers of ACS by Applying MS-based Technologies 289

10.3 Atherosclerotic Plaque Dissection through Proteomics 299

10.4 Conclusions 302

References 303

11 Valvular Heart Disease, from Physiopathology to Biomarker Discovery 313
Sasha A. Singh and Elena Aikawa

11.1 Introduction 313

11.2 Physiopathology of Valvular Heart Disease, a Historical Perspective 314

References 333

12 Pathophysiology of Heart Failure 341
Giorgia Panichella and Alberto Aimo

12.1 Introduction 341

12.2 Hemodynamic and Structural Changes 342

12.3 Neurohormonal Dysregulation 344

12.4 Cellular and Molecular Mechanisms 351

12.5 Comorbidities and Multisystem Involvement 354

12.6 Right Ventricle in Heart Failure 355

12.7 Genetic Contributions to Heart Failure 356

12.8 Heart Failure as a Continuum Spectrum 357

12.9 Heart Failure with Preserved Ejection Fraction 358

12.10 The Contribution of Proteomics in Heart Failure 360

12.11 Conclusions 362

References 362

13 Diseases of the Aorta, Recent Insights 371
Raghav Gupta, Ashley Dinh, Sarah J. Parker, and Elizabeth L. Chou

13.1 Introduction 371

13.2 Epidemiology of Aortic Aneurysm and Dissection 372

13.3 Aortic Physiology 373

13.4 Investigation of Aortic Aneurysms and Dissections 374

13.5 Summary of Genes Linked to Aortic Aneurysm and Dissection 375

13.6 The Omics of Ascending Thoracic Aortic Aneurysm and Dissection 378

13.7 The Unique Value of Proteomics for Hereditary Aneurysm Research 379

13.8 Application of Proteomics to Aortic Aneurysms and Dissections 380

13.9 Beyond Bulk Proteomics for Mechanistic Discovery in Aortic Aneurysms and Dissections 381

13.10 Conclusion 385

References 385

14 Unveiling Sex and Gender Differences in Cardiovascular Diseases 391
Daniela Trabattoni, Giovanni Teruzzi, Giuseppe Calligaris, and Sebastiano Gili

14.1 Introduction 391

14.2 Sex-Related Differences in Clinical Presentation, Risk Factors, and Diagnostic Evaluation of CAD 391

14.3 Primary Prevention 392

14.4 Detection of Coronary Artery Disease 394

14.4.9 Mechanical and Emotional Stressors 400

14.5 Acute Coronary Syndromes in Obstructive Coronary Disease 407

14.6 Gender Differences in PCI Outcomes 407

14.7 The Role of Coronary Imaging in Imaging 409

14.8 Psychological Issues in Gender Cardiovascular Medicine 413

14.9 Pathophysiology Basis of Non-Atherosclerotic Coronary Disease in Women 416

14.10 The Contribution of Proteomics in Unveiling Sex and Gender Differences 417

References 419

15 Trends in Mass Spectrometry Imaging for Cardiovascular Diseases 431
Johs Dannesboe and Berta Cillero-Pastor

15.1 Introduction 431

15.2 Definition and Basic Principles of Mass Spectrometry Imaging 431

15.3 Brief History of Mass Spectrometry Imaging in Biomedical Research 432

15.4 Importance of Mass Spectrometry Imaging in Cardiovascular Disease Research 433

15.5 Basic Principles and Workflow 433

15.6 Small Molecule and Lipid Imaging in Cardiovascular Research 440

15.7 Challenges and Limitations 442

References 444

16 Network Medicine: A New Paradigm for Cardiovascular Disease Research and Beyond 449
Niv Vigder, Stuart J. Cordwell, and Joseph Loscalzo

16.1 Introduction to Network Medicine 449

16.2 Introduction to Network Science and Biological Networks 450

16.3 Progress Toward Reference Organismal Interactomes 459

16.4 Complex Diseases Manifest as Nodal and Edgetic Perturbations 464

16.5 Expanding the Interactome to Incorporate Complex Biological Phenomena 466

16.6 Context-Specific Interactomes Resolve Complex Biological Heterogeneity 468

16.7 Network Approaches Reveal Novel Disease Genes and Gene Products 471

16.8 (Re)defining Relationships Between Diseases Using Network Medicine 472

16.9 Network Approaches to Disease Reappraisal and Patient Subgrouping 473

16.10 Network Approaches to Disease Pharmacology 476

16.11 Conclusions 478

References 479

17 Recent Advances in Cardiovascular Plasma Proteomics 487
Nicolai B. Palstrøm, Amanda J. Campbell, and Hans C. Beck

17.1 Introduction 487

17.2 Clinical Plasma Proteomics 488

17.3 The Proteomics Toolbox: Analytical Methods in Cardiovascular Clinical Plasma Proteomics 491

17.4 Application of Plasma Proteomics in Cardiovascular Research 500

17.5 Challenges Regarding the Translation of Proteomics into the Clinic 504

17.6 Recent Advances within Cardiovascular Plasma Proteomics 507

17.7 Outlook 509

References 510

18 Unexplored Cardiac Diseases: Takotsubo Syndrome 523
Liam S. Couch

18.1 Introduction 523

18.2 Clinical Presentation 523

18.3 Multifactorial Pathophysiology of Takotsubo Syndrome 524

18.4 The Role of Catecholamine Signaling 525

18.5 Cardiomyocyte Calcium Handling 527

18.6 Deranged Cardiomyocyte Metabolism 527

18.7 Myocardial Inflammation and Edema 528

18.8 Estrogen Withdrawal Post-menopause 529

18.9 Altered Coronary Blood Flow 529

18.10 Genomic Associations 531

18.11 Brain Heart Interaction 531

18.12 Scope for Future Utilization of Proteomics 532

References 532

Index 541