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Cardioskeletal Myopathies
in Children and Young Adults
Edited by
John Lynn Jefferies
Burns C. Blaxall
Jeffrey Robbins
Jeffrey A. Towbin
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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, S.R. Lalani Baylor College of Medicine, Houston, TX,
United States United States
A. Axelsson University of Copenhagen, Copenhagen, B.J. Landis Indiana University School of Medicine,
Denmark Indianapolis, IN, United States
B.C. Blaxall Cincinnati Children’s Hospital Medical D.L. Mann Washington University School of Medicine,
Center, Cincinnati, OH, United States St Louis, MO, United States
S. Bogdanovich The University of Chicago, Chicago, IL, J. Mathew Royal Children’s Hospital, Melbourne, VIC,
United States; Northwestern University Feinberg School Australia
of Medicine, Chicago, IL, United States E.M. McNally The University of Chicago, Chicago, IL,
S.C. Brown University of London, London, United United States; Northwestern University Feinberg School
Kingdom of Medicine, Chicago, IL, United States
M. Byku Washington University School of Medicine, L. Mestroni University of Colorado, Aurora, CO, United
St Louis, MO, United States States
S. Chanprasert Baylor College of Medicine, Houston, S.D. Miyamoto University of Colorado School of
TX, United States Medicine, Aurora, CO, United States
S.D. Colan Harvard Medical School, Boston, MA, United R.A. Moore Cincinnati Children’s Hospital Medical
States Center, Cincinnati, OH, United States
W.J. Craigen Baylor College of Medicine, Houston, TX, A. Redington Cincinnati Children’s Hospital Medical
United States; Texas Children’s Hospital, Houston, TX, Center, Cincinnati, OH, United States
United States J. Robbins Children’s Hospital Research Foundation,
H.C. DeSena Cincinnati Children’s Hospital Medical Cincinnati, OH, United States
Center, Cincinnati, OH, United States T.D. Ryan Cincinnati Children’s Hospital Medical Center,
A. El-Gharbawy University of Pittsburgh School of The University of Cincinnati College of Medicine,
Medicine, Pittsburgh, PA, United States; Children’s Cincinnati, OH, United States
Hospital of Pittsburgh, Pittsburgh, PA, United States J.E. Saffitz Harvard Medical School, Boston, MA, United
B.B. Gardner The University of Chicago, Chicago, IL, States
United States; Northwestern University Feinberg School C.A. Sewry UCL Institute of Child Health, London, United
of Medicine, Chicago, IL, United States Kingdom
C.Y. Ho Brigham and Women’s Hospital, Boston, MA,
R.J. Solaro University of Illinois at Chicago, Chicago, IL,
United States
United States
J.L. Jefferies Cincinnati Children’s Hospital Medical
D.S. Spar Cincinnati Children’s Hospital Medical Center,
Center, The University of Cincinnati College of
Cincinnati, OH, United States
Medicine, Cincinnati, OH, United States
B.L. Stauffer University of Colorado School of Medicine,
D.A. Kass Johns Hopkins University School of Medicine,
Aurora, CO, United States
Baltimore, MD, United States
C.C. Sucharov University of Colorado School of
Z. Khuchua Cincinnati Children’s Hospital Medical
Medicine, Aurora, CO, United States
Center, Cincinnati, OH, United States
xiii
xiv List of Contributors
M.E. Sweet University of Colorado, Aurora, CO, United W. Whiteside Cincinnati Children’s Hospital Medical
States Center, Cincinnati, OH, United States
M.R.G. Taylor University of Colorado, Aurora, CO, I. Wilmot Cincinnati Children’s Hospital Medical Center,
United States The University of Cincinnati College of Medicine,
J.A. Towbin Le Bonheur Children’s Hospital and University Cincinnati, OH, United States
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
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 char-
acterized. 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 pro-
duce 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 under-
standing 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
xv
Chapter 1
Ventricular Systolic Function

D.A. Kass
Johns Hopkins University School of Medicine, Baltimore, MD, United States
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 influ-
ence 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 tropo-
myosin position. This activation/inactivation balance is posttranslationally controlled by multiple kinases, including pro-
tein 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 cardiomy-
opathy 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.
Cardioskeletal Myopathies in Children and Young Adults. http://dx.doi.org/10.1016/B978-0-12-800040-3.00001-7

Copyright © 2017 Elsevier Inc. All rights reserved. 3
4 SECTION | I Physiology and Molecular Basis of Muscle
(A) (B)
CONTROL FHC
MyBPC-/-
1 Myocarditis
Normalized
MKK3/p38 oe
Elastance
100 100 TnI t/t (DCM)
Desmin -/-
PRESSURE (mmHg)
0
0 20 40 60 80 100 120
0
Time (ms)
0
0 50 100 150 0 50 100 150 (C)
VOLUME (mL) VOLUME (mL) 12
%∆ in Pressure-Volume Area
WT R403Q 10
120 120 8
(mmHg*µ L)
80 80 6
4
40 40
2 * *
0 0 0
20 30 40 50 60 20 30 40 50 60
VOLUME µ L VOLUME µL
/-
IP -/-
T -/-
-
T
PC
AI PC
W PC
W
-
yB
yB
yB
M
M
M
+
+
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, reca-
pitulating 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 pro-
tein 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 inflamma-
tion. 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
Ventricular Systolic Function Chapter | 1 5
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, includ-
ing 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 func-
tion 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 over-
lap—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 dem-
onstrate (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
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 inde-
pendent, 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.
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].
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 cat-
ion 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/utro-
phin 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 myo-
cyte 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 sys-
tolic 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 upregu-
lating 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). Cam-
KII 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 ejec-
tion, 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
%DVHOLQH FIGURE 1.3 Force-frequency dependence in intact heart from conscious

`
'REXWDPLQH &RQWURO dog with and without cardiac failure (HF). The normal heart rate reserve
%DVHOLQH ` +) is ∼100%, but this more than doubles when β-adrenergic stimulation is
'REXWDPLQH 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.

different aspects so while they can be directionally altered in a similar manner, this is not always the case. The major limi-
tation 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].
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), stiff-
ness 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
(A) (B) 1.0 HUMAN

MOUSE
100 0.8
Normalized Elastance
0.6
LV Pressure (mmHg)
50 0.4
0.2
0 0.0
0 1 2
0 50 100
Normalized Time
LV Volume (mL)
(C)
(D)
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 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).
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 deter-
minants. 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 cross-
bridge 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 pres-
sure, 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 hyperdy-
namic 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].
(A) (B) (C)

ESPVR
200
120
Pressure (mm Hg)
150
Pressure (mm Hg)
80
100
40
50
0 0
0 100 200 0 10 20 30 40
LV Volume (µL) LV Volume (µL)
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 ana-
lytic 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 proper-
ties, 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 ejec-
tion. 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, ino-
tropes 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 com-
monly used are maximal power indexes and wall stress/adjusted circumferential shortening velocity. Both are measur-
able 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 con-
tractile 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 con-
straint 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 ven-
tricular-vascular coupling plays an important role in setting myocardial performance and efficiency. Fig. 1.7A shows a PV
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 pres-
sure (LVEDP) appeared to correspond to a
decline in stroke work (SW). Reducing “pre-
load” would appear to increase stroke work.
However, if one plots the data as transmural
LVEDP (that is the actual distending pres-
sure 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.
$ % &

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3UHVVXUH PP+J

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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.
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 pres-
sure, 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].
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 match-
ing 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 rela-
tion 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 path-
way, 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.
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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 cardiomy-
opathy with cavity obliteration, has also been a therapeutic target. Traditional negative inotropic agents such as beta-receptor
(A) (B)
(C) (D)
(E) (F)
FIGURE 2.4 Serial sections of normal human skeletal muscle stained for mATPase (dark areas in each panel) at (A) pH 4.3, (B) pH 4.6, and (C) pH
9.4 showing a reciprocal staining pattern of type 1 and 2 fibers at pH 4.3 and 9.4 and subdivision of type 2 fibers into 2A and 2B at pH 4.6; (D) section
stained for cytochrome c oxidase showing higher activity in type 1 fibers [1], low activity in type 2B (2B) fibers, and intermediate intensity of 2A (2A)
fibers corresponding to the varying number of mitochondria in each fiber type. Note also the peripheral areas of high activity corresponding to clusters of
mitochondria that are often adjacent to a capillary (arrow); (E and F) serial sections immunolabeled with antibodies to fast (F) and slow (E) myosin heavy
chains showing a reciprocal 2 fiber pattern with only an occasional hybrid fiber (*).
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FRICASSEED FOWLS OR CHICKENS. (ENTRÉE.)
To make a fricassee of good appearance without great expense,

prepare, with exceeding nicety, a couple of plump chickens, strip off
the skin, and carve them very neatly. Reserve the wings, breasts,
merrythoughts, and thighs; and stew down the inferior joints with a
couple of blades of mace, a small bunch of savoury herbs, a few
white peppercorns, a pint and a half of water, and a small half-
teaspoonful of salt. When something more than a third part reduced,
strain the gravy, let it cool, and skim off every particle of fat. Arrange
the joints which are to be fricasseed in one layer if it can be done
conveniently, and pour to them as much of the gravy as will nearly
cover them; add the very thin rind of half a fine fresh lemon, and
simmer the fowls gently from half to three quarters of an hour; throw
in sufficient salt, pounded mace, and cayenne, to give the sauce a
good flavour, thicken it with a large teaspoonful of arrow-root, and
stir to it the third of a pint of rich boiling cream; then lift the stewpan
from the fire, and shake it briskly round while the beaten yolks of
three fresh eggs, mixed with a spoonful or two of cream, are added;
continue to shake the pan gently above the fire till the sauce is just
set, but it must not be allowed to boil, or it will curdle in an instant.
1/2 to 3/4 hour.
ENGLISH CHICKEN CUTLETS. (ENTRÉE).
Skin and cut into joints one or two young chickens, and remove
the bones with care from the breasts, merrythoughts, and thighs,
which are to be separated from the legs. Mix well together a
teaspoonful of salt, nearly a fourth as much of mace, a little grated
nutmeg, and some cayenne; flatten and form into good shape, the
boned joints of chicken, and the flesh of the wings; rub a little of the
seasoning over them in every part, dip them into beaten egg, and
then into very fine bread-crumbs, and fry them gently in fresh butter
until they are of a delicate brown. Some of the bones and trimmings
may be boiled down in half a pint of water, with a roll of lemon-peel,
a little salt, and eight or ten white peppercorns, to make the gravy
which, after being strained and cleared from fat, may be poured hot
to some thickening made in the pan with a slice of fresh butter and a
dessertspoonful of flour: a teaspoonful of mushroom-powder would
improve it greatly, and a small quantity of lemon-juice should be
added before it is poured out, with salt and cayenne if required. Pile
the cutlets high in the centre of the dish, and serve the sauce under
them, or in a tureen.
CUTLETS OF FOWLS, PARTRIDGES, OR PIGEONS. (ENTRÉE.)
(French Receipt.)
Take closely off the flesh of the breast and wing together, on either
side of the bone, and when the large fillets, as they are called, are
thus raised from three birds, which will give but six cutlets, take the
strips of flesh that lie under the wings, and that of the merrythoughts,
and flatten two or three of these together, that there may be nine
cutlets at least, of equal size. When all are ready, fry to a pale brown
as many diamond-shaped sippets of bread as there are fillets of fowl,
and let them be quite as large; place these before the fire to dry, and
wipe out the pan. Dip the cutlets into some yolks of eggs, mixed with
a little clarified butter, and strew them in every part with the finest
bread-crumbs, moderately seasoned with salt, cayenne, and
pounded mace. Dissolve as much good butter as will be required to
dress them, and fry them in it of a light amber-colour: arrange them
upon the sippets of bread, pile them high in the dish, and pour a rich
brown gravy or Espagnole round, but not over them.
FRIED CHICKEN À LA MALABAR. (ENTRÉE.)
This is an Indian dish. Cut up the chicken, wipe it dry, and rub it
well with currie-powder mixed with a little salt; fry it in a bit of butter,
taking care that it is of a nice light brown. In the mean time cut two or
three onions into thin slices, draw them out into rings, and cut the
rings into little bits about half an inch long; fry them for a long time
gently in a little clarified butter, until they have gradually dried up and
are of a delicate yellow-brown. Be careful that they are not burnt, as
the burnt taste of a single bit would spoil the flavour of the whole.
When they are as dry as chips, without the least grease or moisture
upon them, mix a little salt with them, strew them over the fried
chicken, and serve up with lemon on a plate.
We have extracted this receipt from a clever little work called the
“Hand-Book of Cookery.”
HASHED FOWL. (ENTRÉE.)
After having taken off in joints, as much of a cold fowl or fowls as

will suffice for a dish, bruise the bodies with a paste roller, pour to
them a pint of water, and boil them for an hour and a half to two
hours, with the addition of a little pepper and salt only, or with a small
quantity of onion, carrot, and savoury herbs. Strain, and skim the fat
from the gravy, put it into a clean saucepan, and, should it require
thickening, stir to it, when it boils, half a teaspoonful of flour smoothly
mixed with a small bit of butter; add a little mushroom catsup, or
other store-sauce, with a slight seasoning of mace or nutmeg. Lay in
the fowl, and keep it near the fire until it is heated quite through, and
is at the point of boiling: serve it with fried sippets round the dish. For
a hash of higher relish, add to the bones when they are first stewed
down a large onion minced and browned in butter, and before the
fowl is dished, add some cayenne and the juice of half a lemon.
FRENCH AND OTHER RECEIPTS FOR MINCED FOWL.
(ENTRÉE.)
Raise from the bones all the more delicate parts of the flesh of
either cold roast, or of cold boiled fowls, clear it from the skin, and
keep it covered from the air until it is wanted for use. Boil the bones
well bruised, and the skin, with three quarters of a pint of water until
reduced quite half; then strain the gravy and let it cool; next, having
first skimmed off the fat, put it into a clean saucepan, with a quarter
of a pint of cream, an ounce and a half of butter well mixed with a
dessertspoonful of flour, and a little pounded mace, and grated
lemon-rind; keep these stirred until they boil, then put in the fowl,
finely minced, with three or four hard-boiled eggs chopped small,
and sufficient salt, and white pepper or cayenne, to season it
properly. Shake the mince over the fire until it is just ready to boil, stir
to it quickly a squeeze of lemon-juice, dish it with pale sippets of fried
bread, and serve it immediately. When cream cannot easily be
obtained, use milk, with a double quantity of butter and flour. To
make an English mince, omit the hard eggs, heat the fowl in the
preceding sauce or in a common béchamel, or white sauce, dish it
with small delicately poached eggs (those of the guinea-fowl or
bantam for example), laid over it in a circle and send it quickly to
table. Another excellent variety of the dish is also made by covering
the fowl thickly with very fine bread-crumbs, moistening them with
clarified butter, and giving them colour with a salamander, or in a
quick oven.[90]
90. For minced fowl and oysters, follow the receipt for veal, page 231.
FRITOT OF COLD FOWLS.
Cut into joints and take the skin from some cold fowls lay them into
a deep dish, strew over them a little fine salt and cayenne, add the
juice of a lemon, and let them remain for an hour, moving them
occasionally that they may all absorb a portion of the acid; then dip
them one by one into some French batter (see Chapter V.), and fry
them a pale brown over a gentle fire. Serve them garnished with very
green crisped parsley. A few drops of eschalot vinegar may be mixed
with the lemon-juice which is poured to the fowls, or slices of raw
onion or eschalot, and small branches of sweet herbs may be laid
amongst them, and cleared off before they are dipped into the batter.
Gravy made of the trimmings, thickened, and well flavoured, may be
sent to table with them in a tureen; and dressed bacon (see page
259), in a dish apart.
SCALLOPS OF FOWL AU BÉCHAMEL. (ENTRÉE.)
Raise the flesh from a couple of fowls as directed for cutlets in the
foregoing receipt, and take it as entire as possible from either side of
the breast; strip off the skin, lay the fillets flat, and slice them into
small thin scallops; dip them one by one into clarified butter, and
arrange them evenly in a delicately clean and not large frying-pan;
sprinkle a seasoning of fine salt over, and just before the dish is
wanted for table, fry them quickly without allowing them to brown;
drain them well from the butter, pile them in the centre of a hot dish,
and sauce them with some boiling béchamel. This dish may be
quickly prepared by taking a ready-dressed fowl from the spit or
stewpan, and by raising the fillets, and slicing the scallops into the
boiling sauce before they have had time to cool.
Fried, 3 to 4 minutes.
GRILLADE OF COLD FOWLS.
Carve and soak the remains of roast fowls as for the fritot which
precedes, wipe them dry, dip them into clarified butter, and then into
fine bread-crumbs, and broil them gently over a very clear fire. A little
finely-minced lean of ham or grated lemon-peel, with a seasoning of
cayenne, salt, and mace, mixed with the crumbs will vary this dish
agreeably. When fried instead of broiled, the fowls may be dipped
into yolk of egg instead of butter; but this renders them too dry for
broiling.
FOWLS À LA MAYONNAISE.
Carve with great nicety a couple of cold roast fowls; place the
inferior joints, if they are served at all, close together in the middle of
a dish, and arrange the others round and over them, piling them high
in the centre. Garnish them with the hearts of young lettuces cut in
two, and hard-boiled eggs, halved lengthwise. At the moment of
serving, pour over the fowls a well-made mayonnaise sauce (see
Chapter VI.), or, if preferred, an English salad-dressing, compounded
with thick cream, instead of oil.
TO ROAST DUCKS.
[Ducks are in season all the year, but are thought to be in their
perfection about June or early in July. Ducklings (or half-grown
ducks) are in the greatest request in spring, when there is no game
in the market, and other poultry is somewhat scarce.]
In preparing these for the spit, be careful
to clear the skin entirely from the stumps of
the feathers; take off the heads and necks,
but leave the feet on, and hold them for a
few minutes in boiling water to loosen the
skin, which must be peeled off. Wash the
inside of the birds by pouring water through
Ducks trussed.
them, but merely wipe the outsides with a
dry cloth. Put into the bodies a seasoning of
parboiled onions mixed with minced sage, salt, pepper, and a slice of
butter when this mode of dressing them is liked; but as the taste of a
whole party is seldom in its favour, one, when a couple are roasted,
is often served without the stuffing. Cut off the pinions at the first joint
from the bodies, truss the feet behind the backs, spit the birds firmly,
and roast them at a brisk fire, but do not place them sufficiently near
to be scorched; baste them constantly, and when the breasts are
well plumped, and the steam from them draws towards the fire, dish,
and serve them quickly with a little good brown gravy poured round
them, and some also in a tureen; or instead of this, with some which
has been made with the necks, gizzards, and livers well stewed
down, with a slight seasoning of browned onion, some herbs, and
spice.
Young ducks, 1/2 hour: full sized, from 3/4 to 1 hour.
Obs.—Olive-sauce may be served with roast as well as with
stewed ducks.
STEWED DUCK. (ENTRÉE.)
A couple of quite young ducks, or a fine, full-grown, but still tender

one, will be required for this dish. Cut either down neatly into joints,
and arrange them in a single layer if possible, in a wide stewpan;
pour in about three quarters of a pint of strong cold beef stock or
gravy; let it be well cleared from scum when it begins to boil, then
throw in a little salt, a rather full seasoning of cayenne, and a few
thin strips of lemon-rind. Simmer the ducks very softly for three
quarters of an hour, or somewhat longer should the joints be large;
then stir into the gravy a tablespoonful of the finest rice-flour, mixed
with a wineglassful or rather more of port wine, and a
dessertspoonful of lemon-juice: in ten minutes after, dish the stew
and send it to table instantly.
The ducks may be served with a small portion only of their sauce,
and dished in a circle, with green peas à la Française heaped high in
the centre: the lemon-rind and port wine should then be altogether
omitted, and a small bunch of green onions and parsley, with two or
three young carrots, may be stewed down with the birds, or three or
four minced eschalots, delicately fried in butter, may be used to
flavour the gravy. The turnips au beurre, prepared by the receipt of
Chapter XVII., may be substituted for the peas; and a well made
Espagnole may take the place of beef stock, when a dish of high
savour is wished for. A duck is often stewed without being divided
into joints. It should then be firmly trussed, half roasted at a quick
fire, and laid into the stewpan as it is taken from the spit; or well
browned in some French thickening, then half covered with boiling
gravy, and turned when partially done: from an hour to an hour and a
quarter will stew it well.
TO ROAST PIGEONS.
[In season from March to Michaelmas, and whenever they can be

had young.]
These, as we have already said, should
be dressed while they are very fresh. If
extremely young they will be ready in twelve
hours for the spit, otherwise in twenty-four.
Take off the heads and necks, and cut off
the toes at the first joint; draw them
carefully, and pour plenty of water through
them: wipe them dry, and put into each bird
Pigeons for roasting.
a small bit of butter lightly dipped into a little
cayenne (formerly it was rolled in minced
parsley, but this is no longer the fashionable mode of preparing
them). Truss the wings over the backs, and roast them at a brisk fire,
keeping them well and constantly basted with butter. Serve them
with brown gravy, and a tureen of parsley and butter. For the second
course, dish them upon young water-cresses, as directed for roast
fowl aux cressons, page 272. About twenty minutes will roast them.
18 to 20 minutes; five minutes longer, if large; rather less, if very
young.
BOILED PIGEONS.
Truss them like boiled fowls, drop them into plenty of boiling water,
throw in a little salt, and in fifteen minutes lift them out, pour parsley
and butter over, and send a tureen of it to table with them.
CHAPTER XV.
Game.
TO CHOOSE GAME.
Buck venison, which is in season only from June to Michaelmas, is

considered finer than doe venison, which comes into the market in
October, and remains in season through November and December:
neither should be cooked at any other part of the year. The greater
the depth of fat upon the haunch the better the quality of the meat
will be, provided it be clear and white, and the lean of a dark hue. If
the cleft of the hoof, which is always left on the joint, be small and
smooth, the animal is young; but it is old when the marks are the
reverse of these.[91] Although the haunch is the prime and favourite
joint of venison, the neck and shoulder are also excellent, dressed in
various ways, and make much approved pies or pasties as they are
usually called. If kept to the proper point, and well dressed, this is the
most tender of all meat; but care is necessary to bring it into a fitting
state for table without its becoming offensive. A free current of air in
a larder is always a great advantage, as it assists materially in
preserving the sweetness of every thing which is kept in it, while a
close damp atmosphere, on the contrary, is more destructive of
animal food of all kinds even than positive heat. The fumes of
creosote are said to be an admirable preservative against
putrescence, but we have not ourselves yet had experience of the
fact. All moisture should be wiped daily, or even more frequently,
from the venison, with soft cloths, when any appears upon the
surface; and every precaution must be taken to keep off the flies,
when the joint is not hung in a wire-safe. Black pepper thickly
powdered on it will generally answer the purpose: with common
care, indeed, meat may always be protected from their attacks, and
to leave it exposed to them in warm weather is altogether
inexcusable in the cook.
91. It must be observed that venison is not in perfection when young: like
mutton, it requires to be of a certain age before it is brought to table. The
word cleft applies also to the thickest part of the haunch, and it is the depth
of the fat on this which decides the quality of the joint.
Hares and rabbits are stiff when freshly killed, and if young, the
ears tear easily, and the claws are smooth and sharp. A hare in cold
weather will remain good from ten to fourteen days; care only must
be taken to prevent the inside from becoming musty, which it will do
if it has been emptied in the field. Pheasants, partridges, and other
game may be chosen by nearly the same tests as poultry: by
opening the bill, the staleness will be detected easily if they have
been too long kept. With few exceptions, game depends almost
entirely for the fine flavour and the tenderness of its flesh, on the
time which it is allowed to hang before it is cooked, and it is never
good when very fresh; but it does not follow that it should be sent to
table in a really offensive state, for this is agreeable to few eaters
and disgusting to many, and nothing should at any time be served of
which the appearance or the odour may destroy the appetite of any
person present.
TO ROAST A HAUNCH OF VENISON.
To give venison the flavour and the

tenderness so much prized by epicures, it
must be well kept; and by taking the
necessary precautions, it will hang a
considerable time without detriment. Wipe it
with soft dry cloths wherever the slightest
moisture appears on the surface, and dust it plentifully with freshly-
ground pepper or powdered ginger, to preserve it from the flies. The
application of the pyroligneous or acetic acid would effectually
protect it from these, as well as from the effects of the weather; but
the joint must then be, not only well washed, but soaked for some
considerable time, and this would be very detrimental. To prepare
the venison for the spit, wash it slightly with tepid water or merely
wipe it thoroughly with damp cloths, and dry it afterwards with clean
ones; then lay over the fat side a large sheet of thickly-buttered
paper, and next a paste of flour and water about three quarters of an
inch thick; cover this again with two or three sheets of stout paper,
secure the whole well with twine, and lay the haunch to a sound
clear fire; baste the paper immediately with butter or clarified
dripping, and roast the joint from three hours and a half to four and a
half, according to its weight and quality. Doe venison will require half
an hour less time than buck venison. Twenty minutes before the joint
is done remove the paste and paper, baste the meat in every part
with butter, and dredge it very lightly with flour; let it take a pale
brown colour, and send it to table as hot as possible with gravy in a
tureen, and good currant jelly. It is not now customary to serve any
other sauces with it; but should the old-fashioned sharp or sweet
sauce be ordered, the receipt for it will be found at page 100.
3-1/2 to 4-1/2 hours.
Obs.—The kind of gravy appropriate to venison is a matter on
which individual taste must decide. When preparations of high
savour are preferred to the pure flavour of the game, the Espagnole
(or Spanish sauce) of Chapter IV. can be sent to table with it; or
either of the rich English gravies which precede it. When a simple
unflavoured one is better liked, some mutton cutlets freed entirely
from fat, then very slightly broiled over a quick fire, and stewed
gently down in a light extract of mutton prepared by Liebeg’s
directions, Chapter I., for about an hour, will produce an excellent
plain gravy: it should be seasoned with salt and pepper (or fine
cayenne) only. When venison abounds, it should be used for the
gravy instead of mutton.

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Cardioskeletal Myopathies in Children

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Cardioskeletal Myopathies in Children and Young Adults. http://dx.doi.org/10.1016/B978-0-12-800040-3.00001-7

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 %DVHOLQH FIGURE 1.3 Force-frequency dependence in intact heart from conscious

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LV Volume (µL) LV Volume (µL)

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To make a fricassee of good appearance without great expense,

After having taken off in joints, as much of a cold fowl or fowls as

A couple of quite young ducks, or a fine, full-grown, but still tender

[In season from March to Michaelmas, and whenever they can be

Buck venison, which is in season only from June to Michaelmas, is

To give venison the flavour and the

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