The Ventricular Structure Functioning as an Antagonistic Continuum
Published Date: May 05, 2017
The Ventricular Structure Functioning as an Antagonistic Continuum
Lunkenheimer PP1*, Redmann K1, Hoffmeister A1, Niederer P2, Stephenson R3, Schmitt B4, Theilmann L5, Becker F6, and Anderson RH7
1Department of Experimental Cardiac- and Thoraco-Vascular Surgery, University Hospital Muenster, Germany
2Institute of Biomedical Engineering, ETH and University of Zürich, Switzerland
3Research Institute for Sports and Exercise Science, Liverpool John Moores University, United Kingdom
4Department of Congenital Heart Disease/ Paediatric Cardiology Deutsches Herzzentrum, Berlin, Germany
5Clinique for Anaesthesiology and Intensive Care University Hospital Muenster, Germany
6Department of Surgery, University Hospital Muenster, Germany
7Institute of Genetic Medicine, Newcastle University, United Kingdom
Paul Lunkenheimer, Former Head of the Department of Thoraco-Vascular and Cardiac Surgery University of Muenster, Domagkstr.11 Priv. Ahausweg 23 48161 Muenster, Germany, E-mail: P.P.Lunkenheimer@web.de
Citation: Lunkenheimer PP, Redmann K, Hoffmeister A, Niederer P, Stephenson R, et al. (2017) The Ventricular Structure Functioning as an Antagonistic Continuum. J Biomed Tech Res 3(1): 104.
The ventricular walls are known to exhibit a lamellar architecture. The lamellar units are composed of densely netted chains of cardiomyocytes. The main orientation of the cardiomyocytes within the lamellar units is surface-parallel, thereby enabling systolic ventricular constriction. The myocardium as a whole represents a structured continuum that comprises, nonetheless, 30 to 40% non- tangential netting with widely variable angles of transverse bending. This latter myocardial mass generates various degrees of auxotonic forces that partially act in dilatory direction. This fact led to the assumption that the ventricular myocardium produces inherently an active bi-directional drive. Referring to both experimental measurements and clinical observations, we present here evidence supporting the concept of an antagonistically functioning myocardial mass. Likewise, we consider local inhomogeneities found in the spatial distribution of the lamellar orientation to stabilize myocardial function. The antagonism, however, can be deleterious in the settings of ventricular hypertrophy and myocardial fibrosis. Auxotonically contracting muscle mass is particularly sensitive to negative inotropic medication, such as provided by low-dose-β-blockade. We propose a therapeutic pathway that can serve to interrupt the vicious circle which is the late consequence of any kind of ventricular hypertrophy.
Keywords: Antagonistic Continuum; Auxotonic Forces; Clinical Observations; Myocardial Mass
It is striking fact that in particular early diastolic dilation occurs as rapidly as systolic ventricular constriction, although it is often assumed that ventricular filling is mostly a passive process driven by the slow venous inflow. The premise of passivity dates back to Harvey , but it was Otto Frank, in 1901, who fostered the notion, arguing that all forces engendered by the myocardium are acting exclusively in a constrictive direction . Extending this concept, he further postulated that the contractile elements within the ventricular walls are aligned parallel to the epicardial surface. In 1813, Brachet JL  had suggested the existence of not only a constrictive and tangential myocardial arrangement, but also a dilating radial myocardial compartment. Brachet JL  argued that it was active contraction of the radial component that produced thinning of the ventricular walls, thus engendering a cycle requiring systolic constriction followed by a diastolic dilatory excitatory stimulus. We now know, of course, that the myocardium is excited but once by a single impulse. This fact, nonetheless, should not be interpreted as denying the potential for the ventricular myocardium to produce an active bi-directional drive, as postulated by Brachet JL, since evidence exists, that true antagonism can be provided by the three-dimensional meshwork of its contained cardiomyocytes.
Principle of Myocardial Structural Organization
The cardiomyocytes are aggregated together by the endomysial component of the fibrous matrix, which binds them together into non-uniform lamellae [4–9]. These lamellae themselves then branch to form a complex three-dimensional mesh. The aggregated units are themselves separated by perimysial spaces within the fibrous matrix. The branches consisting of several off-springs from long chains of myocytes cross the perimysial space on their way to neighbouring lamellae. They are also bundled by endomysial connective tissue [10–12]. The perimysial spaces, which contain loose connective tissues, and which provide the pathways for the vessels and nerves of the walls, produce the planes that permit gliding of the units relative to each other.
There is common consensus that the prevailing tangential alignment of long chains of myocytes fulfils a turn from epicardium to endocardium upon a radial axis . At the same time, the prevailing surface-parallel "sheets" of long chains of myocytes are densely connected in transversal direction, namely running in intruding and extruding direction and intermingling with the parental surface-parallel long chains of myocytes. Those transverse connections of variable length further complicate the confirmation of long chains of myocytes to be arranged in a continuum.
Transverse Myocardial Netting and Its Function
Transverse netting is ubiquitous throughout the bi-ventricular myocardial body. Up to 40% of the myocardial mass is aligned in non-tangential, namely in transversely intruding and extruding direction - at widely variable angles [14–17]. Local distribution of transverse netting is particularly heterogeneous. It is furthermore found that the distribution of the local lamellar orientation is not uniform; rather, it contains notable stochasticity. At first sight, a faint similarity with a bird’s nest becomes apparent  (Figure 1).
Figure 1: Left panel: The cross-section through the wall of a bird´s nest shows a stochastic distribution of the alignment of blades of grass, which nonetheless seems to comply with a triple layer, namely an outer fan (OF), a circular arrangement (C) and an inner fan (IF) enclosing the cavity (VC) of the nest. Right panel: Transparent view of the fiber architecture of a pneumatically distended porcine heart imaged by computed tomography.
Access to Myocardial Structure
Semicircular Transmural Section Technique
We introduced a circular knife section technique  which compensates for the layered turn of the prevailing surface parallel myocardial alignment, so that at least the real alignment relative to the epicardial surface plane of long chains of myocytes in the prevailing so-called “surface-parallel” component of myocardial network can be verified (Figure 2). Histological sections of the ventricular walls prepared in this fashion expose long enough chains of myocytes for the automatic assessment of angles of their inclination relative to the epicardial surface plane in extruding or intruding direction  (Figure 3). We found a wide range of angles throughout the wall from epicardium to the endocardium with a distinct trend to highest angles of intrusion in the sub-endocardial layers.
Figure 2: Upper left side: The cartoon labelled 1 show the turn of the helical sheets of long chains of aggregated cardiomyocytes. In the cartoon numbered 2, the wall has been sectioned from epicardium to endocardium by cutting with the semicircular knife. Within the core removed by the knife turns up the layered sequence of rotating sheets, with one short segment of each sheet sectioned parallel to the long axes of the long chains of aggregated cardiomyocytes. Each little segment extends one step deeper in the wall towards the endocardium. In cartoon labelled 3, the "staircase-like" arrangement of the sequence of short segments in histology is seen as a continuous diagonal island. Right and lower side: Three slices of myocardium are cut out by the semi-circular knife from the left ventricular wall (Lower panel). This histological section was made from a slice between the superior and inferior walls and from the epicardium at the lower margin to the endocardium at its upper margin. “AVG” is the atrio-ventricular grove, and “MVS” is the hinge of the mural leaflet of the mitral valve. “AM” is atrial myocardium, “INF” is the inferior wall, and “SUP” is the superior wall. Fine black lines within the diagonal island of the myocardium show the staircase-like sequence of short segments. The diagonal island is likewise interspersed with chains of cardiomyocytes in intruding and extruding directions.
Figure 3: The angles of inclination relative to the ventricular epicardial surface plane are distributed in local specific way as shown here in four segments of one diagonal island extending between epicardium (upper edge) and endocardium ( lower edge) with highest concentration of intruding structures in the subendocardium (left end) . Angle 0 means parallel to the surface plane.
With respect to the horizontal mass which is Krehl’s Triebwerkzeug , it appears that this structure is not a compact cuff. In synopsis with observations on long sections and cross-sections of the distended heart in computed tomography (see below) Krehl´s Triebwerkzeug rather has the appearance of basketwork with wide spaces left in between. Through those spaces are running aggregates in variably oblique direction.
Diffusion-Tensor-Imaging (MRTDTI) on Semicircular Sections of the Pneumatically Distended Porcine Left Ventricular Wall
The wide range of angles of transverse netting is clearly exposed by use of MRT DTI. Thereby, porcine hearts were cut with circular knives . The slices were embedded in Agar-Agar and then analyzed by diffusion tensor imaging (Figure 4). Structures that exhibit the shape of islands document the angle of oblique transversal inclination that manifest itself as a strict function of the diameter of the knives used. The smaller the knives, the shorter the resulting “diagonal islands” and the steeper we found their angle of inclination from epicardium to endocardium. This particular finding proves that the transmural netting of the prevailing tangential structure is an essential part of the continuum that includes a wide range of transversely inclined branches which then obviously must be of variable lengths [21,22].
Figure 4: Three slices imaged by DTI-MRT (upper = apical, mid = mid-ventricular, lower = basal level) from a porcine heart in which the “diagonal islands” show the range of angles of intrusion.
Computed Tomography on the Pneumatically Distended Heart Muscle Uncovers Its Fan-Shaped Transverse Netting
To make use of the higher spatial resolution of computed tomography and in particular of micro-computed tomography, we distended the heart muscles perimysial space by inflating air through the coronary arteries [23,24]. The resulting contrast between air and myocardium exposed the heart muscles fan-like and helical structure. This pattern is particularly local-specific which means it varies between base, apex and in transmural extension (Figure 5). The distribution of perimysial cleavage planes as clearly contrasted in computed tomography by air, divides the basic mass of myocardium by perimysial gliding surfaces according to its local functional necessities. This assumption implies that with pathological alterations in wall-thickness, motion pattern and distribution in topical wall stress, the shape and alignment of perimysial cleavage planes might change, too.
Figure 5: Three micro-computed tomographic cross-sections through the bi-ventricular myocardial body at the sub-basal (B), mid-ventricular (M) and epi-apical(A) level showing the lamellar structure forming two counter-clockwise running fans in the outer and inner zone of the wall, respectively. The alleged continuous circular structure turns out to be a transition zone between the two opposing helical formations, which themselves vary in thickness and angulation from area to area.
Functional Confirmation of Transverse Netting
Intramural Contractile Function
To demonstrate the functional impact of the dense transverse netting of the prevailing surface-parallel helical sheets we cut out from a beating porcine heart by use of a triple circular knife (all three knives put together, the one inside the other) two neighbouring slices of myocardium. We put both slices into nutrient baths and one of them we stimulated electrically (Figure 6). It instantly contracted. You see the “diagonal island” which forms a straight bulge which runs diagonally from epicardium to endocardium, because the contained long chains of myocytes form a bundled continuum. This means that the surface parallel segments which are intermingled with their transverse netting structures fuse to an oblique transmural (endo-epicardial) force transmission.
Figure 6: Upper two sections: Neighbouring slices of myocardium from a beating porcine heart were cut by using all 3 circular knives put together, the smaller ones inside the others. We put both harvested slices in nutrient baths, and stimulated the lower slide electrically. It instantly contracted. Lower panel: A freshly excised slice was rapidly heat-denatured to induce contraction. Again the diagonal island shortened and deformed the slice, while the remaining discontinuous, cross-sectioned myocardium ruffled while contracting.
Repartition of Wall Stress is Local-Specific
Endless, yet branching chains of myocytes are housed within unnumbered sequences of aggregates, residing in each of them only for a short distance until they leave it to cross the perimysial space and to enter the next aggregate. In each aggregate each segment of an individual long chain of myocytes faces local- specific loading conditions. So, on its endless way through the ventricular cone and through the unnumbered aggregates, in which they are embedded intermittently, the long chains of myocytes undergo, segment per segment, virtually extreme variations in loading conditions while contracting here against a particularly high and there against a very low resistance. The reason is that the chains of myocytes are firmly embedded in endomysium to which they are suspended by a dense sequence of struts [1,11]. As a result, the chain of myocyte is not free to move within the aggregate, but has to bear the load which burdens the specific aggregate. The local loading conditions of each aggregate depend first on its position in the ventricular wall between base, apex, around its circumference and through its depth and, in particular, on its alignment relative to the ventricular surface plane. Namely, a surface-parallel alignment allows the aggregate to shorten proportional to ventricular wall constriction , while in case the aggregate is aligned at an angle to the ventricular surface plane, shortening is confined by the effect of systolic wall thickening . The different loading conditions are documented by two different signals, with the unloading type of force development measured in the surface-parallel aggregates and an auxotonic signal generated by aggregates in oblique intruding or extruding direction (Figure 7).
Figure 7: The unloading (left) and the auxotonic (right) type of local force development measured focally by needle force probes
Figure 8: Upper panel: Layered transmural distribution of diastolic, systolic and developed (systolic minus diastolic) forces in the left ventricular base, mid-portion, and apex in the control state and 6 weeks after induction of left ventricular hypertrophy by aortic banding. Lower panel: Mean layered transmural distribution of auxotonic and unloading forces in the left ventricular wall of 10 porcine hearts in the control state and 6 weeks after induction of left ventricular hypertrophy by aortic banding.
Figure 9: Response of diastolic, systolic and developed forces of the auxotonic and unloading type of signal measured in 10 dog hearts during inflation of an intra-aortic balloon, medication with thiopental and dobutamin, respectively, 500 ml saline given intravenously and fast withdrawal of 2 lit blood from the left atrium . The differences in both signals are significant *p <0.05; **p <0, 01.
There are no quantitative figures describing the effect of endomysial and perimysial connective tissue in confining the freedom of motion of each aggregate relative to its neighbours. Nonetheless, we measured the loading of aggregates in function of global ventricular size depending on ventricular filling, of wall thickness, which varies a lot throughout the left ventricular wall, and of intracavitary pressure, which changes over the heart cycle and depending on ventricular filling and outflow resistance (Figure 8) [27,28].
By measuring forces with the use of needle force probes we have documented in the normal heart the highest level of contractile forces in the left ventricular base with a decrease in forces towards the apex (Figure 8). In the hypertrophic heart, in contrast, the highest level of contractile forces we measured in the mid-part of the left ventricular wall. In the normal heart we regularly measured low forces in the middle layers of the left ventricular wall. In the hypertrophic heart, this low-level zone is less pronounced, indicating a marked shift of loading towards the ventricular mid-layers beside a general increase in load in all layers. The highest incidence of auxotonic forces we measured in the sub endocardium with a marked decrease towards the outer layers (Figure 8). The unloading type of forces definitely prevailed in the outer mural layers with a decrease towards the endocardium. This monotonous distribution gets somewhat disturbed while left ventricular hypertrophy develops.
Thus, a markedly heterogeneous repartition of contractile forces prevails already throughout the normal left ventricular wall. In the hypertrophic heart, stress alignment is further remodelled.
In animal experiments on dogs we have likewise measured that typical daily variations in heart function, including the effect of catecholamine and barbiturates (instead of Beta-blockers) [27,29,30], changes in ventricular filling and outflow resistance (balloon in the aorta), keep the aggregate under permanently variable loading conditions (Figure 9) .
Non-Invasive Clinical Confirmation of Auxotonic Activity in the Left Human Ventricular Wall
Using MRI 3D tagging which is based on the three-dimensional (3D) Complementary Spatial Modulation of Magnetization (CSPAMM) technique, Schmitt et al.  succeeded in confirming non-invasively, on humans the asymmetrical action of beta-blocking agents. Twelve volunteers in supine position were treated with increasing doses of Esmolol (Brevibloc 100 mg / 10 ml intravenously). Each dose was infused over a period of 12 to 13 min, while circumferential shortening (Figure 10), radial shortening, and longitudinal shortening were measured. At low doses of 5, 10, and 25 µg / kg-1 / min-1 Esmolol (Figure 10 upper panel), augmented peaks, shortened time to peak, and a steeper upslope were measured. This left shift of the curves indicates faster and stronger ventricular constriction. Peaks of circumferential and radial shortening were enhanced. Total contraction time was shortened, obviously because of a loss in intrinsic resistance by loss in auxotonic forces which allows the helical alignment to shorten faster. More time has been left for diastolic recovery. In contrast, at higher doses ranging from 50 to 150 µg/ kg-1 / min-1 Esmolol (Figure 10 lower panel), both, systole and diastolic relaxation became longer. The peak value decreased to levels lower than at baseline. The time to peak increased and the upslope flattened. This right shift of the curve under high dose-beta-blockade announces weakening of contraction. It ultimately leads to shortened diastole, and it indicates drug-induced global negative inotropism. By low-dose selective beta-blockade of the transverse intruding netting under MRI 3D tagging, Schmitt P, et al.  have evidenced the prevalence of intrinsic antagonism for the first time non-invasively.
Figure 10: The graphs show the effect of rising doses of Esmolol on left ventricular circumferential shortening in human volunteers: upper graph: 0 ( control ), 5, 10 and 25 µg·kg-1 ·min-1 Esmolol and lower graph: 0 ( control ), 50, 100, and 150 µg kg -1·min-1 Esmolol.
Global Ventricular Function Revisited
Our findings summarized above demonstrate that, over the active heart cycle, the two components, i.e. tangential and radial, are acting synchronously within the framework of the myocardial continuum. The far greater component is acting in constrictive direction, thus producing systolic ventricular emptying. The smaller component, in contrast, is promoting active mural thinning, and hence is acting in dilatory fashion, thus promoting ventricular filling. The demonstrated intrinsic antagonism is able to drive at least four mechanisms. In the first instance, by sustaining mural stiffness, it stabilizes the shape and size of the ventricle. Second, by controlling the velocity, termination, and amount of inward motion, the auxotonic forces decelerate ventricular constriction, thus minimizing the resistance to flow in the already narrowed left ventricular cavity. The third function of the antagonistic activity is to store some of the elastic forces generated during systole. This amount of stored energy will then enhance early diastolic dilation [32–36]. Finally, the heterogeneous distribution of antagonistic activity is likely to sustain a peristaltiform sequence of constriction of the inner ventricular profile, which itself underscores the known spiraling intracavitary flow pattern .
Heterogeneities in Structure and Function are Essential to Global Ventricular Function
By seeing our measured data in synopsis with the structure of aggregates as imaged in electron-microscopy, we infer, that throughout the ventricular wall, each short segment of long chains of myocytes contracts against permanently and rapidly changing resistances and that the amplitudes of contractile forces widely vary over time and between areas, depending on the surrounding structural interdependency [38,39]. Accordingly, each functional unit around any focus of disturbance is prepared to contribute to compensation, so that global ventricular function remains undisturbed, as confirmed by daily clinical experience . The notion that the ventricular structure is conceived such that under various hemodynamic condition, notably ischemia, necrosis, fibrosis or even focally triggered arrhythmias, all myocytes are loaded to the similar extent (uniform wall stress), omitting thus focal peaks in stress throughout the ventricular walls [41–43], is hardly to bring into accordance with our findings regarding the pattern of morphological and functional disparities which we measured in animal as well as in human hearts.
Derailment of the Intrinsic Antagonism
The myocardial continuum exhibiting antagonistic force components appears well equilibrated; yet, its structural base is particularly prone to bring function to derailment in case of myocardial hypertrophy and myocardial fibrosis [44–47]. When scar-tissue invades and destroys the myocytes’ tunneled housing, they get fettered. Force-transmission runs out of register, with a predominant trend to transverse deviation. We measured in fibrotic hearts an increase in relative incidence of auxotonic forces from 30% in the normal heart - to more than 60%, and the level of local forces in those patients exceeded up to three times that in control hearts or in hearts suffering from mitral stenosis. Left ventricular hypertrophy, which is regularly accompanied by fibrosis, leads to a dramatic overrepresentation of auxotonic activity. This means continuously growing reactive power is waste of energy.
Acute Ventricular Dilatation in Concentric Hypertrophy Viewed as a Trial of Intrinsic Repair
Wall thickening in global ventricular hypertrophy goes along with an increase in intruding and extruding transverse bending. In terms of function this means that antagonistic forces increase, resulting in a progressive increase in intrinsic after load which again furthers global ventricular hypertrophy. In an auto-rescue attempt to stop that vicious circle, the ventricle ultimately dilates which goes along with a proportional reduction in wall thickness hence with some straightening of the excessively transverse bent intruding and extruding netting components.
The ventricular walls represent a structured continuum composed of interweaving aggregated chains of cardiomyocytes (lamellae) set in a supporting fibrous tissue matrix. The orientation angles of the lamellar segments thereby cover a wide range in helical as well as transverse direction. Accordingly, forces generated by lamellar segments have a tangential as well as a radial component depending on the orientation angle. An intrinsic antagonism is the consequence of this structure. However, the proportion of constrictive relative to dilative forces has thus far escaped clinical measurement. In particular, left ventricular pressure and its derivatives are function of the intrinsic loading conditions of the myocardium acting as a continuum. The relation between left ventricular pressure and wall stress is therefore not straightforward.
Our experiments to date have shown that the transmural component of the wall, which generates the auxotonic force signal, is particularly sensitive to inotropic medication. By use of that pharmacological investigation we could demonstrate that antagonistic activity is in fact an important cardiodynamic feature and of importance in view of clinical diagnostics. It likewise prompts to reconsider therapeutic concepts such as the use of inotropics and mechanical assist devices. According to our findings, inotropic drugs, acting both asymmetrically on the two antagonistic components, are the more effective in supporting or damping antagonistic activity, the more the heart is hypertrophied. Yet, this effect is neither accessible to quantification. On the other hand, heterogeneity in myocardial structure indicates autarky of regional antagonistic function, which itself offers new therapeutic options such as partial ventriculectomy. Nonetheless, the rare cases in which volume reduction surgery is discussed as a therapeutic option require a careful preoperative assessment of the persisting potential of systolic wall thickening. An excess in fibrotic fettering as well as an excess in antagonistic activity crucially confine ventricular pump function after volume reduction.
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