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Antagonism of contractile forces in left ventricular hypertrophy: a diagnostic challenge for better pathophysiological and clinical understanding
  1. Paul Peter Lunkenheimer1,
  2. Andreas Hagendorff2,
  3. Jean-Marc Lunkenheimer3,
  4. Hartmut Karl Gülker4 and
  5. Peter Niederer5
  1. 1Department of Experimental Thoracic, Cardiac and Vascular Surgery, University of Münster, Münster, Germany
  2. 2Department of Cardiology, University Hospital Leipzig, Leipzig, Germany
  3. 3Department of Cardiology, University Hospital Leipzig, Leipzig, Sachsen, Germany
  4. 4Department of Cardiology, HELIOS University Hospital Wuppertal, Wuppertal, Nordrhein-Westfalen, Germany
  5. 5Institute of Biomedical Engineering, University and ETH (Eidgenössische Technische Hochschule), Zürich, Switzerland
  1. Correspondence to Andreas Hagendorff; Andreas.Hagendorff{at}medizin.uni-leipzig.de

Abstract

Cardiac function is characterised by haemodynamic parameters in the clinical scenario. Due to recent development in imaging techniques, the clinicians focus on the quantitative assessment of left ventricular size, shape and motion patterns mostly analysed by echocardiography and cardiac magnetic resonance. Because of the physiologically known antagonistic structure and function of the heart muscle, the effective performance of the heart remains hidden behind haemodynamic parameters. In fact, a smaller component of oblique transmural netting of cardiac muscle fibres simultaneously engenders contracting and dilating force vectors, while the predominant mass of the tangentially aligned fibres only acts in one direction. In case of hypertrophy, an increased influence of the dilating transmural fibre component might counteract systolic wall thickening, thereby counteract cardiac output. A further important aspect is the response to inotropic stimulation that is different for the tangentially aligned fibre component in comparison to the transmural component. Both aspects highlight the importance to integrate the analysis of intramural fibre architecture into the clinical cardiac diagnostics.

  • Cardiac Imaging Techniques
  • Hypertension
  • Cardiomyopathy, Hypertrophic
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https://doi.org/10.1136/openhrt-2023-002351

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    Introduction

    Almost all biological systems usually have an antagonistic principle of function since counteracting components enable finely graduated adjustments of function by action and counteraction. A separate measurement of the intramural deformation of individual cardiac muscle fibres and their force development is not yet possible. Otto Frank has described the pressure–volume relations of the frog ventricle mainly in relation to the ventricular filling conditions.1 2 Patterson and Starling showed the relation between ventricular filling pressure and cardiac output3 analysing the impact of contractile forces due to ventricular preload. The analysis of the myocardial ultrastructure by electron microscopy and the correlation between morphological alterations and function of the sarcomeres4–6 gave insights into the tension–length relationship of the myocardial fibres. Assuming a strictly tangential arrangement of the fibre architecture within the ventricular walls, the prevailing opinion was determined that the vectors of contractile forces are exclusively parallel to the ventricular surface contour assuming no antagonism of contractile forces within the myocardium, which was not considered in Frank’s model of ventricular function.1 Therefore, currently used terms like myocardial contractility, myocardial wall stress calculated according to the Laplace equation7 and left ventricular (LV) stiffness determined non-invasively8 are discussed with respect to external work of the heart muscle, and not considering myocardial metabolism with its dependency on heart rate,9 which is necessary for plausibility.

    In clinical practice, cardiac function is characterised in haemodynamic terms of ventricular volumes—especially stroke volume—ejection fraction, heart rate, systemic and central venous blood pressure. Due to recent development in imaging techniques, the clinician focus on the quantitative assessment of ventricular size, shape and motion patterns mostly analysed by echocardiography and cardiac MRI (cMRI) targeting more insights into intramural dynamics.10–12 Using modern echocardiographic modalities, the analysis of different compounds of LV deformation including shear stress enables to elucidate intramural dynamics.13–15 Reflection patterns in echocardiography do not necessarily correspond to anatomical structures. However, these speckles are the basis for echocardiographic strain analyses. cMRI tagging and feature tracking can also visualise details of LV deformation without direct targeting of myocardial fibres. Preload, afterload and myocardial metabolism determine myocardial contractility and LV filling properties influenced by several parameters like LV wall thickness, LV wall stiffness and LV relaxation time. Nowadays, assessment of LV function is commonly performed by analysis of the load-dependent parameter LV ejection fraction and LV longitudinal strain. Myocardial work (MW) determined by non-invasive speckle tracking echocardiography combines LV contraction and afterload into a single parameter.13 16–18 Regional MW and regional glucose metabolism was shown to be correlated.19 Thus, this parameter might reflect the potential to characterise non-invasively regional myocardial energetics and enable new options to quantify LV energy waste.20 However, the analysis of MW is based on LV longitudinal strain as only one component of LV deformation. Thus, regional differences of MW allow conclusions about early subclinical abnormalities of myocardial function due to the main component of LV deformation, but it might be still uncertain to draw conclusions from regional MW about the functional state of myocardial fibres which are not contributing to longitudinal deformation. In this context, circumferential, radial and rotational strain analysis is an additional promising tool to analyse the underlying fibre architecture. The active myocardial performance is characterised by two components, constructive and wasted MW, which is strongly correlated to segmental cardiac glucose metabolism. In the clinical scenario, positron emission tomography (PET) with the radiotracer 18F-fluorodeoxyglucose (FDG) is possible in special centres for imaging glucose metabolism.21 However, FDG–PET is mostly used for the detection of viable myocardium in coronary heart disease to distinguish between hibernating, stunning and scar.22 This method is limited due to the non-ubiquitous availability, the high costs and the long investigation time required. The combination of FDG-PET and CMR is rarely described, and the potential clinical utility concerns the detection of myocardial viability, inflammation and specific diseases like sarcoidosis.23 Pathological patterns of MW as well as of reduced glucose metabolism again describe impaired regional myocardial function,21 24 25 which cannot be assigned to specific fibre strands of the myocardial architecture.

    Spirometry estimates global cardiac efficiency in the clinical setting and can distinguish between the causes of limited physical activity, which can be due to cardiac, pulmonary, cerebral or peripheral limitations.26 Even in normal or subclinical conditions, symptoms of exhaustion during stress are fatigue, pain in the peripheral muscles, angina and dyspnoea, which cannot be necessarily assigned to cardiac origin because no sensation subjectively indicates the limits of a healthy heart. Only stress-induced myocardial ischaemia can be detected with relative certainty by reduced regional perfusion with consecutive wall motion abnormalities.

    In clinical settings, the quantification of regional LV deformation is currently possible (figure 1). However, technical improvements of modern cardiac imaging will certainly be able to determine the individual components of intramural geometry of the singular muscle fibres and their energetic state as special factors of intramural contractility in future. The assignment between increased LV wall thickness and cardiac diseases like hypertrophy, oedema, fibrosis and/or storage diseases will surely distinguish between pathological and normal conditions. Therefore, pathological LV hypertrophy and the athlete’s heart as a physiological enlargement of the cardiac cavities can serve as models to gain a better understanding of different mechanisms involved in cardiac deformation and LV remodelling under pathological conditions.

    Figure 1
    Figure 1

    Modalities of non-invasive cardiac imaging by echocardiography and cMRI: (A) regional longitudinal layer strain determined in an apical four-chamber view, (B) regional circumferential layer strain determined in a parasternal short axis view at papillary muscle level, (C) regional radial layer strain determined in a parasternal short axis view at papillary muscle level, (D) cMRI tagging sequences in an apical (above) and basal (below) short axis view to analyse left ventricular rotation. cMRI, cardiac MRI.

    Myocardial morphology and functional anatomy

    During the last 50 years, morphological research unanimously has shown that the parallel alignment of the myocardial fibres based on Frank’s understanding must be replaced by associations of sequentially splitted myocytes forming a continuous spatial network of endless chains of myocytes with no origin or insertion (figure 2).27–34

    Figure 2
    Figure 2

    Cardiodynamic models: (A) Frank’s concentric stress model postulates unidirectional concentric forces and hence anticipates an exclusively tangential alignment of endless chains of myocytes. (B) The antagonistic stress model refers to the continuum of spatially netted myocardium. A segment of the ventricular wall has been divided into five layers to show the layered turn of endless chains of myocytes in helix angles. Superimposed layers are joined by dense transmural netting, which latter develops endo-epicardial, dilatory forces. (C) Histological cross-section through the free wall of the porcine heart in plane with the ventricular base. For better discrimination of the pattern of netting, the myocardium had previously been pneumatically distended by coronary perfusion with compressed air. The section shows (left) a thick subendocardial, densely netted myocardial network with a steep bending towards the endocardium, (mid) a thin layer of circular (vertical) endless chains of myocytes and (right) a small subepicardial layer of endless chains of myocytes which are moderately steep inclined towards the epicardium. (D) The tangential histological section through the left ventricular free wall of a porcine heart shows the prevailing striation, which, however, appears somewhat fuzzy because of the dense in-plane netting of the endless chains of myocytes.

    Less than a hundred chains are bundled and surrounded by connective tissue to form aggregates with muscle fibres of different orientation35 (figure 3). Smaller fibres of endless chains form the connection between respective aggregates as a strong network between two adjacent entities. Within an aggregate, each segment of an endless chain of myocytes contributes to the particular shaping.

    Figure 3
    Figure 3

    Electron-microscopic cross-section through three neighbouring flat aggregates joined by fine connective tissue which allows gliding of the aggregates against one another. The shape of cross-sections of single myocytes within the aggregates varies depending on how the angle of the section plane is oriented to the aggregate section plane.

    Diffusion tension MRI analysis of mural architecture revealed that the orientation of typically 70% of the endless chains are essentially aligned parallel to the ventricular surface.33 34 36 However, the remaining 30% of the aggregates of muscle fibres significantly deviate from the tangential orientation ‘intruding’ towards the endocardium or ‘extruding’ towards the epicardium.33 34 36

    The distribution of local forces

    Invasive multifocal measurement of local forces revealed a heterogeneous pattern of actively developed forces of aggregates depending on their spatial orientation within the myocardium. To elucidate the distribution of forces throughout the ventricular walls, needle force probes, 1.3 mm thick and up to 15 mm long,37 38 have been implanted into the walls of beating hearts, each aligned in right angle to the striation of the layered order of myocardial aggregates (figure 4). With the experience of several thousand experiments on dogs, pigs and rabbits,39 we also did measurements on patients during cardiac surgery in agreement with ethical standards.40 41

    Figure 4
    Figure 4

    Miniaturised needle force probe; 15 mm long, 1.3 mm thick, (1) strain gauge, (2) bending beam, (3) temperature sensor, (4) pointed end of the needle probe, (5) side window serving as escape-fluid, (6) outer tube and (7) support of the bending beam.

    Recorded force signals mirror the different functions of the aggregates to which the force probe was coupled. An afterloaded (=auxotonic) signal, which rose during the entire ejection period and outlasted the LV end-systolic pressure drop (figure 5), was measured when the force probe was coupled to oblique transmurally aligned aggregates. In contrast, the predominant mass of surface-parallel aggregates generated an ‘unloading signal’, which slightly dropped from the beginning of ejection. Its end-systolic decay run parallel to LV pressure drop.

    Figure 5
    Figure 5

    Histological cross-section through the porcine heart near the apex exposing in the pneumatically distended myocardium tangential and oblique transmural netting. Auxotonic forces (upper left and right) are measured in oblique transmural netting depending on the angle of deflection from the tangential. The unloading force (lower right) is measured in the tangential structure.

    The predominant tangentially aligned muscle aggregates generate the constrictive forces causing ventricular ejection and dominate wall deformation. Auxotonic dilatory forces impede ventricular constriction mitigating regional wall thickening during systole. The transmural deflection of non-tangential chains of muscle aggregates increases in line with wall thickening. This process reaches the maximum at end-systole. With further wall thickening in myocardial hypertrophy, transmural deviation of several subendocardial intruding aggregates exceeds 45°. Measured dilatory forces increase with rising intruding or extruding inclination of non-tangential aggregates.42 Therefore, the ratio of contracting to dilating forces increases within the complete heart cycle particularly in the subendocardial layers of spiralling chains of aggregates. This scenario is particularly pronounced in the hypertrophic heart.

    Antagonistic structure and function of the heart muscle

    Tangential structures generate ventricular constrictive forces, while intruding and extruding network components simultaneously generate a constrictive and a dilatory force vector (figure 2).39 Therefore, the myocardial structure obviously sustains an antagonistic function. Dominant contracting forces are opposed to dilatory forces, both cooperating as a functional unit. In the normal heart, mutual interaction is an equilibrium, though it varies continuously during the cardiac cycle. This equilibrium persists during phasic myocardial realignment as a continuously repetition. However, it is prone to derail in the diseased heart.

    Contractile function of each single myocyte is continuously controlled according to the Frank-Starling mechanism,1 7 43 which is partly linked to the intraventricular pressure, partly varies in local-specific dimensions by force of mutual interaction of tangential and non-tangential netting components. The van Anrep44 effect delivers additional energy when focal, late-systolic loading conditions exceed existing afterload. Thus, haemodynamic preload and afterload is supplemented by an intrinsic preload and afterload. This intrinsic preload and afterload are tuned by local specific antagonistic activity which varies with spatial alignment of chains of aggregates. The heterogeneous distribution of intrinsic ventricular loading cannot be analysed in the clinical scenario.

    An active contractile limitation of wall thickening by oblique transmural netting is essential part of ventricular shaping. Though endless chains of myocytes connect aggregates with each other to form a continuum, they primarily contribute to the function of the respective host aggregate. Each segment of an endless chain of myocytes bundled within an aggregate, serves shaping it according to local geometry and coupling conditions. Therefore, the one aggregate generates an unloading force, the next an auxotonic force.

    This kind of interaction also applies to the global heart muscle while actively contracting in longitudinal, circumferential and radial directions. Active shortening in longitudinal and circumferential direction necessarily causes a passive increase in wall thickness. Active wall thinning necessarily causes passive longitudinal and circumferential elongation. This spatial interaction mutually tunes the preload and afterload in neighbouring areas throughout the myocardial continuum.

    Selective sensitivity to positive and negative inotropes at low dosage

    A hitherto unknown feature of obliquely intruding and extruding aggregates is their statistically higher sensitivity to low-dosed positive and negative inotropic stimulation than that of tangential aggregates (figure 6).40 41 45 This asymmetric response to inotropes applies only to low-dose therapy with catecholamine and ß-blockers. In contrast, oblique transmural and tangential aggregates show identical sensitivity to currently used high doses of positive and negative inotropes. Asymmetric sensitivity to low-dosed inotropic medication primarily enables to manipulate selectively the inotropic state of the intruding and extruding aggregates.46 47 While interacting with the prevailing tangential netting global ventricular myocardium must be involved. This hypothesis is supported by observations regarding pathological hypertrophy in the state of unbalanced antagonism48 49

    Figure 6
    Figure 6

    Asymmetrical response of focal myocardial netting to inotropes measured intraoperatively by two needle force probes in six patients. The first probe was coupled to tangential, constrictive aggregates (blue), the other was coupled to non-tangential, dilatory aggregates (red)). Sequential intravenous infusion of first low-dosed positive inotrope Dobutamine (15 µg/kg/min) and then a single dose of 20 mg of the negative inotrope ßblocker Esmolol showed statistically different sensitivity of both netting components to inotropes.

    Pathophysiological potential of selective sensitivity to inotropes

    The hypertrophied heart muscle is the result of an adaptive primarily physiological process in the presence of increased pressure or volume condition like in pregnancy or in response to continuous physical exertion. Clinical observations confirm that this adaptation is reversible. The process of pathological myocardial hypertrophy presumably cause an antagonistic imbalance with respect to contractile and dilatory forces of the muscle aggregates.

    In the scenario of permanently elevated level of positive inotropes triggering of selective hypertrophy of the dilatory active oblique transmural netting occurs.50 51Further impeding of wall thickening and an enhanced interaction within the netted continuum cause an increase in tangential forces. The consecutive hypertrophy of the tangential structures causes an increase of wall thickness.42 46 In consequence, transmural straightening of non-tangential netting increases and causes more antagonistic transmural dilatory forces. A self-enhancing process continues causing an imbalance of antagonistic forces and structures. This process probably finds its limitation by limited oxygen transport to tissue. In this context, the distribution of developed forces measured in hypertrophied porcine hearts is important.52 Contrary to the Laplace’s law, the forces are highest in the subendocardial layers of the spiral aggregates. The resulting compression and strangulation of myocardial microcirculation primarily occurs in the layers, in which coronary supply is limited anyway.

    The asymmetrical sensitivity to low dosed negative inotropes (figure 6) presumably provide a therapeutic approach. The effect of selective sensitivity of non-tangential netting components to low-dosed negative inotropes was described in the literature.40 41 45 In a case report, Emeis et al47 successfully treated a baby born with right ventricular hypertrophy. Under low-dosed ß-blockade, there was complete remission of hypertrophy. Obviously, the self-reinforcing process of myocardial hypertrophy has been interrupted by low dose ß-blockade.

    In the presence of increased LV wall thickness, it is a diagnostic challenge to distinguish between LV hypertrophy due to the physiological response to chronic physical stress or due to a pathological self-enhanced formation. Timely limited therapy with low dosed ß-blockers might be a tool of distinction.

    Summary and conclusion

    The presence of myocardial intrinsic antagonism limits a simplified view to regional myocardial deformation. LV ejection fraction solely does not provide sufficient information about global and regional LV contractility. Stroke volumes, intracavitary pressures and ventricular motion are not suitable to reflect intramural energetics or dynamics in detail. An increase of intramural performance relative to haemodynamic performance correlates with evolving LV hypertrophy. Stress-related LV performance is probably tuned by initially enhanced dilatory performance. Physiological and reversible LV hypertrophy presumably might be distinguished from pathological and irreversible LV hypertrophy as well as pathological LV wall thickness by modern diagnostic tools.53 53 54 The assessment of the spatial coordinates of single fibre strand seems to be helpful to understand the individual importance of myocardial architecture for the disease process in specific cardiac diseases,36 in which ventricular geometry is pathologically changed, for example, ischaemic heart disease,55 dilative and hypertrophic cardiomyopathy56 57 as well as takotsubo cardiomyopathy.58 59 Because non-tangential parts of fibre strands increase LV dilatation with increasing wall thickness,60 specific pharmacological interventions can address selected compounds of myocardial fibres to optimise muscle contractility. The predominant effect of low-dose beta-blockade on circumferential and radial shortening was documented with 3D tagging by CMR, which can be explained by the different compounds of the myocardial fibre architecture.46 New sophisticated modalities of deformation imaging18 24 and CMR tagging23 61 62 might be able to detect better pathological inhomogeneities in the architecture of the ventricular musculature in the future.

    Cardiac imaging diagnostic will certainly be improved considering the antagonism of contractile forces within the heart muscle.

    Ethics statements

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    Ethics approval

    Not applicable.

    References

    1. ↵
      1. Frank O
      . Isometrie und Isotonie des Herzmuskels. Z Biol 1901;41:14–34.
      OpenUrl
    2. ↵
      1. Frank O
      . On the dynamics of cardiac muscle. American Heart Journal 1959;58:282–317. doi:10.1016/0002-8703(59)90345-X
      OpenUrlCrossRefWeb of Science
    3. ↵
      1. Patterson SW,
      2. Starling EH
      . On the mechanical factors which determine the output of the ventricles. J Physiol 1914;48:357–79. doi:10.1113/jphysiol.1914.sp001669
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. KISCH B
      . The Sarcosomes of the heart. J Biophys Biochem Cytol 1956;2(4 Suppl):361–2. doi:10.1083/jcb.2.4.361
      OpenUrlFREE Full Text
    5. ↵
      1. Sonnenblick EH,
      2. Ross J,
      3. Covell JW, et al
      . The Ultrastructure of the heart in systole and diastole. Circulation Research 1967;21:423–31. doi:10.1161/01.RES.21.4.423
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. SONNENBLICK EH,
      2. SPIRO D,
      3. COTTRELL TS
      . Fine structural changes in heart muscle in relation of the Lengthtension curve. Proc Natl Acad Sci U S A 1963;49:193–200. doi:10.1073/pnas.49.2.193
      OpenUrlFREE Full Text
    7. ↵
      1. Laplace PS,
      2. Duprat JBM,
      3. Courcier L
      . Bachelier Charles-Louis-Étienne Huzard-Courcier Démophile Imprimerie de Crapelet (Paris France). Traité de Mécanique Céleste. A Paris A Paris Paris: Chez J.B.M. Duprat Libraire pour LES Mathématiques Quai des Augustins Chez Courcier Imprimeur-Libraire pour LES Mathématiques Quai des Augustins no 71 Bachelier (Successeur de Mme ve Courcier) Libraire Quai des Augustins no 55.
    8. ↵
      1. Chen CH,
      2. Fetics B,
      3. Nevo E, et al
      . Noninvasive single-beat determination of left ventricular end-systolic Elastance in humans. J Am Coll Cardiol 2001;38:2028–34. doi:10.1016/s0735-1097(01)01651-5
      OpenUrlFREE Full Text
    9. ↵
      1. Covell JW,
      2. Ross J,
      3. Taylor R, et al
      . Effects of increasing frequency of contraction on the force velocity relation of left ventricle. Cardiovascular Research 1967;1:2–8. doi:10.1093/cvr/1.1.2
      OpenUrlCrossRefPubMed
    10. ↵
      1. Lang RM,
      2. Badano LP,
      3. Mor-Avi V, et al
      . Recommendations for cardiac chamber Quantification by echocardiography in adults: an update from the American society of echocardiography and the European Association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–71. doi:10.1093/ehjci/jev014
      OpenUrlCrossRefPubMed
    11. ↵
      1. Petersen SE,
      2. Khanji MY,
      3. Plein S, et al
      . European Association of cardiovascular imaging expert consensus paper: a comprehensive review of cardiovascular magnetic resonance normal values of cardiac chamber size and aortic root in adults and recommendations for grading severity. Eur Heart J Cardiovasc Imaging 2019;20:1321–31. doi:10.1093/ehjci/jez232
      OpenUrlPubMed
    12. ↵
      1. Voigt J-U,
      2. Pedrizzetti G,
      3. Lysyansky P, et al
      . Definitions for a common standard for 2d speckle tracking echocardiography: consensus document of the EACVI/ASE/industry task force to standardize deformation imaging. European Heart Journal - Cardiovascular Imaging 2015;16:1–11. doi:10.1093/ehjci/jeu184
      OpenUrl
    13. ↵
      1. Russell K,
      2. Eriksen M,
      3. Aaberge L, et al
      . A novel clinical method for Quantification of regional left ventricular pressure–strain loop area: a non-invasive index of myocardial work. Eur Heart J 2012;33:724–33. doi:10.1093/eurheartj/ehs016
      OpenUrlCrossRefPubMed
    14. ↵
      1. Cvijic M,
      2. Bézy S,
      3. Petrescu A, et al
      . Interplay of cardiac remodelling and myocardial stiffness in hypertensive heart disease: a shear wave imaging study using high-frame rate echocardiography. Eur Heart J Cardiovasc Imaging 2020;21:664–72. doi:10.1093/ehjci/jez205
      OpenUrl
    15. ↵
      1. Caenen A,
      2. Pernot M,
      3. Nightingale KR, et al
      . Assessing cardiac stiffness using ultrasound shear wave Elastography. Phys Med Biol 2022;67:02TR01. doi:10.1088/1361-6560/ac404d
      OpenUrl
    16. ↵
      1. Boe E,
      2. Russell K,
      3. Eek C, et al
      . Non-invasive myocardial work index identifies acute coronary occlusion in patients with non-ST-segment elevation-acute coronary syndrome. Eur Heart J Cardiovasc Imaging 2015;16:1247–55. doi:10.1093/ehjci/jev078
      OpenUrlCrossRefPubMed
    17. ↵
      1. Galli E,
      2. John-Matthwes B,
      3. Rousseau C, et al
      . Echocardiographic reference ranges for myocardial work in healthy subjects: A preliminary study. Echocardiography 2019;36:1814–24. doi:10.1111/echo.14494
      OpenUrl
    18. ↵
      1. Zhu H,
      2. Guo Y,
      3. Wang X, et al
      . Myocardial work by speckle tracking echocardiography accurately assesses left ventricular function of coronary artery disease patients. Front Cardiovasc Med 2021;8:727389. doi:10.3389/fcvm.2021.727389
      OpenUrl
    19. ↵
      1. Ilardi F,
      2. D’Andrea A,
      3. D’Ascenzi F, et al
      . Myocardial work by echocardiography: principles and applications in clinical practice. JCM 2021;10:4521. doi:10.3390/jcm10194521
      OpenUrl
    20. ↵
      1. Marzlin N,
      2. Hays AG,
      3. Peters M, et al
      . Myocardial work in echocardiography. Circ Cardiovasc Imaging 2023;16:e014419. doi:10.1161/CIRCIMAGING.122.014419
    21. ↵
      1. Zuo Y,
      2. Badawi RD,
      3. Foster CC, et al
      . Multiparametric cardiac 18 F-FDG PET in humans: kinetic model selection and Identifiability analysis. IEEE Trans Radiat Plasma Med Sci 2020;4:759–67. doi:10.1109/trpms.2020.3031274
      OpenUrl
    22. ↵
      1. Camici PG,
      2. Prasad SK,
      3. Rimoldi OE
      . Stunning, Hibernation, and assessment of myocardial viability. Circulation 2008;117:103–14. doi:10.1161/CIRCULATIONAHA.107.702993
      OpenUrlFREE Full Text
    23. ↵
      1. Nazir MS,
      2. Ismail TF,
      3. Reyes E, et al
      . Hybrid positron emission tomography–magnetic resonance of the heart: Current state of the art and future applications. Eur Heart J Cardiovasc Imaging 2018;19:962–74. doi:10.1093/ehjci/jey090
      OpenUrl
    24. ↵
      1. Mahdiui ME,
      2. van der Bijl P,
      3. Abou R, et al
      . Myocardial work, an echocardiographic measure of post myocardial infarct scar on contrast-enhanced cardiac magnetic resonance. The American Journal of Cardiology 2021;151:1–9. doi:10.1016/j.amjcard.2021.04.009
      OpenUrl
    25. ↵
      1. Smiseth OA,
      2. Donal E,
      3. Penicka M, et al
      . How to measure left ventricular myocardial work by pressure–strain loops. Eur Heart J Cardiovasc Imaging 2021;22:259–61. doi:10.1093/ehjci/jeaa301
      OpenUrl
    26. ↵
      1. Glaab T,
      2. Taube C
      . Practical guide to cardiopulmonary exercise testing in adults. Respir Res 2022;23:9. doi:10.1186/s12931-021-01895-6
    27. ↵
      1. Sánchez-Quintana D,
      2. Climent V,
      3. Garcia-Martinez V, et al
      . Spatial arrangement of the heart muscle fascicles and Intramyocardial connective tissue in the Spanish fighting Bull (Bos Taurus). J Anat 1994;184 (Pt 2)(Pt 2):273–83.
      OpenUrl
    28. ↵
      1. Robinson ThomasF
      . Lateral connections between heart muscle cells as revealed by conventional and high voltage transmission electron microscopy. Cell Tissue Res 1980;211. doi:10.1007/BF00234392
    29. ↵
      1. Burg M,
      2. Lunkenheimer P,
      3. Niederer P, et al
      . Pneumatic distension of ventricular mural architecture validated histologically. Fortschr Röntgenstr 2016;188:1045–53. doi:10.1055/s-0042-115569
      OpenUrl
    30. ↵
      1. Streeter DD,
      2. Spotnitz HM,
      3. Patel DP, et al
      . Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339–47. doi:10.1161/01.res.24.3.339
      OpenUrlAbstract/FREE Full Text
    31. ↵
      1. Lunkenheimer PP,
      2. Redmann K,
      3. Kling N, et al
      . Three-dimensional architecture of the left ventricular myocardium. Anat Rec 2006;288A:565–78. doi:10.1002/ar.a.20326 Available: http://doi.wiley.com/10.1002/ar.a.v288a:6
      OpenUrlPubMed
    32. ↵
      1. Teh I,
      2. Burton RAB,
      3. McClymont D, et al
      . Mapping cardiac Microstructure of Rabbit heart in different mechanical States by high resolution diffusion Tensor imaging: A proof-of-principle study. Prog Biophys Mol Biol 2016;121:85–96. doi:10.1016/j.pbiomolbio.2016.06.001
      OpenUrl
    33. ↵
      1. Schmid P,
      2. Lunkenheimer PP,
      3. Redmann K, et al
      . Statistical analysis of the angle of intrusion of porcine ventricular myocytes from Epicardium to Endocardium using diffusion Tensor magnetic resonance imaging. Anat Rec 2007;290:1413–23. doi:10.1002/ar.20604 Available: http://doi.wiley.com/10.1002/ar.v290:11
      OpenUrlCrossRefPubMed
    34. ↵
      1. Smerup M,
      2. Agger P,
      3. Nielsen EA, et al
      . Regional and Epi- to Endocardial differences in Transmural angles of left ventricular cardiomyocytes measured in ex vivo pig hearts: functional implications: regional differences in myocardial structure. Anat Rec (Hoboken) 2013;296:1724–34. doi:10.1002/ar.22787 Available: http://doi.wiley.com/10.1002/ar.v296.11
      OpenUrl
    35. ↵
      1. Anderson RH,
      2. Ho SY,
      3. Sanchez-Quintana D, et al
      . Heuristic problems in defining the three-dimensional arrangement of the ventricular myocytes. Anat Rec 2006;288A:579–86. doi:10.1002/ar.a.20330 Available: http://doi.wiley.com/10.1002/ar.a.v288a:6
      OpenUrlPubMed
    36. ↵
      1. Schmid P,
      2. Jaermann T,
      3. Boesiger P, et al
      . Ventricular myocardial architecture as Visualised in postmortem swine hearts using magnetic resonance diffusion Tensor imaging. Eur J Cardiothorac Surg 2005;27:468–72. doi:10.1016/j.ejcts.2004.11.036
      OpenUrlCrossRefPubMed
    37. ↵
      1. Ising H,
      2. Lunkenheimer PP,
      3. Dannenberg H
      . A probe for measuring the myocardial tension (author’s Transl). Biomed Tech (Berl) 1974;19:24–7.
      OpenUrlPubMed
    38. ↵
      1. Lunkenheimer PP,
      2. Lunkenheimer A,
      3. Whimster WF, et al
      . Local myocardial and global ventricular function compared during positive inotropic medication. In: Jacob R, ed. Controversial issues in cardiac pathophysiology. Heidelberg: Steinkopff, 1986: 59–71. doi:10.1007/978-3-662-11374-5
    39. ↵
      1. Lunkenheimer PP,
      2. Redmann K,
      3. Florek J, et al
      . The forces generated within the musculature of the left ventricular wall. Heart 2004;90:200–7. doi:10.1136/hrt.2003.011650
      OpenUrlAbstract/FREE Full Text
    40. ↵
      1. Lunkenheimer PP,
      2. Redmann K,
      3. Cryer CW, et al
      . Beta-blockade at low doses restoring the physiological balance in Myocytic antagonism. Eur J Cardiothorac Surg 2007;32:225–30. doi:10.1016/j.ejcts.2007.03.048
      OpenUrlCrossRefPubMed
    41. ↵
      1. Redmann K,
      2. Lunkenheimer PP,
      3. Isringhaus H, et al
      . Quantitative assessment of the effects of ‘Inodilators’ on the myocardium in patients without primary cardiac insufficiency after coronary surgery: part I - Amrinone. Thorac Cardiovasc Surg 1991;39:123–8. doi:10.1055/s-2007-1013947
      OpenUrlPubMed
    42. ↵
      1. Nielsen E,
      2. Smerup M,
      3. Agger P, et al
      . Normal right ventricular three-dimensional architecture, as assessed with diffusion Tensor magnetic resonance imaging, is preserved during experimentally induced right ventricular hypertrophy. Anat Rec 2009;292:640–51. doi:10.1002/ar.20873 Available: http://doi.wiley.com/10.1002/ar.v292%3A5
      OpenUrlCrossRefPubMed
    43. ↵
      The Linacre lecture on the law of the heart given at Cambridge, 1915. Nature 1918;101:43. doi:10.1038/101043a0
    44. ↵
      1. Reil J-C,
      2. Reil G-H,
      3. Kovács Á, et al
      . Camkii activity contributes to Homeometric Autoregulation of the heart: A novel mechanism for the Anrep effect. J Physiol 2020;598:3129–53. doi:10.1113/JP279607
      OpenUrl
    45. ↵
      1. Lunkenheimer PP,
      2. Redmann K,
      3. Isringhaus H, et al
      . Cardiodynamic effects of dopamine and dobutamine. Thorac Cardiovasc Surg 1992;40:135–9. doi:10.1055/s-2007-1020131
      OpenUrlPubMed
    46. ↵
      1. Schmitt B,
      2. Li T,
      3. Kutty S, et al
      . Effects of incremental beta-blocker dosing on myocardial mechanics of the human left ventricle: MRI 3d-tagging insight into pharmacodynamics supports theory of inner antagonism. Am J Physiol Heart Circ Physiol 2015;309:H45–52. doi:10.1152/ajpheart.00746.2014
      OpenUrlCrossRefPubMed
    47. ↵
      1. Emeis M,
      2. Lunze FI,
      3. Miera O, et al
      . Congenital hypertrophy of the right ventricle successfully treated with very low dose beta blockers. Cardiol Cardiovasc Med 2020;04. doi:10.26502/fccm.92920172
    48. ↵
      1. Lunkenheimer PP,
      2. Niederer P,
      3. Stephenson RS, et al
      . What is the clinical significance of ventricular mural antagonism Eur J Cardiothorac Surg 2018;53:714–23. doi:10.1093/ejcts/ezx382
      OpenUrl
    49. ↵
      1. Peter N,
      2. Pp L
      . The mammalian heart – towards an understanding of the intrinsic antagonistic function of the ventricles. Physiother Res Rep 2018;1. doi:10.15761/PRR.1000115
    50. ↵
      1. Wittstein IS
      . Acute stress cardiomyopathy. Curr Heart Fail Rep 2008;5:61–8. doi:10.1007/s11897-008-0011-3
      OpenUrlCrossRefPubMed
    51. ↵
      1. Schnabel RB,
      2. Hasenfuß G,
      3. Buchmann S, et al
      . Heart and brain interactions: pathophysiology and management of Cardio-psycho-neurological disorders. Herz 2021;46:138–49. doi:10.1007/s00059-021-05022-5
      OpenUrl
    52. ↵
      1. Lunkenheimer PP,
      2. Redmann K,
      3. Dietl KH, et al
      . The assessment of intramural stress alignment on the beating heart in situ using micro-Ergometry: functional implications. Technol Health Care 1997;5:115–22.
      OpenUrl
    53. ↵
      1. Weidemann F,
      2. Niemann M,
      3. Ertl G, et al
      . The different faces of echocardiographic left ventricular hypertrophy: clues to the etiology. J Am Soc Echocardiogr 2010;23:793–801. doi:10.1016/j.echo.2010.05.020
      OpenUrlCrossRefPubMed
    54. ↵
      1. Hagendorff A,
      2. Helfen A,
      3. Brandt R, et al
      . Expert proposal to characterize cardiac diseases with normal or preserved left ventricular ejection fraction and symptoms of heart failure by comprehensive echocardiography. Clin Res Cardiol 2023;112:1–38. doi:10.1007/s00392-022-02041-y
      OpenUrl
    55. ↵
      1. Edwards NFA,
      2. Scalia GM,
      3. Shiino K, et al
      . Global myocardial work is superior to global longitudinal strain to predict significant coronary artery disease in patients with normal left ventricular function and wall motion. J Am Soc Echocardiogr 2019;32:947–57. doi:10.1016/j.echo.2019.02.014
      OpenUrlPubMed
    56. ↵
      1. Schrub F,
      2. Schnell F,
      3. Donal E, et al
      . Myocardial work is a Predictor of exercise tolerance in patients with dilated cardiomyopathy and left ventricular Dyssynchrony. Int J Cardiovasc Imaging 2020;36:45–53. doi:10.1007/s10554-019-01689-4
      OpenUrl
    57. ↵
      1. Galli E,
      2. Vitel E,
      3. Schnell F, et al
      . Myocardial constructive work is impaired in hypertrophic cardiomyopathy and predicts left ventricular fibrosis. Echocardiography 2019;36:74–82. doi:10.1111/echo.14210
      OpenUrlPubMed
    58. ↵
      1. Vitarelli A
      . Myocardial work and Takotsubo syndrome: stress affects work. Int J Cardiovasc Imaging 2022;38:1807–12. doi:10.1007/s10554-022-02655-3
      OpenUrl
    59. ↵
      1. Serena Migliarino SM,
      2. Giuseppe Iuliano GI,
      3. Mario Cristiano MC, et al
      . Evaluation of myocardial work index in predicting in-hospital complication in patients with Takotsubo syndrome. Eur Heart J Cardiovasc Imaging 2023;24(Supplement_1):416. doi:10.1093/ehjci/jead119.416
    60. ↵
      1. Bovendeerd PHM,
      2. Huyghe JM,
      3. Arts T, et al
      . Influence of Endocardial-Epicardial crossover of muscle fibers on left ventricular wall mechanics. Journal of Biomechanics 1994;27:941–51. doi:10.1016/0021-9290(94)90266-6
      OpenUrlCrossRefPubMedWeb of Science
    61. ↵
      1. Mekkaoui C,
      2. Huang S,
      3. Chen HH, et al
      . Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR Tractography framework and histological validation. J Cardiovasc Magn Reson 2012;14:70. doi:10.1186/1532-429X-14-70
      OpenUrlCrossRefPubMed
    62. ↵
      1. Nguyen C,
      2. Fan Z,
      3. Xie Y, et al
      . In vivo diffusion-Tensor MRI of the human heart on a 3 Tesla clinical scanner: an Optimized second order (M2) motion compensated diffusion-preparation approach: Optimized in vivo M2 DT-CMR for a 3t clinical scanner. Magn Reson Med 2016;76:1354–63. doi:10.1002/mrm.26380
      OpenUrl

    Footnotes

    • Contributors All authors made substantial contributions to the conception of the viewpoint and interpretation of data. PPL and PN conceived of the presented idea. PPL wrote the manuscript with support from AH, J-ML and HKG. AH contributed the topic clinical cardaic imaging. PPL and J-ML contributed the figures. PN took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.