Chronic heart failure is a common consequence of various heart diseases. Mechanical force is known to play a key role in heart failure development through regulating cardiomyocyte hypertrophy. In order to understand the complex disease mechanism, this article discussed a multi-disciplinary approach that may aid the illustration of heart failure molecular process.

Introduction

Heart disease is a major cause of mortality in modern society [1,2]. Chronic heart failure (HF) represents 8% of the disease population [3], and more than 70% of which had a history of arterial hypertension and 25% were preceded by ischaemic infarction [4,5]. Studies demonstrated that HF is an end result of interactions of a range of molecular pathways from mechanical signalling, Ca2+ handling to energy metabolism [610]. Mechanical force is suggested to be a key player in HF development [11,12]; therefore, this mini review will focus on the HF mechanisms associated with mechanical forces and how a simple in vivo model, such as fruit fly (Drosophila melanogaster), may aid the studies using an empirical data-based in silico approach.

Cardiac hypertrophic transition and mechanical forces

Blood flow by exerting haemodynamic force helps the heart to evolve from its initial tubular shape to the round mature shape with separate chambers during embryonic development [1315]. During postnatal growth, blood volumetric increment, presented as a load ‘stretch’ force as well as a shear force, continuously stimulates heart hypertrophy [11,12] by adding extra sarcomeres without increasing the cell number. By doing so, the heart reduces its strain in counter-balancing the imposed forces, so the process is also known as adaptive or compensative hypertrophy. The forces are shown to have differentiated effects on muscle cells elongating or myofibrils lengthening [16], for example, only the myofibrils in a sharp angle to the flow direction had the most hypertrophic change versus those in a parallel or perpendicular position to the flow direction. This effect of the force on myofibrils is apparently crucial to both the formation and keeping of the heart shape. Myofibrils in Drosophila melanogaster heart also run spirally along the long axis of the heart so in a range of angles to the flow direction of the haemolymph in the heart. This indicates that there is a shared mechanical regulatory mechanism for heart growth across species.

In addition to meet the demand of body's physiological activities, adaptive hypertrophy also occurs in early arterial hypertensive heart due to pressure overload [17]. Therefore, it has been a long time research topic on the cause of the transition from the adaptive to maladaptive hypertrophy and eventually HF over the hypertension development. Establishment of clinical hypertension means that arterial condition has become rigid or less flexible, suggesting the formation of vascular fibrosis [18]. In the excess pressure resistance hypertension mouse model, the failing heart displays a significant reduction in capillary density [19]. This implies a poor blood supply to some areas of the heart, where cardiac fibrogenesis and tissue damage as widened interstitial space and degeneration of hypertrophied myocardial cells in the failing heart may occur [19,20]. These pathological changes provide valuable insights for understanding the hypertrophic transition.

Heart failure due to organ survival strategy via integrin regulation?

Heart failure (HF) is marked by tissue fibrosis. Studies suggest that the fibrogenesis may start from localized poor blood perfusion or insufficient oxygen supply. This condition will cause ATP production reduction and, in turn, results in uneven magnitude of contractions of the cells across the border of the affected and unaffected areas. As a result, mixed signals will be sensed by integrins and cause varied cellular responses from hypertrophy to atrophy. Consequently, fibrogenesis is triggered for strengthening the heart against the persistent pressure overload. Without rhythmic contractility, the fibrotic tissue causes HF development. This hypothesized route for hypertrophic–atrophic transition is discussed below.

Enhanced contractile magnitude by ‘stretch’ intensified Ca2+ transient

One of the immediate early cardiomyocyte responses to mechanical stretch is a quick calcium influx through highly Ca2+-selective mechanic-sensitive transient receptor potential (TRP) cation channels [2123]. The initial Ca2+ current induces a strong Ca2+ transient through activating the cell membrane-located L-type channels and SR (sarcoplasmic reticulum)-located RyR to release Ca2+ into the cytoplasm (called CIC), as illustrated in Figure 1I–II. The amount of Ca2+ delivered to and the rate of its removal from cytoplasm determine the intensity and duration of myocyte contraction [24] by making more troponin C available from calcium binding to troponin T. Such strong contraction through activating integrins [25] will trigger the cascade of integrin pathways to carry out hypertrophic activities (detailed later).

A schematic diagram of a potential route of HF development under persistent pressure overload.

Figure 1.
A schematic diagram of a potential route of HF development under persistent pressure overload.

A normal functional adult heart (I) may undergo a hypertrophic growth by pressure overload stimulation in early hypertension (II). Upon the stimulation, calcium influx is enhanced via TRPs, which promotes a high level of cytoplasmic Ca2+ transient and, in turn, increases myofilament contraction. Activated integrins by the physical forces from both outside-in and inside-out signallings start clustering and stimulate hypertrophic gene expression programme through its pathways and strengthen focal adhesions or IDs by interaction with other focal adhesion proteins. At the IDs, new sarcomeres are added to expand the myocyte. Continuation of this process, however, leads to localized poor blood perfusion and results in ATP production reduction (III). This condition weakens the contraction and down-regulates focal adhesion. As such, although the outside-in stimulation still remains, sarcomeres in affected areas disassemble and atrophy starts. To compensate the weakened myocytes network, cardiac fibroblasts differentiate to myofibroblasts, and they produce fibrotic tissue against the tearing forces. As a result, heart function is impaired and HF eventually develops (IV).

Figure 1.
A schematic diagram of a potential route of HF development under persistent pressure overload.

A normal functional adult heart (I) may undergo a hypertrophic growth by pressure overload stimulation in early hypertension (II). Upon the stimulation, calcium influx is enhanced via TRPs, which promotes a high level of cytoplasmic Ca2+ transient and, in turn, increases myofilament contraction. Activated integrins by the physical forces from both outside-in and inside-out signallings start clustering and stimulate hypertrophic gene expression programme through its pathways and strengthen focal adhesions or IDs by interaction with other focal adhesion proteins. At the IDs, new sarcomeres are added to expand the myocyte. Continuation of this process, however, leads to localized poor blood perfusion and results in ATP production reduction (III). This condition weakens the contraction and down-regulates focal adhesion. As such, although the outside-in stimulation still remains, sarcomeres in affected areas disassemble and atrophy starts. To compensate the weakened myocytes network, cardiac fibroblasts differentiate to myofibroblasts, and they produce fibrotic tissue against the tearing forces. As a result, heart function is impaired and HF eventually develops (IV).

Cell hypertrophic response induced by the calcium ion influx has been studied at various levels of cardiac functions. First, a decreased amplitude of Ca2+ transient (indicators of reduced Ca2+ release from SR [26,27]) in cells and tissues isolated from failing human hearts correlated with decreased EC coupling gain [28] and reduced myocardial contraction [29,30]. Ca2+ influx is also found to play a role in fibrogenesis, for example, the family member TRPV4 opens and causes Ca2+ influx in response to changes in plasma membrane stretch and promotes differentiation of fibroblasts and tissue fibrosis [3134]. Furthermore, TRPC1 and TRPC6 may be activated directly by stretch and implicated to be associated with HF [3537]. Mice without TRPC1 fail to produce the maladaptive cardiac phenotype [35], indicating that calcium influx is a necessary step of maladaptive hypertrophy in HF development. These findings lead to the proposal [38] that pathological remodelling of calcium handling is one of the routes that can lead to human HF.

Mechanically activated integrin pathways promote cardiac hypertrophy

Integrins are heterodimeric membrane protein, consisting of one α and one β subunit with a single transmembrane domain. There are 24 mammalian integrins formed from different combinations of 8β and 18α isoforms, serving cellular proliferation, differentiation and cell migration, as reviewed elsewhere [25,3944]. Integrins are a constitutive part of cell membrane-associated focal adhesion complex of multiple proteins. In myocardium, the adhesion complex locates between the sarcolemmal membrane and z-discs (called costamere) and specialized intercalated discs (IDs) at the end of longitudinal myocytes [10,41,45]. In response to mechanical stretch force, the extracellular N-terminus of β-integrin subunit binds to extracellular matrix (ECM) collagen, which allows α-subunit to free the β-intracellular C-terminus to interact with other proteins, such as cytoskeleton protein talin and signalling molecules ILK and FAK, directly or indirectly [4648]. Through these interactions, integrins activate hypertrophic activities in the heart.

Integrin ‘involvement’ is another immediate early cardiomyocyte response to physical stimulations [7]. Upon activation by the force generated from internal muscle contraction (inside-out signalling) [25], integrins start clustering within seconds [49] and by 5–10 min, the focal adhesion components or adaptor proteins are connected to the cytoplasmic domain of β-integrins (β1 is a major isoform in mammalian myocardium) and start recruiting actins to sarcomere for hypertrophy or maintaining process [5053] (Figure 1II). By force-sensitive assembling and disassembling of focal adhesion components [40], including mRNA and ribosome mobilizations [41,42,54,55], integrin-mediated adhesion complex plays a pivotal role in heart hypertrophy.

Integrin protein levels increased during the adaptive hypertrophy in arterial constricted mice hearts at early hypertension [56]. This corresponds to the elevated contractility and strengthened IDs [57] as well as forming new IDs at the lateral site with neighbouring membrane of the longitudinal cells observed by Maron and Ferrans [58]. The newly developed lateral IDs provide sites for new sarcomeres to be added to widen the cells. This event described as lateral process and the mechanism postulated by the authors that localized mechanical tensions induce their growth. These tensions are due to shearing forces exerted at side-to-side junction when contraction occurs at different rates or magnitudes in adjacent cells, leading to asymmetric and complementation of these junctions and to the eventual formation of the lateral processes.

In contrast with the stretch-induced calcium influx that has no influence on hypertrophic gene expression [21], in addition to expanding sarcomeres, integrins also stimulate hypertrophic gene expression, such as those for α- and β-myosin heavy chains [59,60], cardiac troponin C and T [61] and α-cardiac actin [59]. This activity of integrin is suggested to be carried out via tyrosine kinase pathways, involving MAP kinase pathways [62]. When β1 integrin is excised, the heart fails to withstand excessive pressure load [63], presumably due partly to an insufficient production of sarcomere proteins. Furthermore, defects in ECM ligand laminin-α4 and ILK caused dilated cardiomyopathy [64]. A similar observation is also reported in patients with atrial fibrillations [65]. Taken together, these evidences demonstrate that by both, or either, of new sarcomere building and hypertrophic gene expressions, integrins play a key role in matching the cardiac capacity to the demand of body's physiological activities.

Hypertrophy to atrophy — via inside-out integrin down-regulation?

Failing hearts at the end-stage dilated cardiomyopathy typically showed hypertrophy, atrophy of myocytes and an increased amount of fibrosis with alteration of decrease in myofilaments, ranging from rarefication to the complete absence of sarcomeres in cells filled with unspecified cytoplasm [20]. Efforts, since decades ago [66], in understanding the adaptive hypertrophic transition to the pathological setting have revealed that integrins, among other cardiac genes, show an expression pattern with an increased level in early adaptive hypertrophy, but a decreased level in later maladaptive hypertrophy in hypertension development [63]. Re-expressed foetal isoform α-skeletal actin and increased β-myosin heavy chain mRNAs may fall back to previous levels following the hypertrophy regress within weeks of stimulus removal in physiological hypertrophy [11,6769], for instance, in trained athletes [70,71]. In non-compensative hypertrophy and HF, however, elevated α-skeletal actin reduces back to control animal level while the pressure condition is still in place [19,68]. Furthermore, short-time (2 weeks) conditional cardiac expression of AKT(1), a serine/threonine protein kinase that mediates cellular growth responses, in transgenic mouse induced a reversible compensative hypertrophy, whereas its continuous expression for 6 weeks caused HF [72]. Explanation of the prolonged hypertrophy that promotes an adverse opposite effect is incomplete yet.

Persistent pressure overload should continuously stimulate cardiac hypertrophy. But, evidence indicates that myocytes could expand out of proportion to the interstitial space, where vascular network lies, in the confined heart and lead to poor supply of nutrients and oxygen [73]. This is supported by a significant reduction in capillary density [19] and reduced energy production in the failing heart [74]. As a result, decreased contractility of myofilaments in affected tissue areas is expected, which through inside-out signalling of integrin could weaken the focal adhesions or IDs and cause localized atrophy. This role of the inside-out regulation of integrin is believed here because outside-in signal of pressure overload is unchanged if not stronger, so that the stretch-enhanced calcium transient and resulted strengthened contractility should not decrease. Furthermore, fatty acid oxidation, which produces up to 90% ATP in adult, is decreased in the failing hearts [74] with accompanied alteration of mitochondrial structure [58,75] and abnormality of metabolism pathway that result in decreased energy production, energy transfer and energy utilization [74,76]. Altogether, it is suggested that during hypertension development, cardiac persistent pressure overload is through the inside-out down-regulation of integrin to turn the initial adaptive hypertrophy to atrophy of the heart.

Cardiac fibrogenesis compensates for weakened failing heart?

In the heart, interconnected fibroblasts with the deposited ECM, consisting of collagens, elastin, fibronectin and ground material, hold cardiomyocytes together [77]. Hypertrophied left ventricles produced total more collagens with increased type III in the early hypertension [78], which has a strong bond (160pN) to resist rupture forces [57,79]. Excess pressureload on the heart as well as hypoxia can trigger cardiac fibroblasts differentiated into myofibroblasts [80,81], and the latter produces different proportion of collagen III and collagen I from the former and matrix metalloproteinases with the balance to promote cardiac fibrogenesis [82]. In advanced hypertension in human and the aortic constricted mice, the hearts have significantly increased pericellular collagen weave fibres [18,83], where they are proposed to provide support to the collapsed or weakened intercalated structure that built up in early phase of compensative hypertrophy in the hypertension patients [73]. Those fibrotic areas form barriers or gaps, so that the normal passage of electrical current of action potentials in the heart is blocked. As a result, arrhythmia develops. Fibrotic tissue does not contract, thus giving the impaired contractility of the heart. Both the functional aspects provide the traditional diagnostic basis of a (chronic) failing heart.

Cardiac interstitial fibrosis formation induced in arterial hypertension by excess pressure does not involve cell injury compared with the scar formation induced in coronary arterial disease by cell death followed by inflammatory response [7,84]. But HF development post the formation of the-scar in coronary disease likely shares the same developing route with the hypertension-induced HF, which is also strongly associated with ageing population [4]. Thus, to balance the myocyte hypertrophy to a level that does not trigger the transition of fibroblasts to myofibroblasts is believed a way to halt further pathological and age-related cardiac regression and potentially reverse the pathological remodelling.

Modern imaging technology can localize the region of the fibrotic tissue by its increased stiffness and using the relationship analysis of stress (pressure imposed on heart wall) and strain (heart deformation) to predict a deleterious cardiac failure [85,86]. For example, slowed relaxing period of a local area of a heart can be captured from congenital cardiomyopathy patients by the imaging-based strain (deformation) rate analysis [85]. Sensitivity of such analysis can even capture the congenital disease carrier before the formation of fibrotic scar tissue, that is, in the state of increasing in myocardial collagen synthesis without overt disease [85,87]. Therefore, the imaging technologies promise an early diagnosis tool for the transition of adaptive hypertrophy to HF.

Studies in computational modelling of mammalian heart

Primary elemental aspects of the heart to be brought together to computationally simulate or faithfully analyze heart behaviour were described by Hanna [88]: 1) description of the shape and size of the left ventricle (LV), 2) the orientation and motion of muscle fibres in the LV wall, 3) the mechanics and thermodynamics of isolated muscle fibre contraction, 4) the haemodynamic load imposed on the LV by the systemic circulation and 5) the assimilation of these four elements into a functional model. Subsequently, a finite-element mathematical method is employed to build a heart model that can analyze those elemental aspects and more, such as cardiac tissue's inhomogeneity, anisotropy and non-linear material properties [89]. Such a model with detailed 3D cardiac geometry and myofibre architecture [90] has been continuously improved in parametric sensitivity [9193], for example, analyzing tissue contractile properties between fibrosis and myocardium. Improvement in modelling cardiac response to imposed mechanical forces is expected to be supported from clinical capabilities, in analyzing localized strain rate of hearts with congenital disease [85].

Heart modelling is currently an active research field. A wide range of structural and functional modelling methods and their applications have been developed in the past decade. To name a few, there are models for investigating structural and molecular determinants of ventricular electromechanical function [94]; anatomically detailed continuum models for integrating biophysical processes into simulations of regional-specific mechanics and electrophysiology of the intact heart [95]; models for molecular and subcellular-scale study of energy consumption, such as nucleotide diffusion in the cardiac myofilament lattice [96]; models for multi-scale modelling of large biomolecular complexes at atomic resolution [97]; models for exploring arrhythmia mechanism with respect to transmembrane ionic current flow in cardiomyocytes [98,99] and models for detailed description of histoanatomy up to micro-scale resolution [100,101]. An up-to-date overview of the evolution of the methodologies, used in constructing heart models and their applications, is provided in an excellent review by Lopez-Perez et al. [102].

It is noticeable, however, that there seems to be no heart model available in the area of mechanical signalling transduction despite the essentiality of this area in the study of heart development and disease. However, relevant in vitro studies in modelling the dynamic behaviour of cellular micro-structural networks influenced by genes in the mechanotransduction pathways, such as integrins, have generated interesting insights [103,104]. The challenge is how to best use the rich in vitro observations, that is how to correctly integrate the in vitro findings into the corresponding state of heart physiology or disease to enhance heart-modelling capability. This issue is discussed in the last section.

D. melanogaster heart studies

Drosophila has a single tubular cardiovascular system, also known as dorsal vessel [105]. During postembryonic larval development, it is formed by a posterior resided heart (∼1–2 mm long), which has rhythmic contractility and three pairs of ostia opening at both sides of the heart, and a narrow aorta that spans most of the remaining body length, which passively guides haemolymph (blood equivalent) flow out of the cardiovascular system [106]. In the open circulatory system, haemolymph flows through extravascular interstitials and back into the heart again via the ostia [106]. Two rows of cardioblast join up at cell membrane along the body midline by specialized focal adhesion junctions, which resemble the heart's ‘IDs’ of vertebrates. Myofilaments mainly form longitudinal bundles, inserted at the boundary between adjacent cardioblasts [107]. In the study, the heart wall is shown, on both the luminal and the outer surfaces, to be covered by a layer of ECM. The ECM layers are connected to the cardiomyocyte layer by hemi-adhesion junctions, presumably at the z-lines like the vertebrate's costamere.

Studies of D. melanogaster heart have made valuable contributions towards our understanding of heart biology and disease in the last two decades [108110]. Identification of heart fate determination gene tinman led to the discovery of vertebrate homologue Nkx 2.5 [109,111]. Structural and functional homology of many genes between D. melanogaster and vertebrate hearts, for example potassium channel, involves cardiac rhythmic activity [112]; βPS integrin, the human β1 homologue, influences heart ageing [113,114]; NOT3 regulates heart function [115] and tropomyosin mutation causes arrhythmia [116]. Furthermore, expressing mutated human gene (δ-sarcoglycan) in fruit fly is capable of recapitulating human dilated cardiomyopathy [117], supporting the observation that heart physiology is homology between mammalian and D. melanogaster heart [106]. These data provide the basis that haemodynamic force's regulation of fly heart behaviour is highly interspecies interpretable.

Since βPS integrin, the D. melanogaster homologue of human β1 [43], also expresses in the fly heart, it is intriguing to learn whether the important mechanotransduction pathway is shared by D. melanogaster. Thus, we developed a computational modelling method [118] based on heart volumetric dynamics. With the method, we estimated the shear force imposed on the wall of the larval heart by haemolymph flow when the expression of βPS gene (mys) was knocked down using the Gal4–UAS system [119]. The force estimation is based on the analysis for wall shear stress (τ) in the arterial system: τ = 4ηqr3 [120], where η is haemolymph viscosity (similar to human plasma); q is the haemolymph flow rate, estimated based on the volumetric dynamics of 3D computational model heart that was geometrically created using the imaging of third instar larval heart with transgene 1029-Gal4;UAS-RedStinger;UAS-mysRNAi and r is the average radius of the model heart.

As shown in Figure 2B, the shear stress corresponding to peak systolic contraction is the highest, and it reduced seven times in the knockdown hearts compared with the control. Immunoconfocal microscopic analysis revealed that this shear stress reduction corresponded to the discontinuation or detachment of myofilaments along the heart ventral midline (Figure 2A). An accompanied change is the row of discrete integrin-intense ‘bars’ (presumably the fly's ‘IDs’) disappeared in the knockdown hearts. Further knockdown (by exposing the larvae carrying the same Gal4-UAS integrin knockdown construct to higher temperature) of the gene resulted in a massive loss of the myofibrils (unpublished data not shown). The correlation of the downgradient of integrin levels with the severer myofibril's damage appears to resemble the disappearing of myocardium in dilated cardiomyopathy in failing human hearts.

Reduced shear force in larval D. melanogaster heart with myofilaments disconnected between cells due to βPS integrin knockdown.

Figure 2.
Reduced shear force in larval D. melanogaster heart with myofilaments disconnected between cells due to βPS integrin knockdown.

(A) Confocal microscopic images of third instar larval hearts (anteriors to the left and ventral side up) that were dissected and immunolabelled by anti-βPS integrin antibodies (green) and myofibrillar F-actin (red) were labelled by Rhodamine phalloidin. ‘IDs’ (arrow heads) in control heart in top panels (left: a confocal image; right: a schematic diagram) show as intense ‘integrin-bars’ in two lines, presumably one on ventral and the other on dorsal midline. In contrast, integrin knockdown heart in bottom panels (left: a confocal image; right: a schematic diagram) shows myofilament's discontinuation along the heart midline and leaves a detachment look of the myocytes at edge as indicated by arrows. Accompanied phenotype is the disappearing of the regularly spaced integrin-intense IDs. In the knockdown heart, myofilaments discontinue at appearing to be the cell borders with small and irregular doted integrin distributions. PE: pericardial cell is shown by its integrin distribution. (B) Shear stress is reduced from 15.42 ± 9.34 dyne/cm2 (n = 5) in control to 2.123 ± 2.219 dyne/cm2 (n = 6) in βPS knockdown hearts (1029-Gal4/UAS-mysRNAi). **P = 0.0078 by Student t-test.

Figure 2.
Reduced shear force in larval D. melanogaster heart with myofilaments disconnected between cells due to βPS integrin knockdown.

(A) Confocal microscopic images of third instar larval hearts (anteriors to the left and ventral side up) that were dissected and immunolabelled by anti-βPS integrin antibodies (green) and myofibrillar F-actin (red) were labelled by Rhodamine phalloidin. ‘IDs’ (arrow heads) in control heart in top panels (left: a confocal image; right: a schematic diagram) show as intense ‘integrin-bars’ in two lines, presumably one on ventral and the other on dorsal midline. In contrast, integrin knockdown heart in bottom panels (left: a confocal image; right: a schematic diagram) shows myofilament's discontinuation along the heart midline and leaves a detachment look of the myocytes at edge as indicated by arrows. Accompanied phenotype is the disappearing of the regularly spaced integrin-intense IDs. In the knockdown heart, myofilaments discontinue at appearing to be the cell borders with small and irregular doted integrin distributions. PE: pericardial cell is shown by its integrin distribution. (B) Shear stress is reduced from 15.42 ± 9.34 dyne/cm2 (n = 5) in control to 2.123 ± 2.219 dyne/cm2 (n = 6) in βPS knockdown hearts (1029-Gal4/UAS-mysRNAi). **P = 0.0078 by Student t-test.

Shear stress estimated here is close to the reported value in prepupa using a different method [69], which validates the approximation capacity of our approach. An integrin level-dependent myofibril phenotype, from disorganization to massive loss of the myofibril content, provides evidence that larval development is a highly sensitive period for studying the force regulation of heart behaviour, particularly at the indicated transition between physiopathology that uniquely allows exploration of the cardiomyopathy at its starting moment. Consider the relation between myofibril orientation and the direction of the shear force [16], fly's larval heart lends itself a powerful in vivo tool for exploring the force regulation mechanisms.

Quantitative mechanic forces as reference for interspecies data interpretation

It is hoped that the above discussions have argued for the need to employ a spatial–temporal computational modelling approach to illustrate the dynamic hypertrophic gene networks underlying heart physio-pathological process. A current major issue in doing so is lacking a linker or standard reference to correctly integrate vastly available in vitro-generated molecular data into a 3D model of defined state of physiology or disease at organ's organization level. Phenotypes in a quantitative correlation with mechanic forces allow the integration of the former based on the latter as a reference system. But the correlations between individual molecules or genes and organ states are hard to obtain from in vivo studies in vertebrates because of the tissue organizational complexity-associated poor experimental accessibility. Such hurdle can be overcome by translating D. melanogaster heart studies into the vertebrate system by taking the advantage of physiological homology between the two species. This is because the D. melanogaster heart exists as both a perfect organ and a single layer of cardiomyocytes, which, to a certain extent, resembles mammalian cardiomyocytes in culture, and the advantage of which is that the single sheet of cells allows force-phenotype to be studied at (sub)cellular level in situ.

As outlined in the diagram below, this proposed data intertranslation across species is not expected to be a straightforward one. Arrows indicate the direction that data feed to, and two directional arrows indicate the verification steps needed in the data-intertranslational process.

Conclusion

This mini review focused the discussions on our current understanding of HF development. Overgrowing by hypertrophy of the myocytes under persistent pressure overload in advanced hypertension is believed to cause a chain reaction that leads to down-regulation of integrins and pathways by weakened contractility due to insufficient energy productions. As a result, atrophy followed by HF develops. A major issue in tackling the chronic HF is the poor accessibility of the complex cardiac system in vertebrates. For this reason, D. melanogaster larval heart studies have been proved capable of providing an indirect alternative research approach to aid a correct integration of mammalian in vitro findings of hypertrophic molecular genetics by in silico means. Together with a combined effort of physiology, molecular genetics, biofluid dynamics, biomechanics, imaging technology and computational biology, ultimate control of HF may be achieved sooner.

Abbreviations

EC coupling, excitation-contraction coupling; ECM, extracellular matrix; FAK, focal adhesion kinase; HF, heart failure; IDs, intercalated discs; ILK, integrin linked kinase; LV, left ventricle; MAP kinase, mitogen-activated protein kinase; MMPs, matrix metalloproteinases; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; TRP, transient receptor potential.

Acknowledgments

I thank Dr Jian Chang (The Medium School, Bournemouth University) and Dr Mandun Zhang (School of Computer Science and Engineering, Hebei University of Technology, Tianjin, China) for designing and executing the 3D larval heart modelling and haemodynamic calculations. My thanks also go to Dr David A. Johnston (Biomedical Imaging Unit, Faculty of Medicine, University of Southampton) for the excellent immunoconfocal microscopy work.

Competing Interests

The Author declares that there are no competing interests associated with this manuscript.

References

References
1
Kannel
,
W.B.
(
2000
)
Vital epidemiologic clues in heart failure
.
J. Clin. Epidemiol.
53
,
229
235
doi:
2
Hobbs
,
R.E.
(
2004
)
Guidelines for the diagnosis and management of heart failure
.
Am. J. Ther.
11
,
467
472
doi:
3
Mosterd
,
A.
and
Hoes
,
A.W.
(
2007
)
Clinical epidemiology of heart failure
.
Heart
93
,
1137
1146
doi:
4
Go
,
A.S.
,
Mozaffarian
,
D.
,
Roger
,
V.L.
,
Benjamin
,
E.J.
,
Berry
,
J.D.
,
Borden
,
W.B.
et al.  (
2013
)
Heart disease and stroke statistics — 2013 update: a report from the American Heart Association
.
Circulation
127
,
e6
e245
doi:
5
Brouwers
,
F.P.
,
de Boer
,
R.A.
,
van der Harst
,
P.
,
Voors
,
A.A.
,
Gansevoort
,
R.T.
,
Bakker
,
S.J.
et al.  (
2013
)
Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND
.
Eur. Heart J.
34
,
1424
1431
doi:
6
Berridge
,
M.J.
(
2003
)
Cardiac calcium signalling
.
Biochem. Soc. Trans.
31
(
Pt 5
),
930
933
doi:
7
Bishop
,
J.E.
and
Lindahl
,
G.
(
1999
)
Regulation of cardiovascular collagen synthesis by mechanical load
.
Cardiovasc. Res.
42
,
27
44
doi:
8
Hasenfuss
,
G.
(
1998
)
Animal models of human cardiovascular disease, heart failure, and hypertrophy
.
Cardiovasc. Res.
39
,
60
76
doi:
9
Heineke
,
J.
and
Molkentin
,
J.D.
(
2006
)
Regulation of cardiac hypertrophy by intracellular signalling pathways
.
Nat. Rev. Mol. Cell Biol.
7
,
589
600
doi:
10
Sussman
,
M.A.
,
McCulloch
,
A.
and
Borg
,
T.K.
(
2002
)
Dance band on the Titanic: Biomechanical Signaling in Cardiac Hypertrophy
.
Circ. Res.
91
,
888
898
doi:
11
Komuro
,
I.
,
Shibazaki
,
Y.
,
Kurabayashi
,
M.
,
Takaku
,
F.
and
Yazaki
,
Y.
(
1990
)
Molecular cloning of gene sequences from rat heart rapidly responsive to pressure overload
.
Circ. Res.
66
,
979
985
doi:
12
Sadoshima
,
J.
and
Izumo
,
S.
(
1997
)
The cellular and molecular response of cardiac myocytes to mechanical stress
.
Annu. Rev. Physiol.
59
,
551
571
doi:
13
Hove
,
J.R.
,
Köster
,
R.W.
,
Forouhar
,
A.S.
,
Acevedo-Bolton
,
G.
,
Fraser
,
S.E.
and
Gharib
,
M.
(
2003
)
Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis
.
Nature
421
,
172
177
doi:
14
Barbera
,
A.
,
Giraud
,
G.D.
,
Reller
,
M.D.
,
Maylie
,
J.
,
Morton
,
M.J.
and
Thornburg
,
K.L.
(
2000
)
Right ventricular systolic pressure load alters myocyte maturation in fetal sheep
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
279
,
R1157
R1164
PMID:
[PubMed]
15
Rugonyi
,
S.
,
Shaut
,
C.
,
Liu
,
A.
,
Thornburg
,
K.
and
Wang
,
R.K.
(
2008
)
Changes in wall motion and blood flow in the outflow tract of chick embryonic hearts observed with optical coherence tomography after outflow tract banding and vitelline-vein ligation
.
Phys. Med. Biol.
53
,
5077
5091
doi:
16
Wang
,
D.
,
Zheng
,
W.
,
Xie
,
Y.
,
Gong
,
P.
,
Zhao
,
F.
,
Yuan
,
B.
et al.  (
2014
)
Tissue-specific mechanical and geometrical control of cell viability and actin cytoskeleton alignment
.
Sci. Rep.
4
,
6160
doi:
17
Burchfield
,
J.S.
,
Xie
,
M.
and
Hill
,
J.A.
(
2013
)
Pathological ventricular remodeling — mechanisms: part 1 of 2
.
Circulation
128
,
388
400
doi:
18
Piek
,
A.
,
de Boer
,
R.A.
and
Silljé
,
H.H.W.
(
2016
)
The fibrosis-cell death axis in heart failure
.
Heart Fail. Rev.
21
,
199
211
doi:
19
Perrino
,
C.
,
Naga Prasad
,
S.V.
,
Mao
,
L.
,
Noma
,
T.
,
Yan
,
Z.
,
Kim
,
H.-S.
et al.  (
2006
)
Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction
.
J. Clin. Invest.
116
,
1547
1560
doi:
20
Schaper
,
J.
,
Froede
,
R.
,
Hein
,
S..
,
Buck
,
A.
,
Hashizume
,
H.
,
Speiser
,
B.
et al.  (
1991
)
Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy
.
Circulation
83
,
504
514
doi:
21
Sadoshima
,
J.
,
Takahashi
,
T.
,
Jahn
,
L.
and
Izumo
,
S.
(
1992
)
Roles of mechanosensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes
.
Proc. Natl Acad. Sci. USA
89
,
9905
9909
doi:
22
Gees
,
M.
,
Colsoul
,
B.
and
Nilius
,
B.
(
2010
)
The role of transient receptor potential cation channels in Ca2+ signaling
.
Cold Spring Harb. Perspect. Biol.
2
,
a003962
doi:
23
Sachs
,
F.
(
2010
)
Stretch-activated ion channels: what are they?
Physiology
25
,
50
56
doi:
24
Yue
,
D.T.
,
Marban
,
E.
and
Wier
,
W.G.
(
1986
)
Relationship between force and intracellular [Ca2+] in tetanized mammalian heart muscle
.
J. Gen. Physiol.
87
,
223
242
doi:
25
Hynes
,
R.O.
(
2002
)
Integrin: bidirectional allosteric signaling machines
.
Cell
110
,
673
687
doi:
26
Beuckelmann
,
D.J.
,
Nabauer
,
M.
and
Erdmann
,
E.
(
1992
)
Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure
.
Circulation
85
,
1046
1055
doi:
27
Pieske
,
B.
,
Kretschmann
,
B.
,
Meyer
,
M.
,
Holubarsch
,
C.
,
Weirich
,
J.
,
Posival
,
H.
et al.  (
1995
)
Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy
.
Circulation
92
,
1169
1178
doi:
28
Gomez
,
A.M.
,
Valdivia
,
H.H.
,
Cheng
,
H.
,
Lederer
,
M.R.
,
Santana
,
L.F.
,
Cannell
,
M.B.
et al.  (
1997
)
Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure
.
Science
276
,
800
806
doi:
29
Hasenfuss
,
G.
,
Pieske
,
B.
,
Holubarsch
,
C.
,
Alpert
,
N.R.
and
Just
,
H.
(
1993
)
Excitation-contraction coupling and contractile protein function in failing and nonfailing human myocardium
.
Adv. Exp. Med. Biol.
346
,
91
100
doi:
30
Hasenfuss
,
G.
,
Mulieri
,
L.A.
,
Leavitt
,
B.J.
,
Allen
,
P.D.
,
Haeberle
,
J.R.
and
Alpert
,
N.R.
(
1992
)
Alteration of contractile function and excitation-contraction coupling in dilated cardiomyopathy
.
Circ. Res.
70
,
1225
1232
doi:
31
Du
,
J.
,
Xie
,
J.
,
Zhang
,
Z.
,
Tsujikawa
,
H.
,
Fusco
,
D.
,
Silverman
,
D.
et al.  (
2010
)
TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation
.
Circ. Res.
106
,
992
1003
doi:
32
Davis
,
J.
,
Burr
,
A.R.
,
Davis
,
G.F.
,
Birnbaumer
,
L.
and
Molkentin
,
J.D.
(
2012
)
A TRP6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo
.
Dev. Cell.
23
,
705
715
doi:
33
Adapala
,
R.K.
,
Thoppil
,
R.J.
,
Luther
,
D.J.
,
Paruchuri
,
S.
,
Meszaros
,
J.G.
,
Chilian
,
W.M.
et al.  (
2013
)
TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals
.
J. Mol. Cell Cardiol.
54
,
45
52
doi:
34
Rahaman
,
S.O.
,
Grove
,
L.M.
,
Paruchuri
,
S.
,
Southern
,
B.D.
,
Abraham
,
S.
,
Niese
,
K.A.
et al.  (
2014
)
TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
.
Journal of Clinical Investigation
124
,
5225
5238
doi:
35
Seth
,
M.
,
Zhang
,
Z.S.
,
Mao
,
L.
,
Graham
,
V.
,
Burch
,
J.
,
Stiber
,
J.
et al.  (
2009
)
TRPC1 channels are critical for hypertrophic signaling in the heart
.
Circ. Res.
105
,
1023
1030
doi:
36
Wu
,
X.
,
Eder
,
P.
,
Chang
,
B.
and
Molkentin
,
J.D.
(
2010
)
TRPC channels are necessary mediators of pathologic cardiac hypertrophy
.
Proc. Natl Acad. Sci. USA
107
,
7000
7005
doi:
37
Kuwahara
,
K.
,
Wang
,
Y.
,
McAnally
,
J.
,
Richardson
,
J.A.
,
Bassel-Duby
,
R.
,
Hill
,
J.A.
et al.  (
2006
)
TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling
.
J. Clin. Invest.
116
,
3114
3126
doi:
38
Lou
,
Q.
,
Janardhan
,
A.
and
Efimov
,
I.R.
(
2012
)
Remodeling of calcium handling in human heart failure
.
Adv. Exp. Med. Biol.
740
,
1145
1174
. doi:
39
Israeli-Rosenberg
,
S.
,
Manso
,
A.M.
,
Okada
,
H.
and
Ross
,
R.S.
(
2014
)
Integrins and integrin-associated proteins in the cardiac myocyte
.
Circ. Res.
114
,
572
586
doi:
40
Wolfenson
,
H.
,
Lavelin
,
I.
and
Geiger
,
B.
(
2013
)
Dynamic regulation of the structure and functions of integrin adhesions
.
Dev. Cell
24
,
447
458
doi:
41
Samarel
,
A.M.
(
2005
)
Costameres, focal adhesions, and cardiomyocyte mechanotransduction
.
Am. J. Physiol. Heart Circ. Physiol.
289
,
H2291
H2301
doi:
42
Hynes
,
R.O.
(
1992
)
Integrins: versatility, modulation, and signaling in cell adhesion
.
Cell
69
,
11
25
doi:
43
Bökel
,
C.
and
Brown
,
N.H.
(
2002
)
Integrins in development: moving on, responding to, and sticking to the extracellular matrix
.
Dev. Cell
3
,
311
321
. doi:
44
Ross
,
R.S.
and
Borg
,
T.K.
(
2001
)
Integrins and the myocardium
.
Circ. Res.
88
,
1112
1119
doi:
45
McCain
,
M.L.
and
Parker
,
K.K.
(
2011
)
Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function
.
Pflugers Arch., Eur. J. Physiol.
462
,
89
104
doi:
46
Calderwood
,
D.A.
(
2004
)
Talin controls integrin activation
.
Biochem. Soc. Trans.
32
,
434
437
doi:
47
Lui
,
S.
,
Caldenwook
,
D.A.
and
Ginsberg
,
M.H.
(
2000
)
Integrin cytoplasmic domain-binding proteins
.
J. Cell Sci.
113
(
Pt 20
),
3563
3571
PMID:
[PubMed]
48
Srivastava
,
D.
and
Yu
,
S.
(
2006
)
Stretching to meet needs: integrin-linked kinase and the cardiac pump
.
Genes Dev.
20
,
2327
2331
doi:
49
Giannone
,
G.
,
Ronde
,
P.
,
Gaire
,
M.
,
Beaudouin
,
J.
,
Haiech
,
J.
,
Ellenberg
,
J.
et al.  (
2004
)
Calcium rises locally trigger focal adhesion disassembly and enhance residency of focal adhesion kinase at focal adhesions
.
J. Biol. Chem.
279
,
28715
28723
doi:
50
Ren
,
X.D.
,
Kiosses
,
W.B.
,
Sieg
,
D.J.
,
Otey
,
C.A.
,
Schlaepfer
,
D.D.
and
Schwarts
,
M.A.
(
2000
)
Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover
.
J. Cell Sci.
113
,
3673
3678
PMID:
[PubMed]
51
Fassler
,
R.
,
Rohwedel
,
J.
,
Maltsev
,
V.
,
Bloch
,
W.
,
Lentini
,
S.
,
Guan
,
K.
et al.  (
1996
)
Differentiation and integrity of cardiac muscle cells are impaired in the absence of β1 integrin
.
J. Cell Sci.
109
,
2989
2999
PMID:
[PubMed]
52
Delon
,
I.
and
Brown
,
N.H.
(
2007
)
Integrins and the actin cytoskeleton
.
Curr. Opin. Cell Biol.
19
,
43
50
doi:
53
Galbraith
,
C.G.
,
Yamada
,
K.M.
and
Sheetz
,
M.P.
(
2002
)
The relationship between force and focal complex development
.
J. Cell Biol.
159
,
695
705
doi:
54
Chicurel
,
M.E.
,
Singer
,
R.H.
,
Meyer
,
C.J.
and
Ingber
,
D.E.
(
1998
)
Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions
.
Nature
392
,
730
733
doi:
55
Pines
,
M.
,
Das
,
R.
,
Ellis
,
S.J.
,
Morin
,
A.
,
Czerniecki
,
S.
,
Yuan
,
L.
et al.  (
2012
)
Mechanical force regulates integrin turnover in Drosophila in vivo
.
Nat. Cell Biol.
14
,
935
943
doi:
56
Babbitt
,
C.J.
,
Shai
,
S.Y.
,
Harpf
,
A.E.
,
Pham
,
C.G.
,
Ross
,
R.S.
(
2002
)
Modulation of integrins and integrin signaling molecules in the pressure-loaded murine ventricle
.
Histochem. Cell Biol.
118
,
431
439
57
Roca-Cusachs
,
P.
,
Iskratsch
,
T.
and
Sheetz
,
M.P.
(
2012
)
Finding the weakest link — exploring integrin-mediated mechanical molecular pathways
.
J. Cell Sci.
125
,
3025
3038
doi:
58
Maron
,
B.J.
and
Ferrans
,
V.J.
(
1973
)
Significance of multiple intercalated discs in hypertrophied human myocardium
.
Am. J. Pathol.
73
,
81
96
PMID:
[PubMed]
59
Matsson
,
H.
,
Eason
,
J.
,
Bookwalter
,
C.S.
,
Klar
,
J.
,
Gustavsson
,
P.
,
Sunnegardh
,
J.
et al.  (
2007
)
Alpha-cardiac actin mutations produce atrial septal defects
.
Hum. Mol. Genet.
17
,
256
265
doi:
60
Ching
,
Y.H.
,
Ghosh
,
T.K.
,
Cross
,
S.J.
,
Packham
,
E.A.
,
Honeyman
,
L.
,
Loughna
,
S.
et al.  (
2005
)
Mutation in myosin heavy chain 6 causes atrial septal defect
.
Nat. Genet.
37
,
423
428
doi:
61
Hershberger
,
R.E.
,
Parks
,
S.B.
,
Kushner
,
J.D.
,
Li
,
D.
,
Ludwigsen
,
S.
,
Jakobs
,
P.
et al.  (
2008
)
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy
.
Clin. Transl. Sci.
1
,
21
26
doi:
62
Clark
,
E.A.
and
Brugge
,
J.S.
(
1995
)
Integrins and signal transduction pathways: the road taken
.
Science
268
,
233
239
doi:
63
Shai
,
S.Y.
,
Harpf
,
A.E.
,
Babbitt
,
C.J.
,
Jordan
,
M.C.
,
Fishbein
,
M.C.
,
Chen
,
J.
et al.  (
2002
)
Cardiac myocyte-specific excision of the β1 integrin gene results in myocardial fibrosis and cardiac failure
.
Circ. Res.
90
,
458
464
doi:
64
Knöll
,
R.
,
Postel
,
R.
,
Wang
,
J.
,
Krätzner
,
R.
,
Hennecke
,
G.
,
Vacaru
,
A.M.
et al.  (
2007
)
Laminin-α4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells
.
Circulation
116
,
515
525
doi:
65
Zhu
,
H.
,
Zhang
,
W.
,
Zhong
,
M.
,
Zhang
,
G.
and
Zhang
,
Y.
(
2011
)
Differential gene expression during atrial structural remodeling in human left and right atrial appendages in atrial fibrillation
.
Acta Biochim. Biophys. Sin.
43
,
535
541
doi:
66
Grossman
,
W.
,
Jones
,
D.
and
McLaurin
,
L.P.
(
1975
)
Wall stress and patterns of hypertrophy in the human left ventricle
.
J. Clin. Invest.
56
,
56
64
doi:
67
Boheler
,
K.R.
and
Dillmann
,
W.H.
(
1988
)
Cardiac response to pressure overload in the rat: the selective alteration of in vitro directed RNA translation products
.
Circ. Res.
63
,
448
456
doi:
68
Schwartz
,
K.
,
de la Bastie
,
D.
,
Bouveret
,
P.
,
Oliviero
,
P.
,
Alonso
,
S.
and
Buckingham
,
M.
(
1986
)
Alpha-skeletal muscle actin mRNA's accumulate in hypertrophied adult rat hearts
.
Circ. Res.
59
,
551
555
doi:
69
Izumo
,
S.
,
Lompré
,
A.-M.
,
Matsuoka
,
R.
,
Koren
,
G.
,
Schwartz
,
K.
,
Nadal-Ginard
,
B.
et al.  (
1987
)
Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals
.
J. Clin. Invest.
79
,
970
977
doi:
70
Ehsani
,
A.A.
,
Hagberg
,
J.M.
and
Hickson
,
R.C.
(
1978
)
Rapid changes in left ventricular dimensions and mass in response to physical conditioning and deconditioning
.
Am. J. Cardiol.
42
,
52
56
doi:
71
Maron
,
B.J.
,
Pelliccia
,
A.
,
Spataro
,
A.
and
Granata
,
M.
(
1993
)
Reduction in left ventricular wall thickness after deconditioning in highly trained Olympic athletes
.
Br. Heart J.
69
,
125
128
doi:
72
Shiojima
,
I.
,
Sato
,
K.
,
Izumiya
,
Y.
,
Schiekofer
,
S.
,
Ito
,
M.
,
Liao
,
R.
et al.  (
2005
)
Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure
.
J. Clin. Invest.
115
,
2108
2118
doi:
73
Mirotsou
,
M.
,
Dzau
,
V.J.
,
Pratt
,
R.E.
and
Weinberg
,
E.O.
(
2006
)
Physiological genomics of cardiac disease: quantitative relationships between gene expression and left ventricular hypertrophy
.
Physiol. Genomics
27
,
86
94
doi:
74
Abel
,
E.D.
and
Doenst
,
T.
(
2011
)
Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy
.
Cardiovas. Res.
90
,
234
242
doi:
75
Rimbaud
,
S.
,
Garnier
,
A.
and
Ventura-Clapier
,
R.
(
2009
)
Mitochondrial biogenesis in cardiac pathophysiology
.
Pharmacol. Rep.
61
,
131
138
doi:
76
Ventura-Clapier
,
R.
,
Garnier
,
A.
and
Veksler
,
V.
(
2004
)
Energy metabolism in heart failure
.
J. Physiol.
555
(
Pt 1
),
1
13
doi:
77
Borg
,
T.K.
and
Caulfield
,
J.B.
(
1981
)
The collagen matrix of the heart
.
Fed. Proc.
40
,
2037
2041
PMID:
[PubMed]
78
Weber
,
K.T.
,
Janicki
,
J.S.
,
Shroff
,
S.G.
,
Pick
,
R.
Chen
,
R.M.
and
Bashey
,
R.I.
(
1988
)
Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium
.
Circ. Res.
62
,
757
765
doi:
79
Niland
,
S.
,
Westerhausen
,
C.
,
Schneider
,
S.W.
,
Eckes
,
B.
,
Schneider
,
M.F.
and
Eble
,
J.A.
(
2011
)
Biofunctionalization of a generic collagenous triple helix with the α2β1 integrin binding site allows molecular force measurements
.
Int. J. Bioch. Cell Biol.
43
,
721
731
doi:
80
Ng
,
C.P.
,
Hinz
,
B.
and
Swartz
,
M.A.
(
2005
)
Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro
.
J. Cell Sci.
118
,
4731
4739
doi:
81
Clancy
,
R.M.
,
Zheng
,
P.
,
O'Mahony
,
M.
,
Izmirly
,
P.
,
Zavadil
,
J.
,
Gardner
,
L.
et al.  (
2007
)
Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: implications for progression to scarring in autoimmune-associated congenital heart block
.
Arthritis Rheum.
56
,
4120
4131
doi:
82
Berk
,
B.C.
,
Fujiwara
,
K.
and
Lehoux
,
S.
(
2007
)
ECM remodeling in hypertensive heart disease
.
J. Clin. Invest.
117
,
568
575
doi:
83
Rossi
,
M.A.
(
1998
)
Pathologic fibrosis and connective tissue matrix in left ventricular hypertrophy due to chronic arterial hypertension in humans
.
J. Hypertens.
16
,
1031
1041
doi:
84
Silver
,
M.A.
,
Pick
,
R.
,
Brilla
,
C.G.
,
Jalil
,
J.E.
,
Janicki
,
J.S.
and
Weber
,
K.T.
(
1990
)
Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis
.
Cardiovasc. Res.
24
,
741
747
doi:
85
Brouwer
,
W.P.
,
van Dijk
,
S.J.
,
Stienen
,
G.J.M.
,
van Rossum
,
A.C.
,
van der Velden
,
J.
and
Germans
,
T.
(
2011
)
The development of familial hypertrophic cardiomyopathy: from mutation to bedside
.
Eur. J. Clin. Invest.
41
,
568
578
doi:
86
Watanabe
,
S.
,
Shite
,
J.
,
Takaoka
,
H.
,
Shinke
,
T.
,
Tanino
,
Y.
,
Otake
,
H.
et al.  (
2011
)
Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure
.
J. Cardiol.
58
,
245
252
doi:
87
Ho
,
C.Y.
,
López
,
B.
,
Coelho-Filho
,
O.R.
,
Lakdawala
,
N.K.
,
Cirino
,
A.L.
,
Jarolim
,
P.
et al.  (
2010
)
Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy
.
N. Engl. J. Med.
363
,
552
563
doi:
88
Hanna
,
W.T.
(
1973
)
A simulation of human heart function
.
Biophys. J.
13
,
603
621
doi:
89
Yin
,
F.C.P.
(
1981
)
Ventricular wall stress
.
Circ. Res.
49
,
829
842
doi:
90
Nielsen
,
P.M.
,
Le Grice
,
I.J.
,
Smaill
,
B.H.
and
Hunter
,
P.J.
(
1991
)
Mathematical model of geometry and fibrous structure of the heart
.
Am. J. Physiol.
260
(
4 Pt 2
),
H1365
H1378
PMID:
[PubMed]
91
Vetter
,
F.J.
and
McCulloch
,
A.D.
(
1998
)
Three-dimensional analysis of regional cardiac function: a model of rabbit ventricular anatomy
.
Prog. Biophys. Mol. Biol.
69
,
157
183
doi:
92
Hunter
,
P.J.
,
McCulloch
,
A.D.
and
ter Keurs
,
H.E.
(
1998
)
Modelling the mechanical properties of cardiac muscle
.
Prog. Biophys. Mol. Biol.
69
,
289
331
doi:
93
Stevens
,
C.
,
Remme
,
E.
,
LeGrice
,
I.
and
Hunter
,
P.
(
2003
)
Ventricular mechanics in diastole: material parameter sensitivity
.
J. Biomech.
36
,
737
748
doi:
94
McCulloch
,
A.D.
(
2000
)
Modeling cardiac structure-function relationship in silico
.
Int. J. Bioelectrom.
2
,
2
PMID:
[PubMed]
95
Vetter
,
F.J.
,
Rogers
,
J.M.
and
McCulloch
,
A.D.
(
1998
)
A finite element model of passive mechanics and electrical propagation in the rabbit ventricles
.
Comp. Cardiol.
1998
,
705
708
doi:
96
Kekenes-Huskey
,
P.M.
,
Liao
,
T.
,
Gillette
,
A.K.
,
Hake
,
J.E.
,
Zhang
,
Y.
,
Michailova
,
A.P.
et al.  (
2013
)
Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice
.
Biophys. J.
105
,
2130
2140
doi:
97
Liao
,
T.
,
Zhang
,
Y.
,
Kekenes-Huskey
,
P.M.
,
Cheng
,
Y.
,
Michailova
,
A.
,
McCulloch
,
A.D.
et al.  (
2013
)
Multi-core CPU or GPU-accelerated multiscale modeling for biomolecular complexes
.
Mol. Based Math. Biol.
1
,
164
179
doi:
98
Luo
,
C.-H.
and
Rudy
,
Y.
(
1994
)
A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes
.
Circ. Res.
74
,
1071
1096
doi:
99
Morotti
,
S.
,
Edwards
,
A.G.
,
McCulloch
,
A.D.
,
Bers
,
D.M.
and
Grandi
,
E.
(
2014
)
A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII
.
J. Physiol.
592
,
1181
1197
doi:
100
Burton
,
R.A.B.
,
Plank
,
G.
,
Schneider
,
J.E.
,
Grau
,
V.
,
Ahammer
,
H.
,
Keeling
,
S.L.
et al.  (
2006
)
Three-dimensional models of individual cardiac histoanatomy: tools and challenges
.
Ann. N Y Acad. Sci.
1080
,
301
319
doi:
101
Aslanidi
,
O.V.
,
Nikolaidou
,
T.
,
Jichao
,
Z.J.
,
Smaill
,
B.H.
,
Gilbert
,
S.H.
,
Holden
,
A.V.
et al.  (
2013
)
Application of micro-computed tomography with iodine staining to cardiac imaging, segmentation, and computational model development
.
IEEE Trans. Med. Imaging
32
,
8
17
doi:
102
Lopez-Perez
,
A.
,
Sebastian
,
R.
and
Ferrero
,
J.M.
(
2015
)
Three-dimensional cardiac computational modelling: methods, features and applications
.
BioM. Eng. Online
14
,
35
doi:
103
Ingber
,
D.E.
(
2008
)
Tensegrity-based mechanosensing from macro to micro
.
Prog. Biophy. Mol. Biol.
97
,
163
179
. doi:
104
Grosberg
,
A.
,
Kuo
,
P.-L.
,
Guo
,
C.-L.
,
Geisse
,
N.A.
,
Bray
,
M.-A.
,
Adams
,
W.J.
et al.  (
2011
)
Self-organization of muscle cell structure and function
.
PLoS Comp. Biol.
7
,
e1001088
doi:
105
Rizki
,
T.
(
1978
) The circulatory system and associated cells and tissues. In
The Genetics and Biology of Drosophila
(
Ashburner
,
M.
and
Wright
,
T.R.F.
, eds), pp.
397
448
,
Academic Press
,
New York
106
Choma
,
M.A.
,
Suter
,
M.J.
,
Vakoc
,
B.J.
,
Bouma
,
B.E.
and
Tearney
,
G.J.
(
2011
)
Physiological homology between Drosophila melanogaster and vertebrate cardiovascular systems
.
Dis. Models Mech.
4
,
411
420
doi:
107
Rugendorff
,
A.
,
Younossi-Hartenstein
,
A.
and
Hartenstein
,
V.
(
1994
)
Embryonic origin and differentiation of the Drosophila heart
.
Roux's Arch. Dev. Biol.
203
,
266
280
doi:
108
Bodmer
,
R.
and
Venkatesh
,
T.V.
(
1998
)
Heart development in Drosophila and vertebrates: conservation of molecular mechanisms
.
Dev. Genet.
22
,
181
186
doi:
109
Harvey
,
R.P.
(
1996
)
NK-2Homeobox genes and heart development
.
Dev. Biol.
178
,
203
216
doi:
110
Ocorr
,
K.
,
Perrin
,
L.
,
Lim
,
H.-Y.
,
Qian
,
L.
,
Wu
,
X.
and
Bodmer
,
R.
(
2007
)
Genetic control of heart function and aging in Drosophila
.
Trends Card. Med.
17
,
177
182
doi:
111
Azpiazu
,
N.
and
Frasch
,
M.
(
1993
)
Tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila
.
Genes Dev.
7
,
1325
1340
doi:
112
Lalevée
,
N.
,
Monier
,
B.
,
Sénatore
,
S.
,
Perrin
,
L.
and
Sémériva
,
M.
(
2006
)
Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel
.
Curr. Biol.
16
,
1502
1508
doi:
113
Vanderploeg
,
J.
,
Vazquez Paz
,
L.L.
,
MacMullin
,
A.
and
Jacobs
,
J.R.
(
2012
)
Integrins are required for cardioblast polarisation in Drosophila
.
BMC Dev. Biol.
12
,
8
doi:
114
Nishimura
,
M.
,
Kumsta
,
C.
,
Kaushik
,
G.
,
Diop
,
S.B.
,
Ding
,
Y.
,
Bisharat-Kernizan
,
J.
et al.  (
2014
)
A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging
.
Aging Cell
13
,
431
440
doi:
115
Neely
,
G.G.
,
Kuba
,
K.
,
Cammarato
,
A.
,
Isobe
,
K.
,
Amann
,
S.
,
Zhang
,
L.
et al.  (
2010
)
A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function
.
Cell
141
,
142
153
doi:
116
Ma
,
L.
,
Bradu
,
A.
,
Podoleanu
,
A.G.
and
Bloor
,
J.W.
(
2010
)
Arrhythmia caused by a Drosophila tropomyosin mutation is revealed using a novel optical coherence tomography instrument
.
PLoS ONE
5
,
e14348
doi:
117
Wolf
,
M.J.
,
Amrein
,
H.
,
Izatt
,
J.A.
,
Choma
,
M.A.
,
Reedy
,
M.C.
and
Rockman
,
H.A.
(
2006
)
Drosophila as a model for the identification of genes causing adult human heart disease
.
Proc. Natl Acad. Sci. USA
103
,
1394
1399
doi:
118
Ma
,
L.
,
Zhang
,
M.
,
Chang
,
J.
,
Bloor
,
J.W.
,
Yang
,
X.
,
Zhang
,
J.J.
(
2016
)
Numerical Study of the Shear Stress and Pressure Force in Drosophila Larval.
Heart. Biosc. Rep.
(
in review
)
119
Brand
,
A.H.
and
Perrimon
,
N.
(
1993
)
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
.
Development
118
,
401
415
PMID:
[PubMed]
120
Reneman
,
R.S.
,
Arts
,
T.
and
Hoeks
,
A.P.G.
(
2006
)
Wall shear stress — an important determinant of endothelial cell function and structure — in the arterial system in vivo
.
J. Vasc. Res.
43
,
251
269
doi: