A thermodynamically consistent monte carlo cross-bridge model with a trapping mechanism reveals the role of stretch activation in heart pumping.

Changes in intracellular calcium concentrations regulate heart beats. However, the decline in the left ventricular pressure during early diastole is much sharper than that of the Ca2+ transient, resulting in a rapid supply of blood to the left ventricle during the diastole. At the tissue level, cardiac muscles have a distinct characteristic, known as stretch activation, similar to the function of insect flight muscles. Stretch activation, which is a delayed increase in force following a rapid muscle length increase, has been thought to be related to autonomous control in these muscles. In this numerical simulation study, we introduced a molecular mechanism of stretch activation and investigated the role of this mechanism in the pumping function of the heart, using the previously developed coupling multiple-step active stiffness integration scheme for a Monte Carlo (MC) cross-bridge model and a bi-ventricular finite element model. In the MC cross-bridge model, we introduced a mechanism for trapping the myosin molecule in its post-power stroke state. We then determined the rate constants of transitions for trapping and escaping in a thermodynamically consistent manner. Based on our numerical analysis, we draw the following conclusions regarding the stretch activation mechanism: (i) the delayed force becomes larger than the original isometric force because the population of trapped myosin molecules and their average force increase after stretching; (ii) the delayed force has a duration of more than a few seconds owing to a fairly small rate constant of escape from the trapped state. For the role of stretch activation in heart pumping, we draw the following conclusions: (iii) for the regions in which the contraction force decreases earlier than the neighboring region in the end-systole phase, the trapped myosin molecules prevent further lengthening of the myocytes, which then prevents further shortening of neighboring myocytes; (iv) as a result, the contraction forces are sustained longer, resulting in a larger blood ejection, and their degeneration is synchronized.

A Multiple Step Active Stiffness Integration Scheme to Couple a Stochastic Cross-Bridge Model and Continuum Mechanics for Uses in Both Basic Research and Clinical Applications of Heart Simulation.

In a multiscale simulation of a beating heart, the very large difference in the time scales between rapid stochastic conformational changes of contractile proteins and deterministic macroscopic outcomes, such as the ventricular pressure and volume, have hampered the implementation of an efficient coupling algorithm for the two scales. Furthermore, the consideration of dynamic changes of muscle stiffness caused by the cross-bridge activity of motor proteins have not been well established in continuum mechanics. To overcome these issues, we propose a multiple time step scheme called the multiple step active stiffness integration scheme (MusAsi) for the coupling of Monte Carlo (MC) multiple steps and an implicit finite element (FE) time integration step. The method focuses on the active tension stiffness matrix, where the active tension derivatives concerning the current displacements in the FE model are correctly integrated into the total stiffness matrix to avoid instability. A sensitivity analysis of the number of samples used in the MC model and the combination of time step sizes confirmed the accuracy and robustness of MusAsi, and we concluded that the combination of a 1.25 ms FE time step and 0.005 ms MC multiple steps using a few hundred motor proteins in each finite element was appropriate in the tradeoff between accuracy and computational time. Furthermore, for a biventricular FE model consisting of 45,000 tetrahedral elements, one heartbeat could be computed within 1.5 h using 320 cores of a conventional parallel computer system. These results support the practicality of MusAsi for uses in both the basic research of the relationship between molecular mechanisms and cardiac outputs, and clinical applications of perioperative prediction.

Ionic mechanisms of ST segment elevation in electrocardiogram during acute myocardial infarction.

ST elevation on an electrocardiogram is a hallmark of acute transmural ischemia. However, the underlying mechanism remains unclear. We hypothesized that high ischemic sensitivities of epicardial adenosine triphosphate-sensitive potassium (IKATP) and sodium (INa) currents play key roles in the genesis of ST elevation. Using a multi-scale heart simulation under moderately ischemic conditions, transmural heterogeneities of IKATP and INa created a transmural gradient, opposite to that observed in subendocardial injury, leading to ST elevation. These heterogeneities also contributed to the genesis of hyper-acute T waves under mildly ischemic conditions. By contrast, under severely ischemic conditions, although action potentials were suppressed transmurally, the potential gradient at the boundary between the ischemic and normal regions caused ST elevation without a contribution from transmural heterogeneity. Thus, transmural heterogeneities of ion channel properties may contribute to the genesis of ST-T changes during mild or moderate transmural ischemia, while ST elevation may be induced without the contribution of heterogeneity under severe ischemic conditions.

Patient-specific heart simulation can identify non-responders to cardiac resynchronization therapy.

To identify non-responders to cardiac resynchronization therapy (CRT), various biomarkers have been proposed, but these attempts have not been successful to date. We tested the clinical applicability of computer simulation of CRT for the identification of non-responders. We used the multi-scale heart simulator "UT-Heart," which can reproduce the electrophysiology and mechanics of the heart based on a molecular model of the excitation-contraction mechanism. Patient-specific heart models were created for eight heart failure patients who were treated with CRT, based on the clinical data recorded before treatment. Using these heart models, bi-ventricular pacing simulations were performed at multiple pacing sites adopted in clinical practice. Improvement in pumping function measured by the relative change of maximum positive derivative of left ventricular pressure (%ΔdP/dtmax) was compared with the clinical outcome. The operators of the simulation were blinded to the clinical outcome. In six patients, the relative reduction in end-systolic volume exceeded 15% in the follow-up echocardiogram at 3 months (responders) and the remaining two patients were judged as non-responders. The simulated %ΔdP/dtmax at the best lead position could identify responders and non-responders successfully. With further refinement of the model, patient-specific simulation could be a useful tool for identifying non-responders to CRT.

Ventricular fiber optimization utilizing the branching structure.

In this paper, we propose an algorithm that optimizes the ventricular fiber structure of the human heart. A number of histological studies and diffusion tensor magnetic resonance imaging analyses have revealed that the myocardial fiber forms a right-handed helix at the endocardium. However, the fiber formation changes its orientation as a function of transmural depth, becoming a left-handed helix at the epicardium. To determine how nature can construct such a structure, which obtains surprising pumping performance, we introduce macroscopic modeling of the branching structure of cardiac myocytes in our finite element ventricular model and utilize this in an optimization process. We put a set of multidirectional fibers around a central fiber orientation at each point of the ventricle walls and simulate heartbeats by generating contraction forces along each of these directions. We examine two optimization processes using the workloads or impulses measured in these directions to update the central fiber orientation. Both processes improve the pumping performance towards an optimal value within several tens of heartbeats, starting from an almost-flat fiber orientation. However, compared with the workload optimization, the impulse optimization produces better agreement with experimental studies on transmural changes of fiber helix angle, streamline patterns of characteristic helical structures, and temporal changes in strain. Furthermore, the impulse optimization is robust under geometrical changes of the heart and tends to homogenize various mechanical factors such as the stretch and stretch rate along the fiber orientation, the contraction force, and energy consumption. Copyright © 2015 John Wiley & Sons, Ltd.

Polymorphic mutations of the Mn-SOD gene in intact human lymphocytes and oral squamous cell carcinoma cell lines.

Mutations of the superoxide dismutase (SOD) genes are associated with neoplastic and non-neoplastic diseases. However, the existence of polymorphic mutations of manganese SOD (Mn-SOD) has not been explored in squamous cell carcinoma (SCC) cells or in normal cells. In the present study, we examined mutations in the 5' flanking region of the Mn-SOD gene and Mn-SOD mRNA using 10 human oral SCC (OSC) cell lines and intact lymphocytes obtained from 10 healthy donors and one patient with OSC. The polymerase chain reaction products of DNA obtained from lymphocytes revealed insertions at many sites (-1833, -1575, -1093, -1056, -325, -318, and -310) in 10 of the 11 donors. Transitions and (or) transversions were also observed at -1638 and -216 in lymphocytes from six donors and one donor, respectively. In DNA obtained from OSC cells, insertions and transitions and (or) transversions were more frequent than those in DNA from lymphocytes. In addition, deletions at -1341 and -1288 were observed in all lines except for one line. In these mutations, the transcription factor binding sites were not involved except for the AP-2 binding site (-102) in three cell lines. In Mn-SOD mRNA, Val at -9 position was varied to Ala in lymphocytes from two donors and three OSC cell lines, respectively. In the remaining cell lines, Mn-SOD mRNA from lymphocytes and OSC cell lines revealed heterozygosity (Ala/Val) and homozygosity (Val/Nal), respectively. The Mn-SOD activities in lymphocytes were 3.8-5.8 x 10(-4) U/10(6) cells and the activities in OSC cell lines were 1.8-8.3 x 10(-4) U/10(6) cells. These Mn-SOD activities were not correlated with the mutations of DNA and mRNA. From these results, it is indicated that polymorphic mutations of Mn-SOD exist in human normal cells and that the deletions might be obtained in the course of malignant transformation of OSC although decrease in Mn-SOD activity is not involved in the transformation.