How are the cardiomyocytes aggregated together within the walls of the left ventricular cone?

The manner of packing together of the cardiomyocytes within the walls of the cardiac ventricles has now been investigated for over half a millennium. In 1669, Lower dissected the ventricular mass, likening the arrangement to skeletal musculature, in the form of a myocardial band extending between the right and left atrioventricular junctions. Pettigrew subsequently showed obvious helical arrangements to be evident within the ventricular walls, but emphasised that the cardiomyocytes were attached to each other, and could not justifiably be compared with skeletal cardiomyocytes. Torrent-Guasp then reactivated the notion that the ventricular mass was formed of a solitary band. Unlike Lower, he dissected the band as extending between the pulmonary to the aortic roots. Multiple investigations conducted using gross dissection and histology, and more recently diffusion tensor magnetic resonance imaging and computed tomographic analysis, have shown an absence of any anatomical boundaries within the walls that might permit the mass uniformly to be dissected so as to reveal the band. A response to a recent letter to the Journal, nonetheless, claimed that the dissections had been validated by clinicians interpreting the findings so as to provide an explanation for ventricular cardiodynamics, arguing that the findings provided a suitable anatomical model for this purpose. Anatomical models, however, are of no value unless they are anatomically correct. In this review, therefore, we summarise the evidence showing that the cardiomyocytes making up the ventricular walls, rather than forming a ventricular myocardial band, are instead aggregated together to form a three-dimensional myocardial mesh.

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.

Antagonism of contractile forces in left ventricular hypertrophy: a diagnostic challenge for better pathophysiological and clinical understanding.

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.

Mathematical foundations of biomechanics.

The aim of biomechanics is the analysis of the structure and function of humans, animals, and plants by means of the methods of mechanics. Its foundations are in particular embedded in mathematics, physics, and informatics. Due to the inherent multidisciplinary character deriving from its aim, biomechanics has numerous connections and overlapping areas with biology, biochemistry, physiology, and pathophysiology, along with clinical medicine, so its range is enormously wide. This treatise is mainly meant to serve as an introduction and overview for readers and students who intend to acquire a basic understanding of the mathematical principles and mechanics that constitute the foundation of biomechanics; accordingly, its contents are limited to basic theoretical principles of general validity and long-range significance. Selected examples are included that are representative for the problems treated in biomechanics. Although ultimate mathematical generality is not in the foreground, an attempt is made to derive the theory from basic principles. A concise and systematic formulation is thereby intended with the aim that the reader is provided with a working knowledge. It is assumed that he or she is familiar with the principles of calculus, vector analysis, and linear algebra.

V.1. Ultrasound imaging and Doppler flow velocity measurement.

High frequency ultrasound (2 - 8 MHz typically) has established itself as a major medical imaging method associated with a wide range of clinical applications. Advantages include real-time applicability, lower cost compared with other medical imaging technologies, possibility of measuring blood flow velocities and desk-top instrumentation. Disadvantage is associated with lower image quality than is obtained with x-ray or magnetic resonance methods.

V.2. X-ray-based medical imaging: X-ray projection technique, image subtraction method, direct digital X-ray imaging, computed tomography (CT).

X-ray projection imaging, introduced in the early 20th century, was for a long time the only and still is a major routine diagnostic procedure that can be performed on the intact human body. With the advent of Computed Tomography in 1973, for the first time, a true 3D imaging of anatomical structures became feasible. Besides, digital recording and processing allowed further developments such as subtraction angiography in real-time or direct x-ray imaging without wet photographic methods.

V.3. Basic elements of nuclear magnetic resonance for use in medical diagnostics: Magnetic Resonance Imaging (MRI), magnetic resonance spectroscopy (MRS).

Magnetic Resonance Imaging (MRI) has established itself as a major imaging modality in life science research and clinical practice. It is characterized by high spatial resolution, high soft tissue contrast, non-invasiveness, and universal applicability in terms of orientation and location of imaging areas. The procedure allows furthermore the investigation of physiological and pathophysiological processes, in particular in combination with magnetic resonance spectroscopy (MRS). MR methodology is not exhausted, new procedures and areas of application develop widely in life science and medicine. This article is limited to basic physical aspects.

Pressure-dependent hydrometra dimensions in hysteroscopy.

AIM: To investigate the relation between intrauterine pressures and volumes for virtual-reality-based surgical training in hysteroscopy. MATERIAL AND METHODS: Ten fresh extirpated uteri were insufflated by commercial hysteroscopy pump and imaged by computer tomography (CT) under intrauterine air pressure in distension-collapse cycles between 0 , 20 (150 mmHg), and 0 kPa, performing a CT scan at every step at about 2.7 kPa (20 mmHg). RESULTS: An initial threshold pressure to distend the cavity was avoided by introducing the insufflation tube up to the fundus. The filling and release phases of seven uteri that were completely distended showed the typical characteristics of a hysteresis curve which is expected from a viscoelastic, nonlinear, anisotropic soft tissue organ like the uterus. In three cases tightening the extirpated uterus especially at the lateral resection lines caused significant problems that inhibited registration of a complete distension-collapse cycle. Interpolated volumes for complete distended cavities and extrapolated for incomplete data sets, derived from the digitally reconstructed three-dimensional (3D) geometries, ranged from 0.6 to 11.4 mL at 20 kPa. These values highly correlate with the uterine volume (not insufflated) considering different biometric data of the uteri and patient data. Linear (R(2) = 0.66) and quadratic least-squares fits (R(2) = 0.74) were used to derive the formulas y = 0.069x and y = 0.00037x(2) + 0.036x, where x is the uterine volume in mL (not insufflated) and y is the cavity volume in mL at 20 kPa intrauterine pressure. CONCLUSIONS: Our experimental hysteroscopical setup enabled us to reconstruct the changes in volumes of insufflated uteri under highly realistic conditions in 3D. The relation between intrauterine pressure and cavity volume in distension-collapse cycles describes a typical hysteresis curve.

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.

Imaging of tissue structures and mechanical analysis.

The anatomical structure of biological tissues and their mechanical function are closely related. Forces have a decisive influence on growth and remodeling of tissues; furthermore, intra- and extravascular transport processes are mostly controlled mechanically and the metabolism of many cells is influenced by flow-induced shear stresses. In order to facilitate a mechanical analysis of biological systems, the anatomical tissue structure has to be determined with the aid of 3D imaging methods. In particular, the anisotropic fibrous architecture of the organs involved along with appropriate constitutive relations have to be considered. Examples of structure-(mechanical) function relationships are discussed in an exemplary fashion for bone, the heart and the uterus. The behavior of biological structures under unphysiological loading situations, such as they may occur in accidents, is addressed.

Inverse finite element characterization of the human myometrium derived from uniaxial compression experiments.

The low strain-rate behavior of the human myometrium under compression was determined. To this end, uniaxial, unconstrained compression experiments were conducted on a total of 25 samples from three excised human uteri at strain rates between 0.001 s(-1) and 0.008 s(-1). A three-dimensional finite element model of each sample was created and used together with an optimization algorithm to find material parameters in an inverse estimation process. Friction and shape irregularities of samples were incorporated in the models. The uterine specimens in compression were modeled as viscoelastic, non-linear, nearly incompressible and isotropic continua. Simulations of uniaxial, frictionless compressions of an idealized cuboid were used to compare the resulting material parameters among each other. The intra- and inter-subject variability in stiffness of specimens was found to be large and to cover such a wide range that the effect of anisotropy which is of minor influence under compressive deformations in the first place could be neglected. Material parameters for a viscoelastic model based on a decoupled, reduced quadratic strain-energy function were presented for the uterine samples representing a median stiffness.

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.

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.

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.

Three-dimensional fiber architecture of the nonpregnant human uterus determined ex vivo using magnetic resonance diffusion tensor imaging.

The global muscle and collagen fiber orientation in the human uterus has been analyzed hitherto by various standard microscopic techniques. However, no widely accepted model of the fiber architecture of the myometrium could be acquired. The purpose of the present study was to investigate the uterus by magnetic resonance (MR) diffusion tensor imaging (DTI) in a 3D macroscopic approach. Ex vivo MR DTI measurements were performed on five uteri from nonpregnant patients. The main diffusion directions reflecting the orientation of directional structures in the examined tissues were determined from diffusion-weighted spin-echo measurements. A fiber tracking algorithm was used to extrapolate the fiber architecture. The method was validated against histological slides and indirectly through the analysis of leiomyomas, which exhibit less anisotropy than normal myometrium. Significant anisotropy was found in most regions of all examined nonpregnant human uteri. But only two systems of fibers were found running circularly along the intramural part of the uterine tubes. They merged caudally and built a close fitting envelope of circular layers around the uterine cavity. On the cervix, circular fibers were observed in the outer part as well as mostly longitudinal fibers in the inner part. These results confirm the existence of directional structures in the complex fiber architecture of the human uterus. They also indicate that MR DTI is a beneficial and complementary tool to standard microscopic techniques to determine the intrinsic fiber architecture in human organs.

Three-dimensional architecture of the left ventricular myocardium.

Concepts for ventricular function tend to assume that the majority of the myocardial cells are aligned with their long axes parallel to the epicardial ventricular surface. We aimed to validate the existence of aggregates of myocardial cells orientated with their long axis intruding obliquely between the ventricular epicardial and endocardial surfaces and to quantitate their amount and angulation. To compensate for the changing angle of the long axis of the myocytes relative to the equatorial plane of the ventricles with varying depths within the ventricular walls, the so-called helical angle, we used pairs of cylindrical knives of different diameters to punch semicircular slices from the left ventricular wall of pigs, the slices extending from the epicardium to the endocardium. The slices were pinned flat, fixed in formaldehyde, embedded in paraffin, sectioned, stained with azan or hematoxilin and eosin, and analyzed by a new semiautomatic procedure. We made use of new techniques in informatics to determine the number and angulation of the aggregates of myocardial cells cut in their long axis. The alignment of the myocytes cut longitudinally varied markedly between the epicardium and the endocardium. Populations of myocytes, arranged in strands, diverge by varying angles from the epicardial surface. When paired knives of decreasing diameter were used to cut the slices, the inclination of the diagonal created by the arrays increases, while the lengths of the array of cells cut axially decreases. The visualization of the size, shape, and alignment of the myocytic arrays at any side of the ventricular wall is determined by the radius of the knives used, the range of helical angles subtended by the alignment of the myocytes throughout the thickness of the wall, and their angulation relative to the epicardial surface. Far from the majority of the ventricular myocytes being aligned at angles more or less tangential to the epicardial lining, we found that three-fifths of the myocardial cells had their long axes diverging at angles between 7.5 and 37.5 degrees from an alignment parallel to the epicardium. This arrangement, with the individual myocytes supported by connective tissue, might control the cyclic rearrangement of the myocardial fibers. This could serve as an important control of both ventricular mural thickening and intracavitary shape.

The myocardium and its fibrous matrix working in concert as a spatially netted mesh: a critical review of the purported tertiary structure of the ventricular mass.

With the increasing interest now paid to volume reduction surgery, in which the cardiac surgeon is required to resect the ventricular myocardium to an extent unenvisaged in the previous century, it is imperative that we develop as precise knowledge as is possible of the basic structure of the ventricular myocardial mass and its functional correlates. This is the most important in the light of the adoption by some cardiac surgeons of an unvalidated model which hypothesises that the entire myocardial mass can be unravelled to produce one continuous band. It is our opinion that this model, and the phylogenetic and functional correlates derived from it, is incompatible with current concepts of cardiac structure and cardiodynamics. Furthermore, the proponents of the continuous myocardial band have made no effort to demonstrate perceived deficiencies with current concepts, nor have they performed any histological studies to validate their model. Clinical results using modifications of radius reduction surgery based on the concept of the continuous myocardial band show that the procedure essentially becomes ineffective. As we show in this review, if we understand the situation correctly, it was the erstwhile intention of the promoters of the continuous band to elucidate the basic mechanism of diastolic ventricular dilation. Their attempts, however, are doomed to failure, as is any attempt to conceptualise the myocardial mass on the basis of a tertiary structure, because of the underlying three-dimensional netting of the myocardial aggregates and the supporting fibrous tissue to form the myocardial syncytium. Thus, the ventricular myocardium is arranged in the form of a modified blood vessel rather than a skeletal muscle. If an analogy is required with skeletal muscle, then the ventricular myocardium possesses the freedom of motion, and the ability for shaping and conformational self-controlling that is better seen in the tongue. It is part of this ability that contributes to the rapid end-systolic ventricular dilation. Histologic investigations reveal that the fibrous content of the three-dimensional mesh is relatively inhomogeneous through the ventricular walls, particularly when the myocardium is diseased. The regional capacity to control systolic mural thickening, therefore, varies throughout the walls of the ventricular components. The existence of the spatially netted structure of the ventricular mass, therefore, must invalidate any attempt to conceptualise the ventricular myocardium as a tertiary arrangement of individual myocardial bands or tracts.

A new multichannel near infrared spectrophotometry system for functional studies of the brain in adults and neonates.

We have designed a versatile, multi-channel near-infrared spectrophotometry (NIRS) instrument for the purpose of mapping neuronal activation in the neonatal and adult brain in response to motor, tactile, and visual stimulation. The optical linearity, stability, and high signal to noise ratio (>70 dB) of the instrument were demonstrated using an in vitro validation procedure. In vivo measurements on the adult forearm were also performed. Changes in oxygenation, induced by arterial occlusion of the forearm, were recorded and were shown to compare well with measurements acquired using a conventional NIRS instrument. To demonstrate the capabilities of the instrument, functional measurements in adults and neonates were performed. The instrument exhibited the capability to differentiate with a spatial resolution in the order of cm, local activation patterns associated with a finger tapping sequence.

Wobbled splatting--a fast perspective volume rendering method for simulation of x-ray images from CT.

3D/2D registration, the automatic assignment of a global rigid-body transformation matching the coordinate systems of patient and preoperative volume scan using projection images, is an important topic in image-guided therapy and radiation oncology. A crucial part of most 3D/2D registration algorithms is the fast computation of digitally rendered radiographs (DRRs) to be compared iteratively to radiographs or portal images. Since registration is an iterative process, fast generation of DRRs-which are perspective summed voxel renderings-is desired. In this note, we present a simple and rapid method for generation of DRRs based on splat rendering. As opposed to conventional splatting, antialiasing of the resulting images is not achieved by means of computing a discrete point spread function (a so-called footprint), but by stochastic distortion of either the voxel positions in the volume scan or by the simulation of a focal spot of the x-ray tube with non-zero diameter. Our method generates slightly blurred DRRs suitable for registration purposes at framerates of approximately 10 Hz when rendering volume images with a size of 30 MB.