Cardiac Amyloidosis: Diagnosis and Treatment

Preface
Contents
1: Tribute to Claudio Rapezzi
	References
2: Giampaolo Merlini and the Pavia School
	References
3: A Brief History of Amyloidosis
	3.1	 Characterization of the Structure and Biochemical Composition of Amyloid Deposits
	3.2	 Novel Diagnostic Techniques
	3.3	 Therapeutic Approaches
	3.4	 Conclusions
	References
4: Pathophysiology, Classification, and Epidemiology of Amyloidosis
	4.1	 Definition and Nomenclature
	4.2	 Amyloid Fibers
	4.3	 Pathophysiology of Organ Damage
	4.4	 Classification and Epidemiology
		4.4.1	 Acquired Forms
		4.4.2	 Forms of Amyloidosis Related to Gene Mutations
	4.5	 Prognostic Significance of Different Types of Amyloidosis
		4.5.1	 AL Amyloidosis
		4.5.2	 ATTR Amyloidosis
	4.6	 Conclusions
	References
5: Amyloid Light Chain (AL) Amyloidosis
	5.1	 Epidemiology and Risk Factors
	5.2	 Pathophysiology
	5.3	 Clinical Manifestations
	5.4	 Diagnosis
	5.5	 Prognosis
	5.6	 Conclusions
	References
6: Hereditary Transthyretin Amyloidosis
	6.1	 Epidemiology
	6.2	 Genetic Basis of ATTRv
	6.3	 The Amyloidogenic Cascade
	6.4	 Clinical Manifestations
		6.4.1	 Heart Involvement
		6.4.2	 PNS Involvement
	6.5	 Other Clinical Manifestations
	6.6	 Prognosis
	6.7	 Presymptomatic Genetic Testing and Monitoring of Carriers
	6.8	 Conclusions
	References
7: Wild-Type ATTR Amyloidosis
	7.1	 Definition and Epidemiology
	7.2	 Pathophysiology
		7.2.1	 Transthyretin
		7.2.2	 The TTR Amyloid Cascade
	7.3	 Clinical Manifestations
		7.3.1	 Cardiac Manifestations
			7.3.1.1	 Heart Failure
			7.3.1.2	 Aortic Stenosis
			7.3.1.3	 Arrhythmias
		7.3.2	 Extracardiac Manifestations
	References
8: Electrocardiographic Patterns
	8.1	 Relevance of ECG Patterns for Diagnosis and Risk Stratification
	8.2	 ECG Patterns in AL Vs. ATTR Amyloidosis
	8.3	 Bradyarrhythmias and Tachyarrhythmias
		8.3.1	 Ventricular Arrhythmias
		8.3.2	 Atrial Arrhythmias
		8.3.3	 Bradyarrhythmias and Conduction Disturbances
	8.4	 Conclusions
	References
9: Echocardiography: A Gatekeeper to Diagnosis
	9.1	 M-mode Echocardiography
	9.2	 2D Echocardiography
	9.3	 Diastolic Function and Right Heart Involvement
	9.4	 Tissue Doppler Imaging
	9.5	 Speckle Tracking Echocardiography
	9.6	 Echocardiography for Differential Diagnosis Between Amyloidosis Subtypes
	9.7	 Echocardiography to Assess the Response to Treatment
	9.8	 Conclusions
	References
10: Cardiovascular Magnetic Resonance: Characterization of Myocardial Involvement
	10.1	 Introduction
	10.2	 Morphological and Functional Assessment
	10.3	 Strain
	10.4	 Diffusion Tensor Imaging
	10.5	 Late Gadolinium Enhancement
	10.6	 T1 Mapping
	10.7	 T2 Mapping
	10.8	 Perfusion
	10.9	 ECV Mapping
	10.10	 Extracardiac Findings
	10.11	 CMR for Prognostic Assessment
	10.12	 CMR for Disease Monitoring
	10.13	 Use of CMR: Current Recommendations by Scientific Societies
	10.14	 Conclusions
	References
11: Biomarkers: Monoclonal Protein and Indicators of Cardiac Damage
	11.1	 Amyloidogenic Precursors of AL Amyloidosis
	11.2	 Biomarkers of Cardiac Damage in Light Chain Amyloidosis
		11.2.1	 Screening and Diagnosis
		11.2.2	 Risk Stratification
		11.2.3	 Treatment Management
	11.3	 Biomarkers of Cardiac Damage in Transthyretin Amyloidosis
		11.3.1	 Screening and Diagnosis
		11.3.2	 Risk Stratification
		11.3.3	 Treatment Management
	11.4	 Conclusions and Future Perspectives
	References
12: Plasma Transthyretin and Its Ligands
	References
13: Cardiac Scintigraphy with Bone-Avid Tracers: Old and New Applications
	13.1	 Background
	13.2	 Evolution of Cardiac Scintigraphy with Technetium-99m-Labeled Bone-Avid Radiotracers
	13.3	 Mechanism of Myocardial Uptake of Bone-Avid Tracers in ATTR-CA
	13.4	 Diagnostic Accuracy of 99mTc-PYP/DPD/HMDP for ATTR-CA
	13.5	 Diagnostic Criteria for ATTR-CA
	13.6	 Imaging Protocols for Tc-99m-PYP/DPD/HMDP Cardiac Scintigraphy
	13.7	 Current Applications of Bone Scintigraphy
		13.7.1	 Diagnosis of ATTR-CA in Patients with Heart Failure
		13.7.2	 Diagnosis of ATTR-CA in Patients with Heart Failure and Severe Aortic Valve Stenosis
		13.7.3	 Screening of At-Risk Patients for Early Detection of ATTR-CA: Carpal Tunnel Syndrome
		13.7.4	 Temporal Trends in Detection of ATTR-CA Due to Use of Bone-Avid Tracer Cardiac Scintigraphy
	13.8	 Novel Applications of Bone Scintigraphy: Assessment of Response to Therapy
	13.9	 Limitations
	13.10	 Conclusion/Summary
	References
14: PET-CT: A Tool for Etiological Diagnosis
	14.1	 PET Radiopharmaceuticals for Amyloid Detection
	14.2	 Conclusions
	References
15: The Role of Tissue Biopsy: Identification of the Amyloid Precursor and Beyond
	15.1	 Introduction
		15.1.1	 Tissue Analyses in Cardiac Amyloidosis
			15.1.1.1	 Histology
			15.1.1.2	 Histochemistry
			15.1.1.3	 Immunohistochemistry
		15.1.2	 Mass Spectrometry-Based Proteomics
	15.2	 Tissue Biopsy in Cardiac Amyloidosis
		15.2.1	 Endomyocardial Biopsy (EMB)
		15.2.2	 Surrogate Biopsy Sites
		15.2.3	 Other Biopsy Sites
	15.3	 Advantages and Limitations of Tissue Biopsy
	15.4	 Tissue Biopsy: Beyond the Diagnostic Purpose and Future Directions
	15.5	 Conclusions
	References
16: From Red Flags to Diagnosis
	16.1	 When Cardiac Amyloidosis Should Be Suspected
	16.2	 Diagnostic Algorithm
	16.3	 Different Approaches to the Suspicion and Diagnosis of CA
		16.3.1	 Red Flags
		16.3.2	 Diagnostic Algorithms
		16.3.3	 Echocardiography
		16.3.4	 Biomarkers
		16.3.5	 Bone Scintigraphy
		16.3.6	 CMR
		16.3.7	 Tissue Biopsy
		16.3.8	 Genetic Testing
	16.4	 Conclusions
	References
17: Risk Prediction and Follow-Up
	17.1	 Follow-Up of Subjects at Risk of Developing CA
		17.1.1	 AL-CA
		17.1.2	 ATTR-CA
	17.2	 Risk Prediction in Patients Diagnosed with CA
	17.3	 Assessment of Treatment Response in Patients with CA
		17.3.1	 AL-CA
		17.3.2	 ATTR-CA
	17.4	 Conclusions
	References
18: Differential Diagnoses in Clinical Mimics
	18.1	 Hypertensive Heart Disease
	18.2	 Aortic Stenosis
	18.3	 Hypertrophic Cardiomyopathy (Sarcomeric and Phenocopies)
	18.4	 Cardiac Sarcoidosis
	18.5	 Haemochromatosis
	18.6	 Light-Chain Deposition Disease
	References
19: Applications of Artificial Intelligence in Amyloidosis
	19.1	 Artificial Intelligence and Machine Learning: Introduction and Use in Medicine
	19.2	 Artificial Intelligence and Cardiac Amyloidosis: Diagnosis
		19.2.1	 Clinical Variables and Biomarkers
		19.2.2	 Electrocardiogram
		19.2.3	 Echocardiography
		19.2.4	 Advanced Imaging Techniques (Cardiovascular Magnetic Resonance and PET)
	19.3	 Artificial Intelligence in Amyloidosis: Outcome
	19.4	 Machine Learning in Amyloidosis: Challenges and Future Perspectives
	19.5	 Conclusions
	References
20: Treatment of Amyloid Light-Chain Amyloidosis
	20.1	 General Principles of Treatment
	20.2	 General Assessment
	20.3	 Assessment of Response
	20.4	 Autologous Bone Marrow Transplantation
	20.5	 Therapy in Patients Not Candidates to Transplantation
	20.6	 Therapy of Relapsing or Non-responding Patients
	20.7	 Selective Anti-fibril Therapy
	20.8	 Conclusions
	References
21: Treatment of ATTR Amyloidosis: From Stabilizers to Gene Editing
	21.1	 Understanding the Amyloidogenic Cascade to Develop Treatments
	21.2	 Imitating Nature with Selective TTR Stabilizers
		21.2.1	 Tafamidis
		21.2.2	 AG10 (Acoramidis)
	21.3	 Suppressing Protein Production with TTR Silencers
	21.4	 Small Interfering RNAs (siRNAs)
		21.4.1	 Patisiran
		21.4.2	 Revusiran
		21.4.3	 Vutrisiran
		21.4.4	 Antisense Oligonucleotides (ASOs)
		21.4.5	 Inotersen
		21.4.6	 Eplontersen
	21.5	 Editing the TTR Gene in Hepatocytes
		21.5.1	 NTLA-2001
	21.6	 Conclusion
	References
22: Treatment of Cardiac Complications
	22.1	 Severe Aortic Stenosis
	22.2	 Atrial Fibrillation: Rhythm and Rate Control
	22.3	 Risk of Thromboembolic Events
	22.4	 Conduction Disturbances
	22.5	 Ventricular Arrhythmias and Dyssynchrony
	22.6	 Heart Failure
	22.7	 Orthostatic Hypotension
	22.8	 Conclusions
	References
23: Monitoring Disease Progression and Response to Disease-Modifying Treatments
	23.1	 Disease Monitoring in Transthyretin Cardiac Amyloidosis
	23.2	 Assessment of Treatment Response in Transthyretin Cardiac Amyloidosis
	23.3	 Disease Monitoring in Light-Chain Cardiac Amyloidosis
	23.4	 Perspectives
	23.5	 Conclusions
	References
24: Cardiac Amyloidosis: Open Issues and Future Perspectives
	24.1	 Mechanisms of Amyloid Formation and Tissue Infiltration
	24.2	 Towards a Completely Noninvasive Diagnostic Algorithm of Cardiac Amyloidosis
	24.3	 Open Issues in the Management of AL-CA
	24.4	 Impact of Earlier Diagnosis
	24.5	 Comparisons Between Different Gene Silencers and Gene Editing Therapies
	24.6	 Monitoring the Cardiac Response to Treatment
	24.7	 Long-Term Safety of TTR Depletion
	24.8	 Organization of Diagnosis, Management of Cardiac Amyloidosis, and Treatment Issues
	References