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Cardioskeletal Myopathies in Children and Young Adults
Azioni libro
Inizia a leggereLunghezza: 1,398 pagine7 ore
- Editore:
- Academic Press
- Pubblicato:
- Oct 22, 2016
- ISBN:
- 9780128005804
- Formato:
- Libro
Descrizione
Cardioskeletal Myopathies in Children and Young Adults focuses on plaques that kill people in their 40’s-50’s and the way they start to form in young adulthood. The Annals of Family Medicine report that approximately half of young adults have at least one cardiovascular disease risk factor (Mar 2010), and an increase in cardiovascular mortality rates in young adults was substantiated in a study at Northwestern Medicine (Nov 2011).
Given the increasing recognition of genetic triggers behind all types of cardiovascular disease, and the growing population of young adults with primary or acquired myocardial disease, the need has arisen for a reference that offers a comprehensive approach to the understanding of basic, translational, and clinical aspects of specific muscle diseases while making the link between young adult and adult health.
Reveals the link between cardiac muscle disease and skeletal muscle disease Explains how genetics and environmental factors effect muscle function of diverse origins Designates current and novel therapeutic strategies that target both cardiac and skeletal muscle systemsInformazioni sul libro
Cardioskeletal Myopathies in Children and Young Adults
Lunghezza: 1,398 pagine7 ore
Descrizione
Cardioskeletal Myopathies in Children and Young Adults focuses on plaques that kill people in their 40’s-50’s and the way they start to form in young adulthood. The Annals of Family Medicine report that approximately half of young adults have at least one cardiovascular disease risk factor (Mar 2010), and an increase in cardiovascular mortality rates in young adults was substantiated in a study at Northwestern Medicine (Nov 2011).
Given the increasing recognition of genetic triggers behind all types of cardiovascular disease, and the growing population of young adults with primary or acquired myocardial disease, the need has arisen for a reference that offers a comprehensive approach to the understanding of basic, translational, and clinical aspects of specific muscle diseases while making the link between young adult and adult health.
Reveals the link between cardiac muscle disease and skeletal muscle disease Explains how genetics and environmental factors effect muscle function of diverse origins Designates current and novel therapeutic strategies that target both cardiac and skeletal muscle systems- Editore:
- Academic Press
- Pubblicato:
- Oct 22, 2016
- ISBN:
- 9780128005804
- Formato:
- Libro
Correlati a Cardioskeletal Myopathies in Children and Young Adults
Anteprima del libro
Cardioskeletal Myopathies in Children and Young Adults
Cardioskeletal Myopathies in Children and Young Adults
Editors
John Lynn Jefferies
Burns C. Blaxall
Jeffrey Robbins
Jeffrey A. Towbin
Table of Contents
Cover image
Title page
Copyright
Dedication
List of Contributors
Cardioskeletal Myopathies: Foreword
Section I. Physiology and Molecular Basis of Muscle
Chapter 1. Ventricular Systolic Function
Introduction
Heart Rate and the Bowditch Effect
Summary
Chapter 2. Basics of Skeletal Muscle Function and Normal Physiology
Introduction
Development of Skeletal Muscle
Muscle Growth
Skeletal Muscle Architecture, Contractile Apparatus, and Fiber Types
The Basement Membrane and Muscle Fiber Plasma Membrane
The Neuromuscular and Myotendinous Junctions
Chapter 3. Molecular Pathways in Cardiomyopathies
Cardiac Muscle Development
Skeletal Muscle Development
Neurohormonal Regulation in the Heart: β-Adrenergic Receptors and the Renin-Angiotensin-Aldosterone System
Sarcomere and Cytoskeleton Organization in Cardiac Muscle
Metabolism/Metabolic Pathways in Cardiac Development
Autophagy in the Cardiovascular System
Apoptosis and Necrosis in the Heart
Epigenetic Regulation of Cardiac Development and Disease
Chapter 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
Section II. Diseases of Cardio-Skeletal Phenotypes
Chapter 5. Dilated Cardiomyopathy and Cardioskeletal Involvement
Definition
Epidemiology
Natural History
Etiology and Pathophysiology
Diagnosis
Management
Future Directions
Chapter 6. Hypertrophic Cardiomyopathy
Introduction
Diagnosis and Etiology
Differential Diagnosis
Natural History and Prognosis
Management
Genetic Testing and Family Evaluation
Conclusions and Future Directions
Chapter 7. Restrictive Cardiomyopathy Associated With Skeletal Myopathies
Introduction
Physiology of Diastole
Diagnostic Testing for Restrictive Cardiomyopathy
Pathophysiology of Restrictive Cardiomyopathy
Restrictive Cardiomyopathy in Patients With Skeletal Myopathy
Summary
Chapter 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
Therapy and Outcome
Conclusions and Summary
Chapter 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
Chapter 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
Chapter 11. Diseases of the Intercalated Disc
Introduction
The Role of Desmosomal Proteins in Cardioskeletal Myopathies
Pathology and Disease Mechanisms in Desmosomal Protein-Related Cardiomyopathies
The Role of Nondesmosomal Proteins in Cardioskeletal Myopathies
Clinical Diagnosis and Management of Cardioskeletal Myopathies
Genetic Testing in Cardioskeletal Myopathies
Chapter 12. Diseases of the Nuclear Membrane
A Cellular Perspective
A Clinical Perspective
An Organismal Perspective
Section III. Metabolic Causes of Disease
Chapter 13. Mitochondrial Disorders Causing Cardioskeletal Myopathies in Childhood
Introduction
Inheritance
Normal Cardiac Metabolism
Cardiomyopathy due to Mitochondrial Dysfunction
Cardiomyopathy due to mtDNA Mutations
Cardiomyopathy due to Mutations in Nuclear DNA
Mitochondrial Fatty Acid Beta Oxidation Defects
Chapter 14. Nonmitochondrial Metabolic Cardioskeletal Myopathies
Introduction
Inborn Errors of Metabolism Associated With Cardiomyopathy and/or Skeletal Muscle Disease Classified by Disorder Group
Laboratory Studies for Confirmation of IEMs
Conclusion
Section IV. Syndromal and Chromosomal Causes of Disease
Chapter 15. Cardio-Skeletal Muscle Disease Associated With Syndromes
Introduction
Cardiac Physiology and Metabolism
Cardiovascular Disorders of Mitochondrial Function
Fabry Disease
Danon Disease
Adenosine Monophosphate–Activated Protein Kinase Deficiency
Congenital Disorders of Glycosylation
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
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
Chapter 16. Cardioskeletal Muscle Disease Associated With Chromosomal Disorders
Congenital Heart Disease and Chromosomal Disorders
CHD and the Microdeletion/Microduplication Syndromes
Conclusion and Future Direction
Section V. Cardio-Skeletal Myopathies Associated With Congenital Heart Disease
Chapter 17. Cardioskeletal Myopathies in Congenital Heart Diseases
Introduction
Exercise Limitation in Acquired Heart Failure
Peripheral Changes in Acquired Heart Failure
Systemic Changes in Heart Failure
Exercise Training in Acquired Heart Failure
Future Directions
Conclusions
Section VI. Future Directions in the Diagnosis and Management of Cardioskeletal Myopathic Disease in Children and Young Adults
Chapter 18. Future Diagnostic Strategies—Pediatric
Introduction
Noninvasive Imaging
Electrophysiology: Advances in Fluoroscopic Radiation Reduction
Emerging Diagnostic Strategies in Cardiac Catheterization
Monitoring in the Cardiac ICU
Integration of Recent Genetic Findings Into Pediatric Cardiology Practice
Conclusions
Chapter 19. Neuromodulation of the Failing Heart
Overview of the Cardiac Autonomic Nervous System
Sympathovagal Imbalance in Heart Failure
Assessment of Autonomic Nervous System Activity
Therapeutic Modulation of the Autonomic Nervous System in Heart Failure
Emerging Therapies for Neuromodulation of the Failing Heart
Future Directions
Overview and Conclusion
Index
Copyright
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Dedication
Dedicated to the children and adults with cardiac and skeletal muscle disease.
List of Contributors
D.J. Abrams, Harvard Medical School, Boston, MA, United States
A. Axelsson, University of Copenhagen, Copenhagen, Denmark
B.C. Blaxall, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
S. Bogdanovich
The University of Chicago, Chicago, IL, United States
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
S.C. Brown, University of London, London, United Kingdom
M. Byku, Washington University School of Medicine, St Louis, MO, United States
S. Chanprasert, Baylor College of Medicine, Houston, TX, United States
S.D. Colan, Harvard Medical School, Boston, MA, United States
W.J. Craigen
Baylor College of Medicine, Houston, TX, United States
Texas Children’s Hospital, Houston, TX, United States
H.C. DeSena, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
A. El-Gharbawy
University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
B.B. Gardner
The University of Chicago, Chicago, IL, United States
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
C.Y. Ho, Brigham and Women’s Hospital, Boston, MA, United States
J.L. Jefferies, Cincinnati Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH, United States
D.A. Kass, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Z. Khuchua, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
S.R. Lalani, Baylor College of Medicine, Houston, TX, United States
B.J. Landis, Indiana University School of Medicine, Indianapolis, IN, United States
D.L. Mann, Washington University School of Medicine, St Louis, MO, United States
J. Mathew, Royal Children’s Hospital, Melbourne, VIC, Australia
E.M. McNally
The University of Chicago, Chicago, IL, United States
Northwestern University Feinberg School of Medicine, Chicago, IL, United States
L. Mestroni, University of Colorado, Aurora, CO, United States
S.D. Miyamoto, University of Colorado School of Medicine, Aurora, CO, United States
R.A. Moore, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
A. Redington, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
J. Robbins, Children’s Hospital Research Foundation, Cincinnati, OH, United States
T.D. Ryan, Cincinnati Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH, United States
J.E. Saffitz, Harvard Medical School, Boston, MA, United States
C.A. Sewry, UCL Institute of Child Health, London, United Kingdom
R.J. Solaro, University of Illinois at Chicago, Chicago, IL, United States
D.S. Spar, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
B.L. Stauffer, University of Colorado School of Medicine, Aurora, CO, United States
C.C. Sucharov, University of Colorado School of Medicine, Aurora, CO, United States
M.E. Sweet, University of Colorado, Aurora, CO, United States
M.R.G. Taylor, University of Colorado, Aurora, CO, United States
J.A. Towbin, Le Bonheur Children’s Hospital and University of Tennessee Health Science Center, Memphis, TN, United States
J. Vockley
University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
W. Whiteside, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
I. Wilmot, Cincinnati Children’s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH, United States
Cardioskeletal Myopathies: Foreword
The development of low-cost, high-throughput gene sequencing technologies capable of interrogating the entire human genome has led to a dramatic acceleration in the pace of scientific discovery and the development of novel therapies that have the potential to modify and even cure genetic disease. For general physicians, this emerging complexity might seem a little overwhelming and perhaps of limited relevance to everyday clinical practice, but it is already clear that while many genetic disorders are rare, they can masquerade as more common diseases and as a consequence are often misdiagnosed or overlooked, sometimes with devastating consequences for individual patients and their families.
Genetic diseases of the heart and blood vessels were among the first conditions for which the genetic basis was characterized. This book is dedicated to one subgroup of heritable disorders—the cardioskeletal myopathies—that can present throughout life with a predominant skeletal myopathy or primarily with heart failure, arrhythmia, and sudden death. The latter scenario is particularly common in disorders such as laminopathies, dystrophinopathies, and desminopathies, which can present for the first time with heart block, tachyarrhythmia, and ventricular failure. However, even in disorders that present with neuromuscular manifestations, cardiac complications are common and as neuromuscular care improves are becoming the major prognostic variable.
In this textbook, some of the world’s greatest authorities on cardiac and skeletal muscle have come together to produce an A to Z of striated muscle disorders, beginning with the molecular biology and physiology of normal muscle and then moving through the mechanisms and consequences of genetic defects to the scenarios that specialists and generalists encounter in their clinical practice, whatever their subspecialty interest. Finally, these different strands are brought together in a review of the therapeutic implications of a specific molecular diagnosis.
The importance of a personalized approach to medicine is increasingly emphasized in public health policy and in the training of new medical practitioners. This textbook is a significant contribution to the collective effort to improve understanding of the pathophysiology of cardioskeletal myopathies and will help physicians adapt and evolve their skills for the new era of molecular medicine.
P. Elliott, University College London & St. Bartholomew’s Hospital, London, United Kingdom
Section I
Physiology and Molecular Basis of Muscle
Outline
Chapter 1. Ventricular Systolic Function
Chapter 2. Basics of Skeletal Muscle Function and Normal Physiology
Chapter 3. Molecular Pathways in Cardiomyopathies
Chapter 4. Abnormal Muscle Pathology and Physiology
Chapter 1
Ventricular Systolic Function
D.A. Kass Johns Hopkins University School of Medicine, Baltimore, MD, United States
Abstract
Ventricular systolic dysfunction is a hallmark of many patients with congenital heart disease. Given its complex genetic roots and anatomical consequences, dysfunction can manifest as depressed or supra-normal contractile performance with dilative or hypertrophic remodeling, fibrosis with restrictive physiology, and/or marked changes in pressure/volume loads. Over the past 15 years, accurate and specific methods to assess myocyte and chamber function combined with powerful genetic tools to dissect causes have yielded major new insights into how systolic function is regulated and altered by disease. Most of these data stem from analyses in animal models or adult human explanted hearts, whereas results from pediatric congenital heart disease subjects remain scant due to ethical considerations. Nevertheless, the research has yielded new insights and methodologies undoubtedly relevant to childhood disease. In this chapter, I review the mechanisms underlying systolic chamber function and its acute regulation, how it is assessed—focusing on in vivo characterization by pressure-volume relationships, its interaction with vascular and pericardial loading, and the influence of disease and therapies.
Keywords
Ventricular systolic function
Introduction
Ventricular systolic dysfunction is a hallmark of many patients with congenital heart disease. Given its complex genetic roots and anatomical consequences, dysfunction can manifest as depressed or supra-normal contractile performance with dilative or hypertrophic remodeling, fibrosis with restrictive physiology, and/or marked changes in pressure/volume loads. Over the past 15 years, accurate and specific methods to assess myocyte and chamber function combined with powerful genetic tools to dissect causes have yielded major new insights into how systolic function is regulated and altered by disease. Most of these data stem from analyses in animal models or adult human explanted hearts, whereas results from pediatric congenital heart disease subjects remain scant due to ethical considerations. Nevertheless, the research has yielded new insights and methodologies undoubtedly relevant to childhood disease. In this chapter, I review the mechanisms underlying systolic chamber function and its acute regulation, how it is assessed—focusing on in vivo characterization by pressure-volume relationships, its interaction with vascular and pericardial loading, and the influence of disease and therapies.
Subcellular Determinants: A Brief Review
Systolic force generation starts with the development of tightly bound actin-myosin crossbridges, which occurs upon hydrolysis of ATP at the myosin head, dissociating an inorganic phosphate while maintaining its attachment to ADP. The probability this crossbridge will form (eg, on-off state) is a function of calcium concentration, and involves interactions between the multiple proteins in the sarcomere complex. Cardiac troponin C (TnC) contains a single Ca²+ binding site that when occupied results in thin filament conformational changes whereby tropomyosin shifts away from its blocking position of actomyosin binding. This follows enhanced troponin C–troponin I interactions, moving TnI to allow the shift in tropomyosin position. This activation/inactivation balance is posttranslationally controlled by multiple kinases, including protein kinase A and C (PKA and PKC respectively), which alter myofilament sensitivity to calcium activation by modifying target residues on TnI and TnT [1,2]. The formation of tightly bound cross bridges is a highly cooperative process, where the probability is enhanced by the preexistence of an actomyosin bridge nearby. The physical distance between actin and myosin, impacted by the trans-sarcomeric molecular spring, titin, alters this probability [3–5]. The capacity for crossbridge force generation is also influenced by the kinetics of antiparallel myofilament sliding regulated by myosin binding protein C, which binds to both actin and myosin and is posttranslationally controlled [6,7].
The individual contributions of various components of the crossbridge activation process and its regulation have been explored principally using site-specific genetic modifications, many based on defects in human congenital disease [8,9]. For example, mouse models recapitulating point mutations in myosin associated with hypertrophic or dilated cardiomyopathy have revealed gain or loss of power generation respectively, both in intact hearts and single molecules [10–12] (Fig. 1.1A). Examples of regulatory thin filament modulation include the cardiac myosin light chain, which is required for normal function and protection against pressure-overload [13]. Another is myosin-binding protein C (MyBP-C) [14], which is the most frequently mutated protein in forms of human hypertrophic cardiomyopathy [15]. MyBP-C is required for normal crossbridge sliding kinetics, and its absence results in a rapid development of force that is quickly terminated so that systole is abbreviated (Fig. 1.1B), leading to heart failure [16–18]. Phosphorylation of MyBP-C by PKA is a major regulator of systolic reserve coupled to beta-adrenergic stimulation (Fig. 1.1C) [18], and reduction of this phosphorylation in heart failure is a mechanism for reduced reserve function in failing hearts [18,19]. Regulatory sites on TnI and TnT [1,2] also potently control sarcomere function, and changes coupled with reduced PKA activation and reciprocally increased PKC activation are common in dilated heart failure.
Figure 1.1 (A) Examples of ventricular function depicted as pressure-volume relations from a normal human subject (control), a patient with familial hypertrophic cardiomyopathy (FHC), and corresponding control and mouse mutant models (R403Q) of a similar hypertrophic disease. In both human and mouse model, there is a rise in systolic stiffening—indicated by the slope (end-systolic elastance) of the line connecting the upper left corners of these relationships—known as the end-systolic PV relation. This was the first example reported where a mouse model of human genetic disease was shown to recapitulate in vivo cardiac behavior in patients. (B) Deletion of myosin-binding protein C (MyBP-C) markedly abbreviates the time course of systole—shown here by normalized elastance activation curves. This early onset relaxation is compared with mouse models where the heart is dysfunctional due to inflammatory (autoimmune myocarditis), signaling (over expression (oe) of MKK3/p38 MAP kinase), protein cleavage (trunctation mutation of troponin I), or gene deletion (desmin knockout). (C) MyBP-C phosphorylation plays a key role in beta-adrenergic stimulation. Data show percent improvement in systolic function based on pressure-volume area index from isoproterenol infusion. MyBP-C − / − mice with wild-type (WT) cardiomyocyte reexpressed showed full rescue of the adrenergic reserve phenotype, whereas those with a form of MyBP-C that could not be PKA phosphorylated (AllP-) appear similar to mice without the protein at all.
Once generated, sarcomere derived force is transduced to the plasma membrane to shorten the cell against its load. This involves structural complexes including the actin-anchoring Z-disk at the terminal ends of the sarcomere [20] and myosin-anchoring M-band region in its center [21]. The Z-disk is linked to intermediate filaments that transduce force to membrane shortening and external load imposed by the interstitium. The latter includes the dystro-sarcoglycan complex and integrin-focal adhesion complexes [22,23]. Gene deletion of these critical transduction proteins such as dystrophin, laminin, sarcoglycan, muscle lim proteins, obscurin, and others, generally results in depressed dilated heart disease, recapitulating changes observed in humans [9].
Systolic function is also determined by calcium homeostasis [24–27]. Excitation-contraction coupling is a cyclical process, with each heartbeat initiated by the voltage-gated calcium channel opening that is followed by a release of Ca²+ from the internal sarcoplasmic reticular (SR) pool. The latter is regulated by a Ca²+ uptake process involving the SR calcium ATPase and multiple regulating proteins, including phospholamban, calsequestrin, hematopoietic lineage substrate-1-associated protein X-1 (HAX-1), sarcolipin, and phosphatase inhibitor I1 [28–31]. SR Ca²+ release is controlled by the ryanodine-sensitive calcium release channel RyR2 [32]. These proteins are often altered in heart disease at the transcriptional, translational, and/or posttranslational levels. For example, phosphorylation by calcium-calmodulin–dependent kinase IIδ and PKA, increase SR calcium release by modifying the ryanodine receptor [32–35], whereas SUMOylation of the SERCA2a is thought to enhance its uptake capacity [36].
Systolic function is also influenced by coupling of the cell to its interstitial environment and vascular supply. Changes in apparent force (or pressure) generation can reflect both myofilament contractile capacity and material stiffness of the interstitium. The latter can be altered by scar as occurs with myocardial infarction, diffuse fibrosis, edema, and inflammation. Myocyte responses to increased work-load trigger a signaling cascade that engages myocytes/cytokines impacting fibrosis, angiogenesis, and interstitial remodeling, and myocytes appear quite central in coordinating this signaling [37,38]. For example, selective gene suppression of cardiomyocyte transforming growth factor beta receptors not only markedly enhances the cardiac functional response to sustained pressure-overload, but does so while blocking interstitial fibrosis and promoting angiogenesis [39]. Myocyte signaling also potently regulates inflammation in the peri-infarct zone, controlling neutrophil accumulation and activation of matrix metalloproteinases. Myocyte derived secretion of various factors, including the antiinflammatory GDF-15 [40] and ER-stress protective thrombospondin-4 [41] play a role in cytoprotection in the stressed heart. Recent studies using stem cells have revealed secretion of nanoparticle exosomes as a stress-communication system [42–44]. These vesicles contain microRNAs (miRNAs) that likely transmit key information regarding muscle function and stress to other cells and organs. Secreted miRNAs have been detected in the blood of patients with dilated heart disease, and may also signal cardiac regional disturbances such as those produced by dyssynchronous contraction from a conduction delay.
Ventricular systolic dysfunction is frequently associated with profound changes in chamber geometry, either dilation or small cavities with excessive wall thickness. Indeed our most common metric for systolic dysfunction, ejection fraction, largely parameterizes the extent of chamber dilation rather than contractility. This is because the numerator (stroke volume) is less altered until heart disease becomes very advanced, whereas the denominator (end-diastolic volume) can change substantially with chronic remodeling. Morphological restructuring of the heart involves breakdown and resynthesis of the interstitium, a process involving metalloproteinases and their inhibitors and matrix signaling and coordination proteins. This dynamic change itself contributes to systolic dysfunction [45–47]. Myocyte geometry is also transformed (longer-thinner in dilated chambers) and this too plays a role in disease [48]. A general assumption has been that enlarged (hypertrophied) myocytes synthesize more myofilaments to enable greater force development to counter wall stress. However, studies have found maximal force generating capacity to be little changed despite larger cells that may relate to heterogeneity of myofilament structure and function [49–51]. This questions the adaptive
nature of myocardial hypertrophy, since this concept depends on the functionality of myofibrils added into the enlarged cells.
Beat-to-Beat Regulation of Systolic Function
There are three primary mechanisms that regulate beat-to-beat systolic performance of cardiac muscle. These are defined by the dependencies of systolic force on sarcomere length at the onset of contraction, the force imposed during contraction, and the intrabeat cycle length. In the intact heart, these components translate to the impact of chamber end-diastolic volume (preload), systemic vascular impedance or wall stress (afterload), and heart rate (HR).
Acute Stretch—The Frank-Starling Effect
Upon acute lengthening, cardiac myocytes exhibit an immediate rise in force without corresponding changes in intracellular calcium. This is followed by a slower secondary rise in force that is calcium dependent (Fig. 1.2A). The first change is referred to as the Frank-Starling effect, the latter the Anrep effect (discussed next). The Frank-Starling response was initially attributed to changes in actin-myosin filament overlap (high length meant inadequate overlap while short lengths meant too much overlap—both reducing force). However, this mechanism did not fit cardiac muscle data as the relation between force and length is very steep and involves little change in filament overlap [52]. In 1982, Hibberd and Jewell [53] revealed a left shift of the steady-state force-Ca²+ relationship at increasing length, both at submaximal and maximal calcium activation, establishing length-dependent Ca²+ activation as the central mechanism. Yet the mechanism for this remains incompletely understood [54]. A prominent current theory is that lengthening reduces inter-filament spacing in the orthogonal direction, thereby favoring crossbridge formation [55]. Stretch extends the flexible-spring region of titin that runs along the sarcomere [5,56] and could pull actin-myosin closer together. Synchrontron X-ray diffraction studies support this [55,57], as do studies in which cardiac myocytes were prestretched to varying levels of passive force (pulling out titin) and subsequent length-dependent Ca²+-force responses found to be related more to passive force than sarcomere length [56]. Titin isoform differences in atrial versus ventricular muscle alter its spring constant and are associated with different length-dependent activation [58]. Some data question the spacing mechanism, as when osmotic force was used for compression of the myofilaments, no change in Ca²+ sensitivity was observed [55]. However, the spacing-sarcomere length relation is unlikely linear, so this correlation may be hard to demonstrate (discussed in [54]). Another hypothesis relates to cooperative filament activation, where bound crossbridges further enhance thin filament activation to facilitate the generation of neighboring crossbridges. Some studies suggest this occurs with strongly activated crossbridges [59,60], others highlight the role of those that are weakly attached [61]. Lastly, the threonine in position 122 of cardiac TnI may impact length-dependent sensitivity [62].
Acute Stress—The Anrep Effect
The afterload dependence, also referred to as Anrep Effect [63], slow force response, or stress-stimulated contractility response, was first described over a century ago. This is characterized by a gradual calcium-dependent rise in force in muscle subjected to a rise in systolic load [64–67]. In the intact heart, this is a mechanism by which the heart can maintain its cardiac output despite increases in afterload pressure, a behavior coined homeometric autoregulation
[68]. Several theories have been forwarded to explain this behavior. One involves Ca²+ entry from reverse mode Na+-Ca²+ exchange that is triggered by a rise in intracellular sodium [69]. In this scheme, strain of Gq-coupled receptors such as endothelin-1 and angiontensin-1 stimulates PI3K and Akt, transactivating epidermal growth factor receptor to stimulate ERK and in turn the plasma membrane Na+/H+ exchanger to provide a source of intracellular sodium [70].
Figure 1.2 (A) Schematic showing impact of increased loading on myocyte contraction. With an acute rise in sarcomere stretch of a cell that can contract against an auxotonic load, there is an immediate increase in developed force, referred to as the Frank-Starling mechanism. This is calcium independent, and followed by a more gradual further increase in developed force coupled with a calcium increase—or Anrep effect. (B) The Anrep effect, or stress-stimulated contractility increase is markedly curtained by activation of protein kinase G by exposure to cyclic GMP (cGMP). Both the calcium and force rise after the initial FS effect are suppressed. (C) Gene deletion of TRPC6 also blunts the Anrep response in isolated myocytes. Here the percent force rise following the initial Frank-Starling effect (e.g., ΔF1 to ΔF2, in Fig. 1.2A ) is shown. The ∼25% normal rise is reduced by about a third in cells lacking TRPC6, and reduced by nearly 80% by cGMP exposure. The latter does not occur at all however, if TRPC6 is missing, thus PKG targets TRPC6 to effect the Anrep mechanism. (D) In a mouse model of Duchenne muscular dystrophy, the Anrep effect is more than doubled over control ( dashed line ), but can be normalized by selective blockade of TRPC6. Data modified from Seo K, Rainer PP, Lee DI, Hao S, Bedja D, Birnbaumer L, et al. Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation. Circ Res 2014;114:823–32.
An alternative is the activation of mechanosensitive cation channels that conduct sodium or calcium. These channels are principally considered members of the transient receptor potential superfamily [71]. Recent studies have shown that the Anrep or stress-stimulated contractility response is profoundly blunted by the activation of protein kinase G (PKG) via cyclic GMP exposure [72] (Fig. 1.2B). Moreover, this modulation requires the presence of transient receptor potential cation channel, subfamily C6 (TRPC6), a mechanically activated canonical TRP channel expressed in cardiac myocytes (Fig. 1.2C). From a disease perspective, studies have found the Anrep response is particularly abnormal and likely contributes to muscle disease in the dystrophinopathies. This was observed in cardiac myocytes from mice lacking dystrophin/utrophin where augmenting load during systole greatly augmented both the delayed calcium and force response, and triggered arrhythmia. Blockade of TRPC6 (Fig. 1.2D) and activation of PKG normalized the response [72]. These data have placed TRPC6 and potentially other interacting TRPC channels (as these proteins form heterotetramers) at the forefront of myocyte mechanosensing, particularly in mechano-filament protein disorders.
Several studies have also proposed nitric oxide signaling is also important for mechanostress transduction [73,74], although this may be model condition dependent as others find oxidant stress signaling but not NO as a major factor [75]. The precise mechanism remains unclear, though PKG inactivation of TRPC6 [76,77] or Gαq-receptor coupled signaling to activation of G-coupled proteins (RGS2 or RGS4) [78,79] could provide a link between NO and mechanosensing. Lastly, in both intact hearts and muscle, the matricellular protein thrombospondin 4 plays a key role in transducing systolic stress; however, this does not apply in isolated myocytes, so this protein engages external but not internal systolic-stress signaling [80].
Heart Rate and the Bowditch Effect
Control of systolic function by stimulation frequency (force-frequency relation, FFR) also dates back over a century to the work of Henry Bowditch [81]. In the normal human, increasing HR from 60 to 150 min−¹ augments contractility by 100%, playing an important role in exercise reserve [82]. Both hearts with dilated failure and hypertrophy display a reduction of this mechanism of systolic reserve. Weir and Yue first showed increasing rate elevates intracellular calcium by greater SR Ca²+ loading and subsequent release [83]. This plays a role in the disparity between FFR in human or larger mammals where two- to three-fold rise in contractility over operating frequencies is observed [82,84], versus in mice where only a 20% rise is found [85]. The mouse SR normally takes up >90% of Ca²+ with each beat as compared to <45% in humans, so there is little room for an increase with faster rates. In chronic heart failure, the FFR is markedly depressed (Fig. 1.3).
The fundamental questions are how does HR enhance SR calcium uptake, and do frequency-dependent ion channels and/or myofilament-Ca²+ interactions play a role. One contributing factor is likely phospholamban (PLB), which inhibits SERCA2a Ca²+ uptake in its unphosphorylated state, but enhances it when phosphorylated at S23,S24 [86,87]. Beta-adrenergic stimulation enhances the FFR (Fig. 1.3) [88], and this may be via PLB dis-inhibition. Studies in PLB-knock out (KO) hearts, which display enhanced basal contractility, show depression of the FFR [89]. Conversely, increasing PLB or specifically the PLB/SERCA2a ratio depresses the FFR [90]. In heart failure, blocking PLB (dominant negative) or upregulating SERCA2a expression enhances the FFR [91,92].
Another factor is calcium-calmodulin–dependent kinase II (CamKII) activated by higher mean calcium. This occurs at faster HRs due to more frequent calcium transients (e.g., integrating excitation-contraction-coupling events/minute). CamKII may modify the FFR by phosphorylating PLB [93,94], though other studies do not support this [95,96]. Alternatives are CamKII activation of SR Ca²+ release via the RyR2 [97] or enhancing L-type Ca²+ channel current (LTCC). The latter has been shown in the setting of CamKII methionine oxidation, which also enhances activity, and has been linked to greater LTCC current and rate-dependent calcium entry [98]. Two other proteins that play a role are TnI and MyBPC. TnI mutants mimicking phosphorylation at S22,S23 show an increased FFR [99] while those with these sites phosphosilenced have a depressed FFR [100]. MyBPC also modulates the FFR—contributing to a frequency-dependent rise in systolic function as well as shortening of the diastolic filling period at higher HRs [18].
Measuring Systolic Function
Pressure–Volume Relations
There are many ways systolic dysfunction is indexed, the most common being the relative amount of shortening or ejection, the maximal rate of pressure rise (dP/dtmax), and capacity of the heart to generate cardiac output or external stroke work for a given preload (end-diastolic volume) [101]. None of these are specific for systolic function, and each reflects different aspects so while they can be directionally altered in a similar manner, this is not always the case. The major limitation to these easily assessed metrics is their modulation by noncardiac factors, namely, load applied by means of muscle stretch (chamber filling), afterload (vascular impedance), or extrinsic constraints such as the pericardium. In the late 1970s a method of depicting cardiac function based on plotting simultaneous cavity pressure and volume first developed by Otto Frank [102] was resurrected and greatly refined by Sagawa, Suga, and colleagues [103]. This framework is now widely used in genetically engineered mouse studies [104] up through and including human studies, and continues to be a gold-standard for defining cardiac integrative function [82,105].
Figure 1.3 Force-frequency dependence in intact heart from conscious dog with and without cardiac failure (HF). The normal heart rate reserve is ∼100%, but this more than doubles when β-adrenergic stimulation is concomitantly provided. In HF hearts, the FFR is markedly depressed, and though this can be improved by β-adrenergic co-stimulation, it remains below controls. Adapted from Senzaki H, Isoda T, Paolocci N, Ekelund U, Hare JM, Kass DA. Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation 2000;101:1040–48.
While not strictly required for its practical utility, an engineering concept behind pressure-volume (PV) analysis is that heart muscle activation is a cyclical process of stiffening and de-stiffening, manifest as a time-varying elastance (elastance is the inverse of chamber compliance). Passive PV relations define rest properties and as contractile proteins interact, this relation steepens to reach a maximal slope at end-systole. At a constant sarcomere length (or chamber volume), stiffness is directly proportional to force (or pressure). If muscle shortens, stiffness is the ratio of F/(L-Lo), where Lo is the systolic muscle length at which no force is generated. Translated to the chamber, elastance is P/(V-Vo). Fig. 1.4A shows simultaneous plots of left ventricular chamber volume (x-axis) and pressure (y-axis), with each heart cycle generating a pressure-volume loop (loops move counterclockwise with time). The set of lines fanning from the origin reflect isochrones (i.e., connecting points on each of the loops at the same instantaneous time in contraction). The slope of each line defines the elastance (stiffness) of the chamber at that time, and this gradually rises from diastole to peak systole. The behavior depicted from PV relations is similar to what can be obtained from a single-myocyte subjected to a physiological
load (Fig. 1.4B).
Figure 1.4 (A) Time-varying elastance from isochrones derived from multiple cardiac cycles at varying preload volumes. The linear spokes connect points on each loop at the same time in the cardiac cycle (isochrones), and their slope is the value of elastance at that time point [Elastance = Pressure/(Volume − Vo)]. (B) The time-varying elastance is the change in this slope throughout the heartbeat (E(t)). When normalized for both peak and time to reach peak, the waveform is remarkably conserved across species—as shown here for mouse and human. (C) Force-length relations obtained in a single cardiac myocyte contracting against a simulated physiological load results in behavior very similar to that observed as pressure-volume relations in intact hearts. (D) Time varying elastance curves in experimental model of heart failure in response to two different types of inotropic stimulation. On the left is the response to the β1 agonist dobutamine, which increases the magnitude of elastance and also accelerates the kinetics of chamber stiffening/de-stiffening. On the right is the response to the myosin ATPase activator, omecantiv mercarbil. In this case, contraction kinetics are prolonged, and relaxation is not accelerated.
The overall shape (normalized to peak and time to peak) of time-varying elastance is remarkably conserved between humans and other species including mouse (Fig. 1.4C) [106]. The curve is also conserved among human patients with a broad range of heart diseases, or subjected to adrenergic or chronotropic stimulation [107]. This conservation has led to the development of several methods to predict peak elastance, a measure of systolic function, from steady state contractions [108,109]. There are examples where the elastance trajectory is altered, and this has provided some insight into its determinants. As previously mentioned, mice lacking MyBP-C display a striking abbreviation of contraction, as crossbridge interactions are not sustained when this protein is missing [18,110] (c.f. Fig. 1.1B). MyBP-C binds to the myosin heavy chains S2 and tail regions [111,112] as well as actin [113] and is thought to impose a restraint on the kinetics of crossbridge cycling, reducing filament velocity and rate of crossbridge attachment [114,115]. The latter was identified with acute length perturbation studies, where force redevelopment reflected crossbridge kinetics. Another pertinent example is the cardiac response to omecamtiv mecarbil [116], a myosin ATPase stimulator. This enhances the probability of a tightly bound crossbridge and so prolongs the systolic stiffening (Fig. 1.4D).
PV analysis was first applied in a comprehensive manner to humans in the mid-1980s, and was later miniaturized for mouse studies in the late 1990s [104,117,118]. While most commonly used to study the left ventricle, right ventricle (RV) relations have been obtained in animal models and recently employed to study human heart disease in forms of pulmonary hypertension [119]. PV analysis provides multiple measures of systolic and diastolic function, including all of the standard indexes discussed already, as well as end-systolic elastance (Ees). The latter is generally measured by the collection of points (one per beat) where elastance is greatest for each beat. Fig. 1.5A displays human left ventricular (LV) pressure-volume data obtained at rest and during transient reduction of preload volume. The bold loop represents the resting condition. The loop width is stroke volume, ratio of width to end-diastolic volume is ejection fraction, and loop area is external (or stroke) work. When ventricular preload is acutely reduced, stroke volume falls (Frank-Starling dependence).
These data appear different to what is almost universally depicted in physiology texts by way of a schematic, as the upper left-hand corner of each loop does not land on the same point at the same pressure by end-systole (Fig. 1.5B). Texts show it this way since preload is presumed not to alter afterload,
and afterload is assumed
to be equal to systolic pressure, so one must reach the identical left-upper corner point. Clearly this does not actually happen, nor could it, since for pressure to remain unchanged while stroke volume is declining with preload, the arterial resistive load would have to fall as well and by exactly the right amount. Indeed, the steepness of the end-systolic PV relation is an important predictor of the extent to which blood pressure will change when ventricular volumes are altered. Patients with hypertrophic and hyperdynamic hearts, typically have high Ees, and display a larger pressure drop with preload reduction as compared to those with dilated depressed hearts and a low Ees [120].
Figure 1.5 Pressure-volume (PV) analysis of cardiac function. (A) Resting ( dark solid loop ) PV loop and multiple cycles derived by varying preload in human subjects. Cycle loop moves counterclockwise. The lower right corner is end-diastole, the upper left is end-systole. The vertical regions on the right and left are periods of isovolumic contraction and relaxation, respectively. The upper left corners of the set of loops define the end-systolic PV relation, a valuable measure of chamber systolic function. (B) Depiction of a pure preload change
as found in the majority of physiology text books. The convergence of all the loop end-systolic points despite different starting end-diastolic volumes is non-physiological. This picture was taken from one of many such diagrams off the internet. (C) Example of ventricular remodeling and cardiac systolic depression with sustained cardiac failure. Data are generated using a mouse model of disease (MKK3 overexpression, activating p38 MAP kinase).
The end-systolic PV relation is commonly treated as linear, with slope Ees; however the actual data are often nonlinear. This issue was first confronted in the 1980s [121,122], though it is rarely dealt with in contemporary studies using the analytic method in genetically engineered animals. Its impact is lessened if the range of pressures over which PV relations are determined and compared is well matched, or nonlinear fits used that parameterize the curve without forcing a linear model. Lastly, one can use curve-fit independent analysis to compare sets of systolic PV relations [18]. A different Ees value per se does not necessarily translate to altered chamber contractility; its position along the volume axis must be considered as well (Fig. 1.5C). Ees is also chamber geometry dependent, increasing in small hearts with identical myocardial/myocyte properties, and is impacted by interstitial matrix/vascular properties as well as myocyte properties. It is most easily interpreted with acute modulations where these other factors are not altered, but can be normalized for chamber size and/or converted to a stress–strain relation to enhance its specificity for contraction.
Integrative Measures of Systolic Function
The first chamber-systolic event is isovolumic contraction often indexed by the peak rate of pressure or force rise prior to ejection. This is typically reduced in dilated cardiomyopathy, preserved or even increased in hypertrophic heart disease, and little altered in fibrotic/restrictive disorders. This peak rate is the most widely used index in mouse studies (easy to measure), but is highly preload dependent so even small differences (few microliters) can impact its value [85,123]. Normalizing dP/dtmax to the instantaneous pressure (IP) when it occurs (dP/dtmax/IP) can reduce preload sensitivity, or, alternatively, one can also regress this peak derivative against simultaneous preload volume [124]. Some contractility changes greatly impact dP/dtmax—notably those associated with changes in PKA activation that alter both contraction kinetics and force. Traditional inotropes working through this pathway, such as dobutamine and milrinone, increase dP/dtmax substantially. However, inotropes such as omecamtiv mercarbil, which enhances Ees and cardiac work by increasing myofibrillar ATPase activity has no impact on dP/dtmax yet enhances Ees [116]. Another example where isovolumic and ejection parameters of contraction can become dissociated is found in muscle lacking MyBP-C, where Ees is quite depressed while dP/dtmax remains normal [18]. Discoordinate contraction reduces dP/dtmax since isovolumic force develops more slowly when part of the muscle is still inactive and so distends as the other region is activated [125].
Early to midsystolic parameters are also widely used to assess function of the intact chamber. The two most commonly used are maximal power indexes and wall stress/adjusted circumferential shortening velocity. Both are measurable from noninvasive flow and pressure data [126,127]. Increasingly, tissue-Doppler methods using strain and strain-rate imaging is used to index systole [128]. These approaches essentially quantify myocardial wall motion—much as might be derived from MRI-based tissue tagging methods [129–131]. Strain rate has been found to correlate with dP/dtmax and indices derived from end-systolic PV relations [132], and clearly is prominently influenced by chamber systolic function. In genetic models of hypertrophic cardiomyopathy, tissue Doppler has been used to define early abnormalities of chamber function that precede the evolution of cardiac hypertrophy [133]. Tissue Doppler has been widely employed to index contractile discoordination in patients with cardiac failure and conduction delay [134,135].
Lastly, late-systolic parameters include ejection fraction, stroke work or stroke volume–preload relations (Frank-Starling or Sarnoff relations, respectively) [136]. Stroke work is better than stroke volume given its reduced afterload dependence, and the SW-EDV relation is both linear and minimally influenced by chamber load. Its slope—used to assess contractility—has units of force, and is chamber-size independent, with normal values ranging 80–110 mm Hg across species as varied as mouse and rat up to human. Methods to assess Ees as well as the SW-EDV slope from single-beat noninvasive data have been reported [137].
Impact of Pericardial Loading on Systolic Function
The intact chamber not only imposes complex filling and ejection loads on the heart during systole to modify its function, but also surrounds all chambers by a pericardial membrane coupling load of one chamber with another. While the influence of the pericardium on cardiac diastolic function is long well recognized, its impact on systolic function relations such as the Frank-Starling relation, remains less appreciated [138]. However, studies have shown the importance of this interaction for generating the descending limb
of the Frank-Starling relation. While increased length and thus sarcomere stretch over 2.4 μm has been suggested to explain a decline in force generated by skeletal muscle because of reduced myofilament overlap [139,140], cardiac tissue cannot be stretched to this extent because of the extracellular matrix and cytoskeletal membrane proteins within the myocyte. Yet, cardiac output is often observed to decline with high preloads or conversely increase with preload reduction, leading to the conclusion that the heart is operating on a descending limb in the failure state. Rather, this inverse load dependence relates to differences in transmural pressure (not absolute chamber pressure) that determine net stretch in the chamber (Fig. 1.6) [141,142]. In patients with DCM, increased intracavity end-diastolic pressures at high volumes are no longer coupled to higher transmural distending pressures, due to concomitantly higher extrinsic (pericardial) constraint. When preload declines, the actual transmural distending pressure can rise as this constraint is removed, so myocyte stretch increases despite the fall in EDP. Plots of cardiac output (CO) versus EDP can appear biphasic, whereas those between CO and EDV are linear. This affects any relationship in which filling pressure is used to index the level of chamber preload.
Ventricular–Arterial Interaction
Ventricular systolic function critically interacts with the vascular loading system into which the chamber ejects, and ventricular-vascular coupling plays an important role in setting myocardial performance and efficiency. Fig. 1.7A shows a PV relation with a diagonal line slanting upward from right to left in each PV loop. The slope of this line is termed the effective arterial elastance (Ea) [143–145] and is equal to the ratio of end-systolic pressure/stroke volume. Ea is not synonymous with vascular stiffness; indeed its numeric value is mostly influenced by mean arterial resistance (Ea = ESP/SV ≈ R × HR). However, it serves as a useful lumped measure of net ventricular after-load—both mean and pulsatile. Unlike arterial pressure, Ea is essentially unaltered even if the filling volume in the heart is changed, as shown in the figure. Studies have used this parameter in conjunction with PV relations and Ees to assess mechanisms of inodilator drugs [146] and examine heart-vascular coupling in human disease conditions and in the general population [146–149].
Figure 1.6 Influence of the pericardial and RV constraint on the appearance of a descending limb of a Frank-Starling relation. In this study, intact dogs were administered a volume load, and at high levels of load, the measured increase in LV end-diastolic pressure (LVEDP) appeared to correspond to a decline in stroke work (SW). Reducing preload
would appear to increase stroke work. However, if one plots the data as transmural LVEDP (that is the actual distending pressure applied to the LV), then the data show a rising phase only. The mechanism relates to the increased role of external constraints that limit actual volume filling of the ventricle while increasing the apparent preload based on intracavitary LV pressure.
Figure 1.7 (A) Resting human PV relations showing normal matching between end-systolic elastance (Ees) and arterial elastance (Ea). This matching results in optimized cardiac function and efficiency. (B) In contrast, the failing heart displays a reduced Ees (depressed systolic function) and elevated Ea (higher afterload). If afterload is reduced as shown in this example by administration of the arterial vasodilator, nitroglycerin, there is an increase in the loop area (stroke work) and correspondingly a rise in ventricular power. (C) Ventricular arterial interaction is also abnormal in many patients with heart failure and hypertrophic disease or a preserved ejection fraction. This is shown here, where a patient performed isometric hand exercise, and the result was a large rise in systolic pressure and workload, and corresponding rise in diastolic pressures (lower boundary). The pressure change is predicted by the higher resting elastance in this type of heart disease.
The Ea/Ees ratio normally falls between 0.6 and 1.2, a range in which there is optimal transfer of energy or work (power or SW) from the heart to arterial system [150–152]. Data from isolated canine hearts first displayed this dependence for both work and cardiac efficiency, and subsequent studies confirmed similar relations in intact hearts [153]. Optimal matching is maintained during exercise despite major alterations in contractility, HR, and vascular tone [152], and this may relate to an evolutionary process designed to maintain efficiency of work transfer and a minimum relative cardiac/body size ratio [154]. Work or power output is far from optimal, in hearts with depressed contractility and increased vascular loading, as seen in failing dilated hearts [155], where this ratio can exceed 3 [146]. In such individuals, vasodilators result in improved work (and power) (Fig. 1.7B), whereas in normal, they would have little net effect.
Combined increases in Ees and Ea can potently influence the pressures developed by the heart in response to changes in chamber filling and arterial load. Increased ventricular systolic stiffening means that even small increases or decreases in preload will amplify into marked changes in systolic pressure (Fig. 1.7C). This contributes to the increased diuretic and orthostatic sensitivity in the elderly. In patients with cardiac failure symptoms yet ejection fraction >50%, such stiffening is increased further [156]—though studies have shown this is likely related to the presence of systolic hypertension and ventricular hypertrophy, both common features of HFpEF patients [147,157]. The hemodynamic consequence is greater sensitivity of the heart to altered loading, exacerbated blood pressure liability, and potentially increased energetic demand to deliver reserve cardiac output [156]. Indeed, growing evidence supports a central role of limited function reserve in this disease, and these mechanical components likely contribute [158–160].
The systemic vasculature poses different loads on the LV than the pulmonary vessels do on the RV. This was highlighted by studies examining the inverse dependence between total mean vascular resistance and lumped compliance for each respective bed (e.g. systemic or pulmonary arteries). In the systemic circulation, vascular stiffening occurs in an anatomically distinct conduit artery segment, much in the thoracic aorta, whereas the smaller distal arteries impose resistance. In the pulmonary bed, the relation is more tightly coupled in peripheral small vessels, so the compliance and resistance are less easily separable (Fig. 1.8A). This has implications for ventricular-vascular coupling of the left versus right heart and corresponding vasculatures. For example, increased LV pulsatile load which occurs with aging can exist without parallel increases in systemic vascular resistance. However, in the RV, both components are linked. Therapies that reduce pulmonary vascular resistance rarely achieve the level required to simultaneously meaningfully reduce pulsatile load related to low vascular compliance; thus, the RV remains subject to very high afterload. Other studies have revealed that the LV diastolic filling pressure contributes a back-pressure to the pulmonary vascular load, increasing the pulsatile load on the RV (Fig. 1.8B). This may contribute to a variety of heart diseases when LV diastolic dysfunction can increase RV load during systole. Reduced pulmonary vascular compliance has been found to provide a strong predictor for worsened outcome in heart failure patients with reduced [161] or preserved [162] ejection fraction.
Treating Systolic Dysfunction
Despite a defining role in cardiac disease in many patients, amelioration of systolic dysfunction by pharmacotherapy has been difficult to affect in a way that also improves long-term outcome. Current therapy relies on a cAMP generating signaling pathway, using beta-1-receptor agonists or phosphodiesterase type 3 inhibitors [163]. Both stimulate intracellular calcium and PKA-dependent phosphorylation events, and while useful acutely, chronic effects are detrimental [164]. Newer approaches are being developed, including blockade of β-receptor kinase GRK-2. GRK-2 phosphorylates the β-receptor to suppress signaling, and stimulate internalization and desensitization. Blockade either by genetic expression of dominant negative forms or recently by the use of a serotonin re-uptake inhibitor compound that blocks GRK-2 as a side-effect [165], appears effective in preclinical models [166,167]. Another approach was gene therapy to increase expression of SERCA2a. While demonstrated to be effective in many preclinical studies [27,91,168,169], and with early encouraging though modest results in initial clinical work [169], a recent 250 patient CUPID2 clinical trial did not report significant benefits (http://ir.celladon.com/releasedetail.cfm?releaseid=908592). The reduced form of nitric oxide—HNO or nitroxyl is also a positive inotrope by mechanisms that differ from cAMP stimulation or NO modulation [170,171]. HNO alters reduced cysteine residues on selective proteins, among which are PLB, tropomyosin, myosin light chain, and the RyR2 [172–174]. This results in enhanced calcium cycling into and out of the SR and myofilament calcium sensitivity. HNO donors are currently being tested in heart failure patients.
Figure 1.8 (A) Reciprocal dependence of mean pulmonary vascular resistance versus total lumped vascular compliance in humans with primary pulmonary hypertension. (B) This contrasts to a broader range of compliance and resistance in the systemic circulatory system. The differences lie in the anatomic distribution of resistance and compliance in the two vascular beds (see text for details). (C) Increasing the LV end-diastolic pressure as indexed by the mean pulmonary capillary wedge pressure has an impact on RV loading primarily by reducing the effective compliance and thus elevating pulsatile load on the RV. This is being shown to predict worse outcomes in heart failure patients.
Improving myofilament calcium responsiveness continues to attract multiple therapy development programs. Referred collectively as calcium sensitizers, these agents can target many different aspects from calcium–troponin C interaction (levosimendan) [175] to ATPase (omecamtiv mercarbil) [116,176]. There are potential advantages of such agents given that they bypass the adrenergic system, and so can work equally well in failing as in normal hearts. They also will have greater impact in hearts where calcium desensitization has occurred, and in conditions where calcium response is augmented, as during exercise. Thus, unlike other inotropic stimulators, these drugs can provide greater augmentation with stress than at rest.
Calcium sensitization has also been linked to a device-based therapy called cardiac resynchronization [177]. In this case, hearts with discoordinate contraction due to electrical conduction delay receive biventricular stimulation to re-store more synchronized contraction and improve chamber mechano-efficiency [178]. CRT improves both acute and chronic cardiac function [179,180], yet does so in a manner that also improves mortality [181]. This remains unique among heart failure therapies. While clearly impacting the heart at the chamber level, this therapy has been shown to confer surprising benefits at the more molecular level [178]. In the case of myofilament function, Kirk et al. [177] found improvement in calcium-sensitivity that was in turn linked to the re-activation of glycogen synthase kinase 3-beta. Ongoing efforts may lead to a novel way to improve myofilament function and thus contractility safely.
Depressing systolic function on purpose in patients with hyperdynamic hearts, such as genetic hypertrophic cardiomyopathy with cavity obliteration, has also been a therapeutic target. Traditional negative inotropic agents such as beta-receptor blockers, L-type calcium channel antagonists, induced muscle ischemia (intracoronary infusion of alcohol to ablate tissue), surgical muscle removal, and even pacemaker-induced dyssynchrony have all been attempted and/or currently employed [125,182]. Newer approaches are screening for molecules that suppress myosin-actin crossbridge formation, which would represent a novel and potentially quite potent means to depress muscle function in hyperdynamic syndromes. Theoretically, a drug that shifted the force-calcium dependence to the right at both systolic and diastolic calcium concentrations might further improve diastolic distensibility and thus cardiac filling, and some have argued such an approach would be antiarrhythmic [183,184].
Summary
For much of the 20th century, physiologists explored both the mechanisms for and ways to assess systolic pump function of the heart. This was not a trivial task given the many ways that performance indexes were impacted, some related to muscle cell function, and others not. Interventions to modulate systolic function were historically limited and remain so today, though new efforts may finally change this and impact treatment options for a large population of patients with depressed or hyperdynamic heart disease. We now have the tools to more precisely determine what the interventions are doing, and in conjunction with new ways to target gene defects and myofibrillar disease in addition to calcium and other signaling, the importance of these assessments and application to human cardiac disease will likely become more prominent.
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