What is the clinical significance of ventricular mural antagonism?

Recent morphological studies provide evidence that the ventricular walls are arranged as a 3D meshwork of aggregated cardiomyocyte chains, exhibiting marked local structural variations. In contrary to previous findings, up to two-fifths of the chains are found to have a partially transmural alignment, thus deviating from the prevailing tangential orientation. Upon contraction, they produce, in addition to a tangential force, a radial force component that counteracts ventricular constriction and aids widening of the ventricular cavity. In experimental studies, we have provided evidence for the existence of such forces, which are auxotonic in nature. This is in contrast to the tangentially aligned myocytes that produce constrictive forces, which are unloading in nature. The ventricular myocardium is, therefore, able to function in an antagonistic fashion, with the prevailing constrictive forces acting simultaneously with a dilatory force component. The ratio of constrictive to dilating force varies locally according to the specific mural architecture. Such antagonism acts according to local demands to preserve the ventricular shape, store the elastic energy that drives the fast late systolic dilation and apportion mural motion to facilitate the spiralling nature of intracavitary flow. Intracavitary pressure and flow dynamics are thus governed concurrently by ventricular constrictive and dilative force components. Antagonistic activity, however, increases deleteriously in states of cardiac disease, such as hypertrophy and fibrosis. ß-blockade at low dosage acts selectively to temper the auxotonic forces.

The functional architecture of skeletal compared to cardiac musculature: Myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band.

How the cardiomyocytes are aggregated within the heart walls remains contentious. We still do not fully understand how the end-to-end longitudinal myocytic chains are arranged, nor the true extent and shape of the lamellar units they aggregate to form. In this article, we show that an understanding of the complex arrangement of cardiac musculature requires knowledge of three-dimensional myocyte orientation (helical and intrusion angle), and appreciation of myocyte packing within the connective tissue matrix. We show how visualization and segmentation of high-resolution three-dimensional image data can accurately identify the morphology and orientation of the myocytic chains, and the lamellar units. Some maintain that the ventricles can be unwrapped in the form of a "helical ventricular myocardial band," that is, as a compartmentalized band with selective regional innervation and deformation, and a defined origin and insertion like most skeletal muscles. In contrast to the simpler interpretation of the helical ventricular myocardial band, we provide insight as to how the complex myocytic chains, the heterogeneous lamellar units, and connective tissue matrix form an interconnected meshwork, which facilitates the complex internal deformations of the ventricular wall. We highlight the dangers of disregarding the intruding cardiomyocytes. Preparation of the band destroys intruding myocytic chains, and thus disregards the functional implications of the antagonistic auxotonic forces they produce. We conclude that the ventricular myocardium is not analogous to skeletal muscle, but is a complex three-dimensional meshwork, with a heterogeneous branching lamellar architecture.

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.

Beta-blockers contribute to treatment of heart failure. Their mechanism of action, however, is incompletely understood. Gradients in beta-blocker sensitivity of helically aligned cardiomyocytes compared with counteracting transversely intruding cardiomyocytes seem crucial. We hypothesize that selective blockade of transversely intruding cardiomyocytes by low-dose beta-blockade unloads ventricular performance. Cardiac magnetic resonance imaging (MRI) 3D tagging delivers parameters of myocardial performance. We studied 13 healthy volunteers by MRI 3D tagging during escalated intravenous administration of esmolol. The circumferential, longitudinal, and radial myocardial shortening was determined for each dose. The curves were analyzed for peak value, time-to-peak, upslope, and area-under-the-curve. At low doses, from 5 to 25 µg·kg(-1)·min(-1), peak contraction increased while time-to-peak decreased yielding a steeper upslope. Combining the values revealed a left shift of the curves at low doses compared with baseline without esmolol. At doses of 50 to 150 µg·kg(-1)·min(-1), a right shift with flattening occurred. In healthy volunteers we found more pronounced myocardial shortening at low compared with clinical dosage of beta-blockers. In patients with ventricular hypertrophy and higher prevalence of transversely intruding cardiomyocytes selective low-dose beta-blockade could be even more effective. MRI 3D tagging could help to determine optimal individual beta-blocker dosing avoiding undesirable side effects.

Models of ventricular structure and function reviewed for clinical cardiologists.

The architectural arrangement of cardiomyocytes aggregated together within the ventricular walls remains controversial. Two models currently attract clinical attention, with neither model standing rigorous anatomical scrutiny. The first is based on the notion that ventricular mass can be unraveled consistently to produce a unique myocardial band. The second model was initially based on the notion that cardiomyocytes were bundled together in uniform fashion, with fibrous shelves interposed in transmural fashion. This concept was subsequently modified to accept the fact that the fibrous matrix supporting the cardiomyocytes within the ventricular walls does not form transmural sheets. Current observations demonstrate that not all cardiomyocytes are aggregated together in tangential fashion. A significant netting component is aligned in obliquely intruding and transversal fashion. The interaction between the tangential and transversal chains of cardiomyocytes with the fibrous matrix produces antagonistic forces, with both unloading and auxotonic forces necessary to explain normal and abnormal cardiodynamics. This article is part of a JCTR special issue on Cardiac Anatomy.

Regional and epi- to endocardial differences in transmural angles of left ventricular cardiomyocytes measured in ex vivo pig hearts: functional implications.

Recent studies point toward the existence of a significant population of cardiomyocytes that intrude transmurally, in addition to those aligned tangentially. Our aim was to investigate the extent of transmural angulation in the porcine left ventricle using diffusion tensor magnetic resonance imaging (DTMRI). Hearts from eight 15 kg pigs were arrested in diastole. The ventricles were filled with polymer to maintain the end-diastolic dimensions. All hearts were examined using DTMRI to assess the distribution of transmural angulation of the cardiomyocytes at 12 predetermined locations covering the entirety of the left ventricle. We found significant differences between the regions, as well as within the transmural subcomponents. In eight out of the 12 predetermined mural segments, the highest mean transmural angle was located sub-endocardially. The greatest mean transmural angles were found in the anterior basal region, specifically 14.9 ± 6.0-degree angle, with the greatest absolute value being 34.3-degree angle. This is the first study to show the significant heterogeneities in the distribution of helical and transmural angles within the entirety of the left ventricular walls, not only for different depths within the ventricular walls, but also between different ventricular regions. The results show unequivocally that not all the contractile elements are aligned exclusively in tangential fashion within the left ventricle. The main function of the transmurally intruding component is most likely to equalize and normalize shortening of the cardiomyocytes at all depths within the myocardium, but our findings also support the notion of antagonistic forces existing within the myocardial walls.

The architecture of the left ventricular myocytes relative to left ventricular systolic function.

OBJECTIVE: Mural thickening, combined with longitudinal and circumferential shortening, and apical along with basal twisting are critical components of the left ventricular systolic deformation that contribute to ventricular ejection. It is axiomatic that the spatial alignment of the actively contracting aggregates of myocytes must play a major role in the resulting ventricular deformation. The need to conserve functional global myocytic architecture, therefore, is an important aspect of the surgical manoeuvres affecting ventricular mass and geometry. To investigate the influence of the global alignment of the myocytes on ventricular contraction, we used a mathematical model simulating the large deformations produced by systolic contraction of the left ventricle of a human heart. METHODS: The alignment and meshing of the myocytes within their supporting fibrous matrix cause mechanical anisotropy, which was included in the mathematical model in the form of a unit vector field, constructed from the measured trajectories of aggregated myocytes in an autopsied human heart. The relationship between ventricular structure and ventricular dynamics was assessed by analysing the influence of systematic deviations of the orientation of the myocytes from their original alignment, in longitudinal as well as radial directions, on the distribution of stress and strain within the myocardium, as well as on the ejection fraction. In addition, simplified idealised geometries were used to investigate the influence of the overall geometrical modifications. RESULTS: Left ventricular function proved to be robust with respect to small-to-moderate rotational variations in myocytic alignment, up to 14 degrees , a finding which we attribute to an equalising effect of the non-uniform anisotropic pattern found in a real heart involving substantial local irregularities in the architecture of the aggregated myocytes. Severe deterioration of function occurred only when deviations in alignment exceeded 30 degrees . CONCLUSIONS: Our findings substantiate the concept of the myocardial walls representing a continuous three-dimensional meshwork, with the absence of any intermediate structures such as discrete bands or tracts extending over the ventricles, which could be destroyed surgically, thereby adversely affecting systolic function. With appropriate indications, they also support the validity of the surgical procedures performed to reduce ventricular radius and therefore to reduce mural stress.

Three-dimensional alignment of the aggregated myocytes in the normal and hypertrophic murine heart.

Several observations suggest that the transmission of myocardial forces is influenced in part by the spatial arrangement of the myocytes aggregated together within ventricular mass. Our aim was to assess, using diffusion tensor magnetic resonance imaging (DT-MRI), any differences in the three-dimensional arrangement of these myocytes in the normal heart compared with the hypertrophic murine myocardium. We induced ventricular hypertrophy in seven mice by infusion of angiotensin II through a subcutaneous pump, with seven other mice serving as controls. DT-MRI of explanted hearts was performed at 3.0 Tesla. We used the primary eigenvector in each voxel to determine the three-dimensional orientation of aggregated myocytes in respect to their helical angles and their transmural courses (intruding angles). Compared with controls, the hypertrophic hearts showed significant increases in myocardial mass and the outer radius of the left ventricular chamber (P < 0.05). In both groups, a significant change was noted from positive intruding angles at the base to negative angles at the ventricular apex (P < 0.01). Compared with controls, the hypertrophied hearts had significantly larger intruding angles of the aggregated myocytes, notably in the apical and basal slices (P < 0.001). In both groups, the helical angles were greatest in midventricular sections, albeit with significantly smaller angles in the mice with hypertrophied myocardium (P < 0.01). The use of DT-MRI revealed significant differences in helix and intruding angles of the myocytes in the mice with hypertrophied myocardium.

Normal right ventricular three-dimensional architecture, as assessed with diffusion tensor magnetic resonance imaging, is preserved during experimentally induced right ventricular hypertrophy.

The three-dimensional architecture of the right ventricular myocardium is a major determinant of function, but as yet no investigator-independent methods have been used to characterize either the normal or hypertrophied state. We aimed to assess and compare, using diffusion tensor magnetic resonance imaging, the normal architecture with the arrangement induced by chronic hypertrophy. We randomized 20 female 5 kg piglets into pulmonary trunk banding (N = 16) and sham operation (N = 4). Right ventricular hypertrophy was assessed after 8 weeks. The excised and fixed hearts were subject to diffusion tensor imaging to determine myocyte helical angles, and the presence of any reproducible tracks formed by the aggregated myocytes. All banding animals developed significant right ventricular hypertrophy, albeit that no difference was observed in terms of helical angles or myocardial pathways between the banded animals and sham group animals. Helical angles varied from approximately 70 degrees endocardially to -50 degrees epicardially. Very few tracks were circular, with helical angles approximating zero. Reproducible patterns of chains of aggregated myocytes were observed in all hearts, regardless of group. The architecture of the myocytes aggregated in the walls of the right ventricle is comparable to that found in the left ventricle in terms of endocardial and epicardial helical angles, however the right ventricle both in the normal and the hypertrophied state lacks the extensive zone of circular myocytes seen in the mid-portion of the left ventricular walls. Without such beneficial architectural remodelling, the porcine right ventricle seems unsuited structurally to sustain a permanent increase in afterload.

The three-dimensional arrangement of the myocytes in the ventricular walls.

The arrangement of the myocytes aggregated together within the ventricular walls has been the subject of anatomic investigation for more than four centuries. The dangers of analyzing the myocardium on the basis of arrangement of the skeletal myocytes have long been appreciated, yet some still described the ventricular myocardium in terms of a unique band extending from the pulmonary trunk to the aorta. Another current interpretation, with much support, is that the ventricular myocytes are compartmentalized in the form of sheets, albeit that the extent of division, and interrelations, of the sheets is less well explained. Histological examination, however, shows that the only muscular unit to be found within the myocardial walls is the cardiac myocyte itself. Our own investigations show that, rather than forming a continuous band, or being arranged as sheets, the myocytes are aggregated together as a three-dimensional mesh within a supporting matrix of fibrous tissue. Within the mesh of aggregated myocytes, it is then possible to recognize two populations, depending on the orientations of their long axes. The first population is aligned with the long axis of the aggregated myocytes tangential to the epicardial and endocardial borders, albeit with marked variation in the angulation relative to the ventricular equator. Correlation with measurements taken using force probes shows that these myocytes produce the major unloading of the blood during ventricular systole. The second population is aligned at angles of up to 40 degrees from the epicardium toward the endocardium. The correlation with measurements from force probes reveals that these intruding myocytes produce auxotonic forces during the cardiac cycle. The three-dimensional arrangement of the mesh also serves to account for the realignment of the myocytes that must take place during ventricular contraction so as to account for the extent of systolic mural thickening.

The three-dimensional arrangement of the myocytes aggregated together within the mammalian ventricular myocardium.

Although myocardial architecture has been investigated extensively, as yet no evidence exists for the anatomic segregation of discrete myocardial pathways. We performed post-mortem diffusion tensor imaging on 14 pig hearts. Pathway tracking was done from 22 standardized voxel groups from within the left ventricle, the left ventricular papillary muscles, and the right ventricular outflow tract. We generated pathways with comparable patterns in the different hearts when tracking from all chosen voxels. We were unable to demonstrate discrete circular or longitudinal pathways, nor to trace any solitary tract of myocardial cells extending throughout the ventricular mass. Instead, each pathway possessed endocardial, midwall, and epicardial components, merging one into another in consistent fashion. Endocardial tracks, when followed towards the basal or apical parts of the left ventricle, changed smoothly their helical and transmural angulations, becoming continuous with circular pathways in the midwall, these circular tracks further transforming into epicardial tracks, again by smooth change of the helical and transmural angles. Tracks originating from voxels in the papillary muscles behaved similarly to endocardial tracks. This is the first study to show myocardial pathways that run through the mammalian left and right ventricles in a highly reproducible manner according to varying local helical and transmural intrusion angles. The patterns generated are an inherent feature of the three-dimensional arrangement of the individual myocytes aggregated within the walls, differing according to the regional orientation and branching of individual myocytes. We found no evidence to support the existence of individual muscles or bands. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.

Models versus established knowledge in describing the functional morphology of the ventricular myocardium.

The myocytes comprising the ventricular mass are arranged so as to function in antagonistic fashion, the walls having the capacity to generate both constrictive and dilatory forces. This dualistic activity is organized on the basis of a site-specific morphologic pattern, permitting marked regional specificity for mural motion and providing a target for regional therapy. Diseased regions can be removed surgically without danger of jeopardizing the remaining healthy mural segments. The sensitivity of the intruding population of myocytes to positive and negative inotropic medication is markedly more pronounced than that of the prevailing tangentially aligned myocytes. This asymmetrical action of inotropes in the setting of global ventricular imbalance promotes the potential to restore constrictive as opposed to dilatory actions.

Statistical analysis of the angle of intrusion of porcine ventricular myocytes from epicardium to endocardium using diffusion tensor magnetic resonance imaging.

Pairs of cylindrical knives were used to punch semicircular slices from the left basal, sub-basal, equatorial, and apical ventricular wall of porcine hearts. The sections extended from the epicardium to the endocardium. Their semicircular shape compensated for the depth-related changing orientation of the myocytes relative to the equatorial plane. The slices were analyzed by diffusion tensor magnetic resonance imaging. The primary eigenvector of the diffusion tensor was determined in each pixel to calculate the number and angle of intrusion of the long axis of the aggregated myocytes relative to the epicardial surface. Arrays of axially sectioned aggregates were found in which 53% of the approximately two million segments evaluated intruded up to +/-15 degrees , 40% exhibited an angle of intrusion between +/-15 degrees and +/-45 degrees , and 7% exceeded an angle of +/-45 degrees , the positive sign thereby denoting an epi- to endocardial spiral in clockwise direction seen from the apex, while a negative sign denotes an anticlockwise spiral from the epicardium to the endocardium. In the basal and apical slices, the greater number of segments intruded in positive direction, while in the sub-basal and equatorial slices, negative angles of intrusion prevailed. The sampling of the primary eigenvectors was insensitive to postmortem decomposition of the tissue. In a previous histological study, we also documented the presence of large numbers of myocytes aggregated with their long axis intruding obliquely from the epicardial to the endocardial ventricular surfaces. We used magnetic resonance diffusion tensor imaging in this study to provide a comprehensive statistical analysis.

Beta-blockade at low doses restoring the physiological balance in myocytic antagonism.

OBJECTIVE: The ventricular mass is organized in the form of meshwork, with populations of myocytes aggregated in a supporting matrix of fibrous tissue, with some myocytes aligned obliquely across the wall so as to work in an antagonistic fashion compared to the majority of myocytes, which are aggregated together in tangential alignment. Prompted by results from animal experiments, which showed a disparate response of the two populations of aggregated myocytes to negative inotropic medication, we sought to establish whether those myocytes that aggregated so as to extend obliquely across the thickness of the ventricular walls are more sensitive to beta-blockade than the prevailing population in which the myocytes are aggregated together with tangential alignment. If the two populations respond in similar differing fashion in the clinical situation, we hypothesize that this might help to explain why drugs blocking the beta-receptors improve function of the ventricular pump in the setting of congestive cardiac failure. METHODS: We implanted needle probes in 13 patients studied during open heart surgery, measuring the forces generated in the ventricular wall and seeking to couple the probes either to myocytes aggregated together with tangential alignment or to those aggregated in oblique fashion across the ventricular walls. In a first series of patients, we injected probatory doses intravenously, amounting to a total bolus of 40-100mg Esmolol, while in a second series, we gave fixed yet rising doses of 5, 10, and 20mg Esmolol in three separate boluses. RESULTS: Forces recorded in the aggregated myocytes with tangential alignment decreased insignificantly upon administration of low doses (57.1+/-12.4 mN-->56.6+/-7.6 mN), while forces recorded in the myocytes aggregated obliquely across the ventricular wall showed a significant decrease in the mean (59.3+/-11.6 mN-->47.4+/-6.4 mN). CONCLUSIONS: The markedly disparate action of drugs blocking beta-receptors at low dosage seems to be related to the heterogeneous extent, and time course, of systolic loading of the myocytes. This, in turn, depends on whether the myocytes themselves are aggregated together with tangential or oblique alignments relative to the thickness of the ventricular walls.

How are the myocytes aggregated so as to make up the ventricular mass?

Of late, it has become fashionable in the surgical literature to describe the ventricular mass as though arranged in the form of a continuous myocardial band, which starts at the aorta and ends at the pulmonary trunk. On the basis of this concept, its supporters have produced revisionist accounts of cardiac development and ventricular function, as well as using it as the basis for proposed surgical maneuvers. They seem unaware, however, that the original concept itself has never been supported by independent anatomic studies, while, to the best of our knowledge, they have not themselves performed anatomic investigations to prove its substance. Furthermore, the current proponents of the "unique myocardial band" ignore a large body of previous anatomic study which showed that the ventricular mass is arranged in the form of a modified blood vessel, with each myocyte anchored to its neighbor within a 3-dimensional myocardial mesh, rather than being arranged in a fashion analogous to skeletal muscles, with discrete origins and insertions of myocardial bands or tracts. In this review, we summarize the evidence showing that there are no anatomic structures within the ventricular myocardium that permit it to be unraveled in systematic fashion so as to produce the purported myocardial band. We also re-visit our own previous investigations, which supported the conventional approach, namely that the myocytes are aggregated together within a supporting fibrous matrix in the form of a 3-dimensional meshwork.

An analysis of the spatial arrangement of the myocardial aggregates making up the wall of the left ventricle.

OBJECTIVE: We used the technique of peeling of myocardial aggregates, usually described as 'fibres', to determine the spatial arrangement of the myocytes in the left ventricular wall of a healthy autopsied human heart. METHODS: We digitised the left ventricular outer and inner boundaries, as well as the pathways in space, of almost 3000 aggregates harvested from the left ventricular myocardium. During the process of gradual peeling, we sought to identify the myocardial aggregates as uniformly as possible. Despite this, interpolation was necessary to complete the pattern so as to construct a unit vector field that represented the preferred direction of the myocardial aggregates throughout the entirety of the walls of the left ventricle of this individual human heart. RESULTS: Apart from the overall systematic arrangement of the aggregates necessary to achieve physiologic ventricular contraction, we documented substantial local heterogeneities in the orientation of the myocardial aggregates. In particular, a significant proportion of aggregates was found to intrude obliquely with respect to the ventricular boundaries, with markedly heterogeneous distribution. Moreover, the distribution of the helical angle of the aggregates relative to the ventricular base varied notably throughout the left ventricular free walls and the septum. Within the generally quite uniform and continuous structure of the ventricular mass, we were, however, unable to identify any organised tracts or functional subunits such as a 'helical ventricular band', nor did we find radial fibrous lamellas coursing across the ventricular wall. CONCLUSION: We suggest that the impact of local anatomical inhomogeneities, associated with gradients in regional contractile function on global ventricular dynamics, has been systematically underestimated in the past. Our analysis confirms furthermore the continuous nature of the myocardium associated with an overall gross organisation of the fibre direction field; however, there is no evidence of substructures compartmentalising the ventricles.