Front Cover

Cardioskeletal Myopathies in Children and Young Adults

Cardioskeletal Myopathies in Children and Young Adults

Copyright

Dedication

Contents

List of Contributors

Cardioskeletal Myopathies: Foreword

I - Physiology and Molecular Basis of Muscle

1 - Ventricular Systolic Function

INTRODUCTION

Subcellular Determinants: A Brief Review

Beat-to-Beat Regulation of Systolic Function

Acute Stretch—The Frank-Starling Effect

Acute Stress—The Anrep Effect

HEART RATE AND THE BOWDITCH EFFECT

Measuring Systolic Function

Pressure–Volume Relations

Integrative Measures of Systolic Function

Impact of Pericardial Loading on Systolic Function

Ventricular–Arterial Interaction

Treating Systolic Dysfunction

SUMMARY

REFERENCES

2 - Basics of Skeletal Muscle Function and Normal Physiology

INTRODUCTION

DEVELOPMENT OF SKELETAL MUSCLE

MUSCLE GROWTH

SKELETAL MUSCLE ARCHITECTURE, CONTRACTILE APPARATUS, AND FIBER TYPES

Architecture

Contractile Apparatus

Fiber Types

THE BASEMENT MEMBRANE AND MUSCLE FIBER PLASMA MEMBRANE

Basement Membrane

Plasma Membrane

Muscle Fiber Cytoskeleton

Innervation and Blood Supply

Proprioreceptors

THE NEUROMUSCULAR AND MYOTENDINOUS JUNCTIONS

The Neuromuscular Junction

Myotendinous Junction

Excitation-Contraction Coupling

Sarcoplasm

REFERENCES

3 - Molecular Pathways in Cardiomyopathies

CARDIAC MUSCLE DEVELOPMENT

Transcriptional Control of Cardiac Development

Chamber Expansion

Trabeculation

Other Contributors to Heart Development

SKELETAL MUSCLE DEVELOPMENT

Early Embryology

Transcriptional Control of Skeletal Myogenesis

NEUROHORMONAL REGULATION IN THE HEART: Β-ADRENERGIC RECEPTORS AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

The β-Adrenergic Receptor (β-AR) System

β1-AR and Phospholamban

β1AR and the Ryanodine Receptor (RyR)

β1-AR and CaMKII

β2-AR

Beta-Blockers and Phosphodiesterase Inhibitor in Pediatric and Adult Dilated Cardiomyopathy

Renin-Angiotensin-Aldosterone-System

SARCOMERE AND CYTOSKELETON ORGANIZATION IN CARDIAC MUSCLE

Sarcomere/Cytoskeleton Organization and Signaling Within Muscle

METABOLISM/METABOLIC PATHWAYS IN CARDIAC DEVELOPMENT

Energy Production Pathways

Glycogen Storage Pathways

Postnatal Regulation of Metabolism

Exercise and Muscle Metabolism

General Changes in Metabolism With Heart Failure

AUTOPHAGY IN THE CARDIOVASCULAR SYSTEM

Autophagy Regulation and Signaling Pathways

Autophagy and Heart Failure

APOPTOSIS AND NECROSIS IN THE HEART

Extrinsic Pathway

Intrinsic Pathway

Necrosis

Endoplasmic Reticulum

Protein Misfolding and Heart Failure

EPIGENETIC REGULATION OF CARDIAC DEVELOPMENT AND DISEASE

DNA Methylation

Histone Modifications

Noncoding RNAs

Long Noncoding RNAs

REFERENCES

4 - Abnormal Muscle Pathology and Physiology

INTRODUCTION

THE MUSCULAR DYSTROPHIES

DUCHENNE MUSCULAR DYSTROPHY

CONGENITAL MUSCULAR DYSTROPHY

LIMB-GIRDLE MUSCULAR DYSTROPHY

EMERY-DREIFUSS MUSCULAR DYSTROPHY

MYOTONIC MUSCULAR DYSTROPHY

SPINAL MUSCULAR ATROPHY

MITOCHONDRIAL MYOPATHY

FRIEDREICH ATAXIA

ANIMAL MODELS

ANATOMY OF BREATHING IN MUSCULAR DYSTROPHY

INSPIRATORY MUSCLES IN MUSCULAR DYSTROPHY

ANIMAL MODELS AND BREATHING DIFFERENCES

TRANSGENE THERAPY

CARDIORESPIRATORY DISEASE

CONCLUSION

REFERENCES

II - Diseases of Cardio-Skeletal Phenotypes

5 - Dilated Cardiomyopathy and Cardioskeletal Involvement

DEFINITION

EPIDEMIOLOGY

NATURAL HISTORY

ETIOLOGY AND PATHOPHYSIOLOGY

Heritable Causes

Familial

Genetic Etiologies

Sarcomere Dysfunction

Nonsarcomeric Defects

Neuromuscular Disorders Associated with DCM

Muscular Dystrophies

Myotonic Dystrophy

Motor and Sensory Neuropathies

Metabolic and Mitochondrial Myopathies

Barth Syndrome

Acquired Cardioskeletal Myopathies

Anthracycline Exposure

Alcohol and Drug Abuse

Ischemic Heart Disease

Dietary Deficiencies and Anemia

Thiamine Deficiency

Selenium Deficiency

Carnitine Deficiency

Anemia

Endocrine Disturbances

Diabetes Mellitus

Hypothyroidism and Hyperthyroidism

Vitamin D

Inflammatory and Autoimmune Conditions

Systemic Lupus Erythematosus

Idiopathic Inflammatory Myopathies

DIAGNOSIS

Laboratory Testing

Imaging Studies

Echocardiography

Radionuclide Techniques

Magnetic Resonance Imaging

Electrophysiology Studies

Ambulatory Electrocardiographic (Holter) Monitoring

Signal Average ECG

Advanced Studies

Endomyocardial and Skeletal Muscle Biopsy

MANAGEMENT

Acquired Cardiomyopathy Management

Medications

β-Blockers

ACE Inhibitors

Angiotensin Receptor Blockers

Aldosterone Antagonists

Digoxin

Hydralazine and Nitrates

Calcium Channel Blockers

Antiarrhythmic Therapy

Anticoagulants

Advanced Therapies

Cardiac Resynchronization Therapy

Mechanical Circulatory Support

FUTURE DIRECTIONS

ACKNOWLEDGMENT

REFERENCES

6 - Hypertrophic Cardiomyopathy

INTRODUCTION

DIAGNOSIS AND ETIOLOGY

Presentation and Symptoms

Heart Failure Symptoms

Chest Pain

Syncope

Palpitations

Symptoms in Infants and Children

Diagnosis

Etiology

Sarcomeric Hypertrophic Cardiomyopathy

Morphology

Features on Cardiac Imaging

Echocardiography

Electrocardiogram

Cardiac Magnetic Resonance Imaging

Pathophysiology

Left Ventricular Outflow Obstruction

Diastolic Dysfunction

Mitral Regurgitation

Left Atrial Enlargement and Atrial Fibrillation

Ventricular Arrhythmias and Sudden Cardiac Death

DIFFERENTIAL DIAGNOSIS

Malformation Syndromes

Metabolic Storage Disorders

PRKAG2 Cardiac Syndrome

Danon Disease

Pompe Disease

Anderson-Fabry Disease

Neurodegenerative Disorders

Friedreich’s Ataxia

Mitochondrial Disorders

Endocrine Disorders

Diabetes

Athlete’s Heart

NATURAL HISTORY AND PROGNOSIS

Sudden Cardiac Death

Heart Failure

Prognosis in Children

MANAGEMENT (FIG. 6.7)

Treatment of Symptoms

Symptomatic Treatment for Patients Without Left Ventricular Outflow Obstruction

Symptomatic Treatment for Patients With Left Ventricular Outflow Obstruction

Treatment of End-Stage Hypertrophic Cardiomyopathy

Cardiac Transplant

Assessing the Risk of Sudden Cardiac Death

Implantation of ICD in High-Risk Patients

Recommendations on Exercise Restrictions

GENETIC TESTING AND FAMILY EVALUATION

Genetic Testing

Family Evaluation (Fig. 6.10)

Preclinical Hypertrophic Cardiomyopathy

CONCLUSIONS AND FUTURE DIRECTIONS

REFERENCES

7 - Restrictive Cardiomyopathy Associated With Skeletal Myopathies

INTRODUCTION

Terminology

Clinical Diagnosis and Course

PHYSIOLOGY OF DIASTOLE

Myocardial and Ventricular Relaxation

Myocardial and Ventricular Compliance

Ventricular Filling Dynamics

Abnormal Diastolic Function

DIAGNOSTIC TESTING FOR RESTRICTIVE CARDIOMYOPATHY

Diastolic Filling Indices

Tissue-Doppler Diastolic Indices

Tissue Doppler and Speckle Tracking Strain and Strain Rate

Cardiac Magnetic Resonance Imaging and Cardiac Computed Tomography

Cardiac Catheterization

PATHOPHYSIOLOGY OF RESTRICTIVE CARDIOMYOPATHY

RESTRICTIVE CARDIOMYOPATHY IN PATIENTS WITH SKELETAL MYOPATHY

Primary Amyloidosis

Desmin Myopathy

Myofibrillar Myopathy

Multicore Myopathy

Laminopathies, Including Emery-Dreifuss Muscular Dystrophy

Distal Myopathy With Rimmed Vacuoles

Mitochondrial Disorders

Nonspecific Myopathy

SUMMARY

REFERENCES

8 - Left Ventricular Noncompaction Cardiomyopathy

INTRODUCTION

PATHOLOGY OF LEFT VENTRICULAR NONCOMPACTION

INCIDENCE OF LEFT VENTRICULAR NONCOMPACTION

CLINICAL FEATURES AND DIAGNOSIS OF LEFT VENTRICULAR NONCOMPACTION

SUBTYPES OF LEFT VENTRICULAR NONCOMPACTION

IMAGING OF LEFT VENTRICULAR NONCOMPACTION

ELECTROCARDIOGRAPHY IN LEFT VENTRICULAR NONCOMPACTION

ARRHYTHMIAS IN LEFT VENTRICULAR NONCOMPACTION

CLINICAL GENETICS OF LEFT VENTRICULAR NONCOMPACTION

MOLECULAR GENETICS OF LEFT VENTRICULAR NONCOMPACTION

ANIMAL MODELS OF LVNC

FKBP12 Null Mutation

MIB1 Mutant

Bmp10 Mutant

Tbx20 Mutant

Numb/Numb-like Mutant

Nkx2-5 Mutant

Smad7 Mutant

NF-ATc Mutant

Jarid2/Jumonji Mutants

Tafazzin (TAZ) Mutant

THERAPY AND OUTCOME

CONCLUSIONS AND SUMMARY

REFERENCES

9 - Diseases of the Cytoskeleton: The Desminopathies

INTRODUCTION

MICROFILAMENTS

MICROTUBULES

DESMIN

DESMIN FUNCTION

IF-ASSOCIATED CARDIOMYOPATHIES: A SUBGROUP OF MYOFIBRILLAR MYOPATHY

THE DESMIN-RELATED CARDIOMYOPATHIES

ANIMAL MODELS: A WINDOW INTO CARDIOMYOPATHIC MECHANISMS

DESMIN-ASSOCIATED PROTEINS: MECHANISTIC INSIGHTS INTO THE DISEASE

PAO CAN CAUSE HEART DISEASE AND FAILURE

THERAPEUTIC TARGETS

REFERENCES

10 - Diseases of Cardiac Sarcomeres

INTRODUCTION

SARCOMERE FUNCTION IN CARDIAC FILLING AND EJECTION

CARDIAC SARCOMERES AS A HUB OF CELLULAR SIGNALING

SARCOMERE CONTROL MECHANISMS AS RATE LIMITING AND MAJOR CONTRIBUTORS TO CARDIAC DYNAMICS

SIGNALING CASCADES IN DISEASES OF THE SARCOMERE

PHOSPHORYLATION AS A MODIFIER OF PATHOLOGY DUE TO SARCOMERE PROTEIN MUTATIONS

TNI PHOSPHORYLATION AND HCM

REDOX AND NITROSATIVE SIGNALING AND CARDIAC SARCOMERES

THERAPIES PREVENTING OR REVERSING PROGRESSION TO HYPERTROPHY, CARDIAC DYSFUNCTION, AND SUDDEN DEATH

SUMMARY

ACKNOWLEDGMENTS

REFERENCES

11 - Diseases of the Intercalated Disc

INTRODUCTION

THE ROLE OF DESMOSOMAL PROTEINS IN CARDIOSKELETAL MYOPATHIES

Evolution of Arrhythmogenic Cardiomyopathy as a Disease Entity

Desmoplakin

Plakophilin-2

Plakoglobin

Desmosomal Cadherins: Desmoglein-2 and Desmocollin-2

PATHOLOGY AND DISEASE MECHANISMS IN DESMOSOMAL PROTEIN-RELATED CARDIOMYOPATHIES

Natural History and Pathology

Differential Diagnosis and the Role of Exercise in Desmosomal Protein-Related Cardiomyopathies

Redistribution of ICD Proteins in Desmosomal Protein-Related Cardiomyopathies

Gap Junction Remodeling in Desmosomal Protein-Related Cardiomyopathies

Protein Trafficking Defects in Desmosomal Protein-Related Cardiomyopathies

THE ROLE OF NONDESMOSOMAL PROTEINS IN CARDIOSKELETAL MYOPATHIES

N-cadherin

Connexins

Voltage-Gated Sodium Channel

Coxsackie-Adenoviral Receptor

A Disintegrin and Metalloptroteinase-17

Desmin

CLINICAL DIAGNOSIS AND MANAGEMENT OF CARDIOSKELETAL MYOPATHIES

GENETIC TESTING IN CARDIOSKELETAL MYOPATHIES

REFERENCES

12 - Diseases of the Nuclear Membrane

A CELLULAR PERSPECTIVE

The Nuclear Membrane

Proteins of the NE

Lamins

The LEM-Domain Protein Family

The LINC Complex

A CLINICAL PERSPECTIVE

NE Proteins and Disease

Striated Muscle Laminopathies

Adipose Tissue Laminopathies and Dysplastic Syndromes

Premature Aging Syndromes

Peripheral Nerve Laminopathies

Genotype-Phenotype Correlations and Overlapping Phenotypes

Genotype-Phenotype Correlations in Cardiomyopathies

AN ORGANISMAL PERSPECTIVE

Animal Models and Therapeutics

Conclusions

REFERENCES

III - Metabolic Causes of Disease

13 - Mitochondrial Disorders Causing Cardioskeletal Myopathies in Childhood

INTRODUCTION

INHERITANCE

NORMAL CARDIAC METABOLISM

CARDIOMYOPATHY DUE TO MITOCHONDRIAL DYSFUNCTION

CARDIOMYOPATHY DUE TO MTDNA MUTATIONS

Sporadic mtDNA Rearrangements

Maternally Inherited Point Mutations

CARDIOMYOPATHY DUE TO MUTATIONS IN NUCLEAR DNA

Defects of Respiratory Chain Subunits and Ancillary Proteins

Other Mitochondrial Defects

MITOCHONDRIAL FATTY ACID BETA OXIDATION DEFECTS

Primary Carnitine Deficiency

CPT IA Deficiency

CACT Deficiency

CPT2 Deficiency

VLCAD Deficiency

LCHAD and Trifunctional Protein Deficiency

MAD Deficiency

REFERENCES

14 - Nonmitochondrial Metabolic Cardioskeletal Myopathies

INTRODUCTION

Metabolic Fuels

Fatty Acid β-Oxidation and Oxidative Phosphorylation

Interaction Between Fatty Acid Oxidation and Glucose Metabolism

Glucose and Glycogen Metabolism

Branched Chain Amino Acids

The Lysosome-Autophagosome System

Glycosylation of Muscle Proteins and α-Dystroglycan Complex

Main Pathophysiological Mechanisms Involved in Cardioskeletal Myopathies

INBORN ERRORS OF METABOLISM ASSOCIATED WITH CARDIOMYOPATHY AND/OR SKELETAL MUSCLE DISEASE CLASSIFIED BY DISORDER GROUP

Inborn Errors of Energy Metabolism

Fatty Acid Oxidation Disorders

Systemic Primary Carnitine Deficiency/Carnitine Transporter Deficiency

Carnitine-Acylcarnitine Translocase Deficiency

CPT2 Deficiency

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Mitochondrial Trifunctional Protein Deficiency

Multiple Acyl-CoA Dehydrogenase Deficiency/Glutaric Aciduria Type II

Disorders of Glycogen Metabolism Associated With Energy Deficiency (Glycogen Storage Diseases Type III,V, VII, and IXb)

Glycogen Storage Disease Type III, GSD III (Cori-Forbes Disease)

Glycogen Storage Disease Type V, GSD V (McArdle Disease)

Glycogen Storage Disease Type VII, GSD VII (Tarui Disease)

Glycogen Storage Disease Type IX (GSD IXd)

Disorders Associated With Accumulation of Toxic Intermediates, Crystals, and Minerals

Propionic Aciduria

Malonyl Carboxylase Deficiency/Malonic Aciduria

Primary Hyperoxaluria

Juvenile Hemochromatosis

Lysosomal Storage Disorders Associated With Cardioskeletal Disorders

LSD with Glycogen Deposition and Secondary Defects in Autophagy

Glycogen Storage Disease Type II, GSD II (Pompe Disease)

Danon Disease

Other Lysosomal Storage Disorders

Fabry Disease (Anderson-Fabry Disease)

Gaucher Disease Type 1

Mucopolysaccharidoses

Generalized Gangliosidosis (GM1 and GM2)

Niemann-Pick Disease

Congenital Disorders of Glycosylation and Alpha-Dystroglycanopathies

Current General Approaches to the Diagnosis of Inborn Errors of Metabolism

LABORATORY STUDIES FOR CONFIRMATION OF IEMS

Current Therapies of Inborn Errors of Metabolism Affecting the Heart and Muscle

Therapy of Acute Symptoms

Replacement Therapy

Other Therapies for Lysosomal Storage Disorders

Substrate Reduction Therapy

Chaperone Therapy

Therapies Under Investigation for Long-Chain Fatty Acid Oxidation Disorders

Why the Need for Translational Research and New Therapies for IEMs?

CONCLUSION

REFERENCES

IV - Syndromal and Chromosomal Causes of Disease

15 - Cardio-Skeletal Muscle Disease Associated With Syndromes

INTRODUCTION

CARDIAC PHYSIOLOGY AND METABOLISM

CARDIOVASCULAR DISORDERS OF MITOCHONDRIAL FUNCTION

Kearns-Sayre Syndrome

MERRF Syndrome

Leigh Syndrome

Sengers Syndrome

Barth Syndrome

Experimental Models of BTHS

Therapeutic Options for BTHS

Inborn Errors of Metabolism

Glycogen and Lysosomal Storage Disorders

Organic Acidemias and Amino Acidopathies

FABRY DISEASE

DANON DISEASE

ADENOSINE MONOPHOSPHATE–ACTIVATED PROTEIN KINASE DEFICIENCY

CONGENITAL DISORDERS OF GLYCOSYLATION

Phosphoglucomutase 1 Deficiency

CHROMOSOMAL SYNDROMES ASSOCIATED WITH CARDIOMYOPATHY

TRISOMY 21 (DOWN SYNDROME)

1P36 DELETION SYNDROME

CHROMOSOME 8P23.1 DELETION

TURNER SYNDROME

OTHER CHROMOSOMAL DISORDERS ASSOCIATED WITH CARDIOMYOPATHY

RASOPATHIES: DISORDERS OF THE RAS-MAPK SIGNALING PATHWAY

PTPN11

SOS1

KRAS

NRAS

HRAS

RAF1

NOONAN SYNDROME WITH MULTIPLE LENTIGINES

NEUROFIBROMATOSIS AND NF1

COFFIN–LOWRY SYNDROME

PIERRE-ROBIN SEQUENCE

SOTOS SYNDROME

MARFAN SYNDROME

EHLERS-DANLOS SYNDROMES

SEPTO-OPTIC DYSPLASIA

ALSTRÖM SYNDROME

CONCLUSIONS

REFERENCES

16 - Cardioskeletal Muscle Disease Associated With Chromosomal Disorders

CONGENITAL HEART DISEASE AND CHROMOSOMAL DISORDERS

Down Syndrome (Trisomy 21)

Trisomy 18

Trisomy 13

Turner Syndrome

Cri-du-chat Syndrome

Wolf-Hirschhorn Syndrome

Jacobsen Syndrome

Cat Eye Syndrome

CHD AND THE MICRODELETION/MICRODUPLICATION SYNDROMES

DiGeorge/Velocardiofacial Syndrome

Williams–Beuren Syndrome and 7q11.23 Reciprocal Duplication

8p23.1 Deletion Including GATA4

1p36 Deletion

1q21.1 Deletion and Duplication

Smith–Magenis Syndrome and Potocki-Lupski Syndrome

Miller–Dieker Syndrome

Kleefstra Syndrome

Deletions of 15q26

17q21.31 Microdeletion Syndrome

CONCLUSION AND FUTURE DIRECTION

REFERENCES

V - Cardio-Skeletal Myopathies Associated With Congenital Heart Disease

17 - Cardioskeletal Myopathies in Congenital Heart Diseases

INTRODUCTION

EXERCISE LIMITATION IN ACQUIRED HEART FAILURE

Exercise Limitation in Congenital Heart Disease

PERIPHERAL CHANGES IN ACQUIRED HEART FAILURE

Skeletal Myopathy and Peripheral Changes in Congenital Heart Disease

SYSTEMIC CHANGES IN HEART FAILURE

Neurohormonal Activation in Heart Failure Associated With CHD

EXERCISE TRAINING IN ACQUIRED HEART FAILURE

Exercise Training in Congenital Heart Disease

FUTURE DIRECTIONS

CONCLUSIONS

REFERENCES

VI - Future Directions in the Diagnosis and Management of Cardioskeletal Myopathic Disease in Children andYoung Adults

18 - Future Diagnostic Strategies—Pediatric

INTRODUCTION

NONINVASIVE IMAGING

Advanced 3D Visualization and Printing Techniques

Interactive Holographic Modeling

ELECTROPHYSIOLOGY: ADVANCES IN FLUOROSCOPIC RADIATION REDUCTION

Reducing Radiation Exposure

CARTO

NavX

Noncontact Mapping

Cost-Benefit Assessment

EMERGING DIAGNOSTIC STRATEGIES IN CARDIAC CATHETERIZATION

3D Rotational Angiography and Multimodality Image Fusion

MRI Guided Cardiac Catheterization

Implantable Devices for Pressure Monitoring

MONITORING IN THE CARDIAC ICU

Noninvasive Monitoring

Invasive Monitoring

Future Directions

INTEGRATION OF RECENT GENETIC FINDINGS INTO PEDIATRIC CARDIOLOGY PRACTICE

Copy Number Variants

Sequence Variants

CONCLUSIONS

REFERENCES

19 - Neuromodulation of the Failing Heart

OVERVIEW OF THE CARDIAC AUTONOMIC NERVOUS SYSTEM

SYMPATHOVAGAL IMBALANCE IN HEART FAILURE

ASSESSMENT OF AUTONOMIC NERVOUS SYSTEM ACTIVITY

NE Spillover Measurement

Blood Pressure and Heart Rate Alterations

Heart Rate

Baroreflex Sensitivity

Heart Rate Variability

Microneurography

123I-Metaiodobenzylguanidine Imaging Techniques

THERAPEUTIC MODULATION OF THE AUTONOMIC NERVOUS SYSTEM IN HEART FAILURE

Pharmacological Therapy

Skeletal Muscle and Exercise Training

Cardiac Resynchronization Therapy

EMERGING THERAPIES FOR NEUROMODULATION OF THE FAILING HEART

Vagus Nerve Stimulation

Baroreflex Activation Therapy

Spinal Cord Stimulation

Renal Denervation

Left Cardiac Sympathetic Denervation

FUTURE DIRECTIONS

OVERVIEW AND CONCLUSION

REFERENCES

Index

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

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