Serum metabolomics assessment of etiological processes predisposing ketosis in water buffalo during early lactation.

Metabolic disorders as ketosis are manifestations of the animal's inability to manage the increase in energy requirement during early lactation. Generally, buffaloes show a different response to higher metabolic demands than other ruminants with a lower incidence of metabolic problems, although ketosis is one of the major diseases that may decrease the productivity in buffaloes. The aim of this study was to characterize the metabolic profile of Mediterranean buffaloes (MB) associated with 2 different levels of ß-hydroxybutyrate (BHB). Sixty-two MB within 50 days in milk (DIM) were enrolled and divided into 2 groups according to serum BHB concentration: healthy group (37 MB; BHB <0.70 mmol/L; body condition score: 5.00; parity: 3.78; and DIM: 30.70) and group at risk of hyperketonemia (25 MB; BHB ≥0.70 mmol/L; body condition score: 4.50; parity: 3.76; and DIM: 33.20). The statistical analysis was conducted by one-way ANOVA and unpaired 2-sample Wilcoxon tests. Fifty-seven metabolites were identified and among them, 12 were significant or tended to be significant. These metabolites were related to different metabolic changes such as mobilization of body resources, ruminal fermentations, urea cycle, thyroid hormone synthesis, inflammation, and oxidative stress status. These findings are suggestive of metabolic changes related to subclinical ketosis status that should be further investigated to better characterize this disease in the MB.

Finite elastic wrinkling deformations of incompressible fiber-reinforced plates.

A two-dimensional plate theory, valid for finite elastic deformations with small strains, is derived for incompressible, fiber-reinforced materials. Single-layer plates and two-layer laminates are considered. Numerical simulations illustrate the substantial effect that fiber reinforcement has on wrinkling patterns in the sheet.

Short communication: Role of Streptococcus pluranimalium in Mediterranean buffaloes (Bubalus bubalis) with different udder health statuses.

The aims of the current study were to describe presence and clinical role over time of Streptococcus pluranimalium isolated in milk samples of Mediterranean buffalo (MB). Two hundred composite milk samples originating from 40 primiparous MB were collected at 10, 30, 60, 90, and 150d in milk (DIM) and from 20 pluriparous MB at 77 to 120 DIM. Milk samples were used for analysis of somatic cell counts, bacteriological cultures, and identification (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry). Nine of 200 (4.5%) samples of primiparous MB and 3 of 20 (15%) samples of pluriparous MB were positive for Strep. pluranimalium. The prevalence of the bacterium in primipari was 0% (0/40) at 10, 30, and 150 DIM, whereas it was 5 (2/40) and 17.5% (7/40) at 60 and 90 DIM, respectively. Eight primipari were positive only once, whereas 1 was positive at 2 different samplings. Mono-infection was not detected in any of the age categories or udder health status. Infections were transient in primipari. Clinical mastitis was observed in primipari once at 90 DIM, subclinical mastitis detected twice in the same animals at 60 and 90 DIM, and intramammary infections were diagnosed 1 and 5 times at 60 and 90 DIM in primipari, respectively, whereas 3 infections were diagnosed in pluripari. The clinical reflections demonstrate for the first time the presence of Strep. pluranimalium in MB and its association with different udder health status. Nevertheless, it cannot be excluded that the bacterium may simply follow a pattern of commensal or opportunistic behavior, taking advantage of a preexisting bacterial udder infection.

Clinical outcomes and molecular genotyping of Staphylococcus aureus isolated from milk samples of dairy primiparous Mediterranean buffaloes (Bubalus bubalis).

Staphylococcus aureus is one of the most important pathogens causing mastitis in dairy cows and in Mediterranean buffaloes. Genotype B (GTB) is contagious in dairy cows and may occur in up to 87% of cows of a dairy herd. It was the aim of this study to evaluate genotypes present, clinical outcomes, and prevalence of Staph. aureus in milk samples of primiparous Mediterranean dairy buffaloes. Two hundred composite milk samples originating from 40 primiparous buffaloes were collected from May to June 2012, at d 10, 30, 60, 90, and 150 d in milk (DIM) to perform somatic cell counts and bacteriological cultures. Daily milk yields were recorded. Before parturition until 40 to 50 DIM, all primiparous animals were housed separated from the pluriparous animals. Milking was performed in the same milking parlor, but the primiparous animals were milked first. After 50 DIM, the primiparous were mixed with the pluriparous animals, including the milking procedure. Individual quarter samples were collected from each animal, and aliquots of 1 mL were mixed and used for molecular identification and genotyping of Staph. aureus. The identification of Staph. aureus was performed verifying the presence of nuc gene by nuc gene PCR. All the nuc-positive isolates were subjected to genotype analysis by means of PCR amplification of the 16S-23S rRNA intergenic spacer region and analyzed by a miniaturized electrophoresis system. Of all 200 composite samples, 41 (20.5%) were positive for Staph. aureus, and no genotype other than GTB was identified. The prevalence of samples positive for Staph. aureus was 0% at 10 DIM and increased to a maximum of 22/40 (55%) at 90 DIM. During the period of interest, 14 buffaloes tested positive for Staph. aureus once, 6 were positive twice, and 5 were positive 3 times, whereas 15 animals were negative at every sampling. At 90 and 150 DIM, 7 (17.5%) and 3 buffaloes (7.5%), respectively, showed clinical mastitis (CM), and only 1 (2.5%) showed CM at both samplings. At 60, 90, and 150 DIM, 1 buffalo was found with subclinical mastitis at each sampling. At 30, 60, 90, and 150 DIM, 2.5 (1/40), 22.5 (9/40), 35 (14/40), and 10% (4/40) were considered affected by intramammary infection, respectively. Buffaloes with CM caused by Staph. aureus had statistically significantly higher mean somatic cell count values (6.06 ± 0.29, Log10 cells/mL ± standard deviation) and statistically significantly lower mean daily milk yields (7.15 ± 1.49, liters/animal per day) than healthy animals (4.69 ± 0.23 and 13.87 ± 2.64, respectively), buffaloes with IMI (4.82 ± 0.23 and 11.16 ± 1.80, respectively), or with subclinical mastitis (5.47 ± 0.10 and 10.33 ± 0.68, respectively). Based on our knowledge, this is the first time that Staph. aureus GTB has been identified in milk samples of dairy Mediterranean buffaloes.

Short communication: effects of systemic treatment with penethamate hydriodide on udder health and milk yields in dry primiparous Mediterranean buffaloes (Bubalus bubalis).

The effects of penethamate hydriodide (Mamyzin, Boehringer Ingelheim, Ingelheim, Germany) on udder health and milk yields were evaluated in primiparous Mediterranean buffaloes (Bubalus bubalis). An intramuscular administration of 10 million international units was performed in 20 buffaloes at 7 d precalving (treatment group; TG), and 20 animals were enrolled as the control group (CG). Evening milk samplings were performed at 10, 30, and 60 d in milk (DIM). Somatic cell count (SCC) values were evaluated on composite milk samples, whereas bacteriological culture and California Mastitis Test were performed on quarter milk. Daily milk yields were recorded after all milkings. After 60 DIM, composite milk samples from each animal were collected for monthly SCC and bacteriological culture until drying off. Statistically significant differences were found between the prevalence of mastitic quarters in the 2 groups at 10 and 30 DIM, and between the incidence of mastitic animals during the examined period (TG: 4/20, 20% vs. CG: 10/20, 50%). Even though lower and higher values of SCC and milk yields were found in TG during each sampling, statistically significant differences were only found at 30 (SCC) and 60 DIM (milk yields). In our study, the antibiotic administration precalving showed good bactericidal activity against the most common udder-specific pathogens that cause mastitis in primiparous Mediterranean buffaloes, and greater efficacy was observed at 10 and 30 DIM compared with 60 DIM. Given the significant decrease in SCC and increase in yields achieved, use of this antibiotic could be economically beneficial in buffalo breeding.

Impact of surgical ventricular restoration on ventricular shape, wall stress, and function in heart failure patients.

Surgical ventricular restoration (SVR) was designed to treat patients with aneurysms or large akinetic walls and dilated ventricles. Yet, crucial aspects essential to the efficacy of this procedure like optimal shape and size of the left ventricle (LV) are still debatable. The objective of this study is to quantify the efficacy of SVR based on LV regional shape in terms of curvedness, wall stress, and ventricular systolic function. A total of 40 patients underwent magnetic resonance imaging (MRI) before and after SVR. Both short-axis and long-axis MRI were used to reconstruct end-diastolic and end-systolic three-dimensional LV geometry. The regional shape in terms of surface curvedness, wall thickness, and wall stress indexes were determined for the entire LV. The infarct, border, and remote zones were defined in terms of end-diastolic wall thickness. The LV global systolic function in terms of global ejection fraction, the ratio between stroke work (SW) and end-diastolic volume (SW/EDV), the maximal rate of change of pressure-normalized stress (dσ*/dt(max)), and the regional function in terms of surface area change were examined. The LV end-diastolic and end-systolic volumes were significantly reduced, and global systolic function was improved in ejection fraction, SW/EDV, and dσ*/dt(max). In addition, the end-diastolic and end-systolic stresses in all zones were reduced. Although there was a slight increase in regional curvedness and surface area change in each zone, the change was not significant. Also, while SVR reduced LV wall stress with increased global LV systolic function, regional LV shape and function did not significantly improve.

Precision medicine in human heart modeling : Perspectives, challenges, and opportunities.

Precision medicine is a new frontier in healthcare that uses scientific methods to customize medical treatment to the individual genes, anatomy, physiology, and lifestyle of each person. In cardiovascular health, precision medicine has emerged as a promising paradigm to enable cost-effective solutions that improve quality of life and reduce mortality rates. However, the exact role in precision medicine for human heart modeling has not yet been fully explored. Here, we discuss the challenges and opportunities for personalized human heart simulations, from diagnosis to device design, treatment planning, and prognosis. With a view toward personalization, we map out the history of anatomic, physical, and constitutive human heart models throughout the past three decades. We illustrate recent human heart modeling in electrophysiology, cardiac mechanics, and fluid dynamics and highlight clinically relevant applications of these models for drug development, pacing lead failure, heart failure, ventricular assist devices, edge-to-edge repair, and annuloplasty. With a view toward translational medicine, we provide a clinical perspective on virtual imaging trials and a regulatory perspective on medical device innovation. We show that precision medicine in human heart modeling does not necessarily require a fully personalized, high-resolution whole heart model with an entire personalized medical history. Instead, we advocate for creating personalized models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between clinical data and medical histories from cohorts of patients using machine learning. We anticipate that this perspective will shape the path toward introducing human heart simulations into precision medicine with the ultimate goals to facilitate clinical decision making, guide treatment planning, and accelerate device design.

Multiscale characterization of heart failure.

Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 µm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure. STATEMENT OF SIGNIFICANCE: Heart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse heart failure.

Using machine learning to characterize heart failure across the scales.

Heart failure is a progressive chronic condition in which the heart undergoes detrimental changes in structure and function across multiple scales in time and space. Multiscale models of cardiac growth can provide a patient-specific window into the progression of heart failure and guide personalized treatment planning. Yet, the predictive potential of cardiac growth models remains poorly understood. Here, we quantify predictive power of a stretch-driven growth model using a chronic porcine heart failure model, subject-specific multiscale simulation, and machine learning techniques. We combine hierarchical modeling, Bayesian inference, and Gaussian process regression to quantify the uncertainty of our experimental measurements during an 8-week long study of volume overload in six pigs. We then propagate the experimental uncertainties from the organ scale through our computational growth model and quantify the agreement between experimentally measured and computationally predicted alterations on the cellular scale. Our study suggests that stretch is the major stimulus for myocyte lengthening and demonstrates that a stretch-driven growth model alone can explain [Formula: see text] of the observed changes in myocyte morphology. We anticipate that our approach will allow us to design, calibrate, and validate a new generation of multiscale cardiac growth models to explore the interplay of various subcellular-, cellular-, and organ-level contributors to heart failure. Using machine learning in heart failure research has the potential to combine information from different sources, subjects, and scales to provide a more holistic picture of the failing heart and point toward new treatment strategies.

Effect of intra-myocardial Algisyl-LVR™ injectates on fibre structure in porcine heart failure.

Recent preclinical trials have shown that alginate injections are a promising treatment for ischemic heart disease. Although improvements in heart function and global structure have been reported following alginate implants, the underlying structure is poorly understood. Using high resolution ex vivo MRI and DT-MRI of the hearts of normal control swine (n = 8), swine with induced heart failure (n = 5), and swine with heart failure and alginate injection treatment (n = 6), we visualized and quantified the fibre distribution and implant material geometry. Our findings show that the alginate injectates form solid ellipsoids with a retention rate of 68.7% ±â€¯21.3% (mean ±â€¯SD) and a sphericity index of 0.37 ±â€¯0.03. These ellipsoidal shapes solidified predominantly at the mid-wall position with an inclination of -4.9°â€¯±â€¯31.4° relative to the local circumferential direction. Overall, the change to left ventricular wall thickness and myofiber orientation was minor and was associated with heart failure and not the presence of injectates. These results show that alginate injectates conform to the pre-existing tissue structure, likely expanding along directions of least resistance as mass is added to the injection sites. The alginate displaces the myocardial tissue predominantly in the longitudinal direction, causing minimal disruption to the surrounding myofiber orientations.

Food contamination by PCBs and waste disposal crisis: Evidence from goat milk in Campania (Italy).

AIM: The study aims at investigating whether, and if so, to what extent the strong presence of urban and industrial waste in a territory may cause PCB contamination in goat milk produced therein. METHODS: We compared PCB concentrations in goat milk from three different locations in the Campania region (Italy). One of the three locations, together with its surrounding area, has long suffered from illegal waste disposal and burning mainly by the so-called Ecomafia. The other locations, not involved in these illegal activities, allowed us to create a control group of goats with characteristics very similar to those of main interest. RESULTS: In milk from the waste contaminated area we identified high PCB concentrations (six indicator PCBs amounted to 170 ng g-1 on lipid weight, on average), whereas there was an almost total absence of such pollutants in milk from the control group. Concentrations of the six indicator PCBs were above the current European maximum residue limit fixed by the EU. At the same time, we found a lower average value of lipid content and a negative relationship between lipid content and PCB concentrations. CONCLUSION: Evidence indicates the potential health risk for consumers living in areas involved in illegal dumping of waste.

Mathematical modeling of cardiac growth and remodeling.

This review provides an overview of the current state of mathematical models of cardiac growth and remodeling (G&R). We concisely describe the experimental observations associated with cardiac G&R and discuss existing mathematical models that describe this process. To facilitate the discussion, we have organized the G&R models in terms of (1) the physical focus (biochemical vs mechanical) and (2) the process that they describe (myocyte hypertrophy vs extracellular matrix remodeling). The review concludes with a discussion of some possible directions that can advance the existing state of cardiac G&R mathematical modeling. WIREs Syst Biol Med 2016, 8:211-226. doi: 10.1002/wsbm.1330 For further resources related to this article, please visit the WIREs website.

Modeling Pathologies of Diastolic and Systolic Heart Failure.

Chronic heart failure is a medical condition that involves structural and functional changes of the heart and a progressive reduction in cardiac output. Heart failure is classified into two categories: diastolic heart failure, a thickening of the ventricular wall associated with impaired filling; and systolic heart failure, a dilation of the ventricles associated with reduced pump function. In theory, the pathophysiology of heart failure is well understood. In practice, however, heart failure is highly sensitive to cardiac microstructure, geometry, and loading. This makes it virtually impossible to predict the time line of heart failure for a diseased individual. Here we show that computational modeling allows us to integrate knowledge from different scales to create an individualized model for cardiac growth and remodeling during chronic heart failure. Our model naturally connects molecular events of parallel and serial sarcomere deposition with cellular phenomena of myofibrillogenesis and sarcomerogenesis to whole organ function. Our simulations predict chronic alterations in wall thickness, chamber size, and cardiac geometry, which agree favorably with the clinical observations in patients with diastolic and systolic heart failure. In contrast to existing single- or bi-ventricular models, our new four-chamber model can also predict characteristic secondary effects including papillary muscle dislocation, annular dilation, regurgitant flow, and outflow obstruction. Our prototype study suggests that computational modeling provides a patient-specific window into the progression of heart failure with a view towards personalized treatment planning.

A computational model that predicts reverse growth in response to mechanical unloading.

Ventricular growth is widely considered to be an important feature in the adverse progression of heart diseases, whereas reverse ventricular growth (or reverse remodeling) is often considered to be a favorable response to clinical intervention. In recent years, a number of theoretical models have been proposed to model the process of ventricular growth while little has been done to model its reverse. Based on the framework of volumetric strain-driven finite growth with a homeostatic equilibrium range for the elastic myofiber stretch, we propose here a reversible growth model capable of describing both ventricular growth and its reversal. We used this model to construct a semi-analytical solution based on an idealized cylindrical tube model, as well as numerical solutions based on a truncated ellipsoidal model and a human left ventricular model that was reconstructed from magnetic resonance images. We show that our model is able to predict key features in the end-diastolic pressure-volume relationship that were observed experimentally and clinically during ventricular growth and reverse growth. We also show that the residual stress fields generated as a result of differential growth in the cylindrical tube model are similar to those in other nonidentical models utilizing the same geometry.

Heterogeneous growth-induced prestrain in the heart.

Even when entirely unloaded, biological structures are not stress-free, as shown by Y.C. Fung׳s seminal opening angle experiment on arteries and the left ventricle. As a result of this prestrain, subject-specific geometries extracted from medical imaging do not represent an unloaded reference configuration necessary for mechanical analysis, even if the structure is externally unloaded. Here we propose a new computational method to create physiological residual stress fields in subject-specific left ventricular geometries using the continuum theory of fictitious configurations combined with a fixed-point iteration. We also reproduced the opening angle experiment on four swine models, to characterize the range of normal opening angle values. The proposed method generates residual stress fields which can reliably reproduce the range of opening angles between 8.7±1.8 and 16.6±13.7 as measured experimentally. We demonstrate that including the effects of prestrain reduces the left ventricular stiffness by up to 40%, thus facilitating the ventricular filling, which has a significant impact on cardiac function. This method can improve the fidelity of subject-specific models to improve our understanding of cardiac diseases and to optimize treatment options.

Residual stress produced by ventricular volume reduction surgery has little effect on ventricular function and mechanics: a finite element model study.

OBJECTIVES: Residual stress is the stress (force per unit area) that remains when all external loads (eg, left ventricular chamber and pericardial pressures) are removed. It has been suggested that ventricular volume reduction surgery can reconstitute the residual stress-strain state of the left ventricle. To determine the extent to which residual stress is involved, we used a mathematical (finite element) model to simulate the effect of volume reduction operations on left ventricular stroke volume/end-diastolic pressure (Starling) relationships, as well as on regional distributions of stress in the local muscle fiber direction (fiber stress). METHODS: The nonlinear stress-strain relationship for the diastolic myocardium was anisotropic with respect to the local muscle fiber direction. An elastance model for active fiber stress was incorporated in an axisymmetric geometric model of the dilated, poorly contractile left ventricular wall. RESULTS: When residual stress is implemented in the model simulation of volume reduction operations, the additional decrease in stroke volume at fixed left ventricular end-diastolic pressure is small (10% volume reduction: 2.0% at 1 mm Hg and 2.0% at 20 mm Hg; 20% volume reduction: 2.2% at 1 mm Hg and 3.1% at 20 mm Hg). Furthermore, there is little change in the mean fiber stress throughout the left ventricular wall (10% volume reduction: +1.0% at end-diastole and -0.3% at end-systole; 20% volume reduction: +2.1% at end-diastole and -1.0% at end-systole). CONCLUSIONS: These results suggest that residual stress produced by volume reduction operations has little effect on left ventricular function and the mean fiber stresses at end-diastole and end-systole.

Mechanism underlying mechanical dysfunction in the border zone of left ventricular aneurysm: a finite element model study.

BACKGROUND: The global left ventricular dysfunction characteristic of left ventricular aneurysm is associated with muscle fiber stretching in the adjacent noninfarcted (border zone) region during isovolumic systole. The mechanism of this regional dysfunction is poorly understood. METHODS: An anteroapical transmural myocardial infarct was created by coronary arterial ligation in an adult Dorset sheep and was allowed to mature into left ventricular aneurysm for 10 weeks. The animal was imaged subsequently using magnetic resonance imaging with simultaneous recording of intraventricular pressures. A realistic mathematical model of the three-dimensional ovine left ventricle with an anteroapical aneurysm was constructed from multiple short-axis and long-axis magnetic resonance imaging slices at the beginning of diastolic filling. RESULTS: Three model simulations are presented: (1) normal border zone contractility and normal aneurysmal material properties; (2) greatly reduced border zone contractility (by 50%) and normal aneurysmal material properties; and (3) greatly reduced border zone contractility (by 50%) and stiffened aneurysmal material properties (by 1000%). Only the latter two simulations were able to reproduce experimentally observed stretching of border zone fibers during isovolumic systole. CONCLUSIONS: The mechanism underlying mechanical dysfunction in the border zone region of left ventricular aneurysm is primarily the result of myocardial contractile dysfunction rather than increased wall stress in this region.

Acquired purpura fulminans induced by alcohol and acetaminophen. Successful treatment with heparin and vitamin K.

Purpura fulminans is a rare syndrome of progressive hemorrhagic necrosis of the skin that may present as a dermatologic emergency. It most commonly affects children during the convalescent phase of a streptococcal infection or a viral exanthem. In adults, it may be associated with sepsis or acquired causes. Its pathogenesis has challenged physicians for decades. It has been discovered that purpura fulminans is almost always associated with disseminated intravascular coagulation and can occur in subjects with inherited or acquired deficiencies of the protein C anticoagulant pathway. Patients with liver compromise may also be potential candidates for coagulopathies secondary to hepatic dysfunction and impaired protein synthesis. It is widely recognized that individuals who consume alcohol on a long-term basis may develop severe hepatotoxicity from ingestion of therapeutic doses of acetaminophen (500 to 1000 mg every 4 to 6 hours). We have observed a patient with chronic alcoholism in whom hepatotoxicity and purpura fulminans developed secondary to the ingestion of acetaminophen.

Large-scale finite element analysis of the beating heart.

The regional mechanics of the beating heart are directly related to factors such as ventricular pumping performance, coronary blood flow, myocardial energetics and oxygen consumption, vulnerability to ischemia and injury, hypertrophy and remodeling, and arrhythmogenesis. Important characteristics include: the complex three-dimensional geometry and fibrous architecture; the nonlinear, nonhomogeneous, anisotropic material properties of the myocardium; the hierarchical collagen connective tissue matrix; the time- and history-dependent active tension development of the cardiac muscle cells; and the three-dimensional anisotropic patterns of cardiac impulse propagation. To model these features realistically requires large-scale computational analysis with sophisticated numerical methods. As described in the chapter by Dr. Hunter and colleagues, an accurate three-dimensional finite element model has been developed to describe the geometry, fiber architecture, and extracellular matrix structure of the heart. The model is based on extensive anatomical measurements in the left and right ventricles (LV and RV) of the canine heart. In this chapter, we illustrate some new approaches to the special problems of large-scale finite element modeling in biomechanics using examples from the analysis of stress and electrical activation in the heart. Prospects for further progress--particularly in coupled problems such as cardiac electromechanics--are examined in light of new developments in high-performance computing.

A distribution-moment model of deactivation in cardiac muscle.

The Distribution Moment (DM) model has simulated experimental data on skeletal muscle, but it has not been used previously to study the mechanics of active contraction in cardiac muscle. In contrast to previous models of striated muscle contraction, all parameters have physical meaning and assumptions concerning biophysical events within the cell are consistent with available data. In order to simulate cardiac muscle deactivation using the DM model it was necessary to make the cross-bridge detachment rates large for large displacements from the neutral equilibrium position of a cross-bridge. To examine the effect of cooperativity on cardiac muscle contraction, we used the DM model's tight coupling scheme with binding of one or two calcium sites regulating contraction. As observed experimentally, our model predicted a reduction of isometric tension development following rapid shortening lengthening transients when contraction is regulated by either one or two calcium binding sites. The predicted deactivating effect increased if the transient was applied late in the twitch when contraction is regulated by two calcium binding sites, but not when it is regulated by one site. This is the first study in which deactivation has been simulated without making any provisions for length-dependent calcium trononin dissociation.