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past event log |
Technion, Haifa, Israel
delivered a set of seminars under the title:
The Seminar series introduced the cardiac system and brought out our experiences in studying and analyzing this highly complicated system from different points of view, attempting to relate and quantify the effects of the major interacting parameters on the cardiac function. The cardiac system represents an array of interacting phenomena, from diffusion, active ionic transport, membrane channels and receptors, cellular metabolism, energy consumption and power generation production, electrical excitation, fiber mechanics, microcirculation , imaging & 3D shape reconstruction, ventricular mechanics, circulation, metabolism, coronary flow and, not least important, pathological factors affecting the cardiac function. Understanding this multi-parameter, multi-levelled, complex system, denoted as the Cardionome, or Cardiome, requires studying the interactions between the various parameters by utilizing integrated models and experimental verifications.
The analyses presented here related micro scale phenomena (cellular, molecular etc) to the macro scale, organ, performance. The presentations ranged from micro to macro and back, and brought out analytical physiological models which have been developed to study and understand the physiological parameter interactions as well as the intra-cellular control mechanisms of cardiac function in response to loads. Finally, molecular motors play a crucial part in the performance of the cardiac system and their analysis serves to better understand the transformation of chemical energy to mechanical work. Furthermore, this knowledge serves as a baseline for the fast growing international interest in Nanotechnology & Nanomedicine and relates to our dreams to do better than God...
The human heart is an ingeniously constructed organ that beats some 3 billion times in a normal life span and assures that the cells in the various organs in the body are continuously nourished by blood carrying oxygen and metabolites. The cell is the common denominator of all living entities and life is sustained by the continuous steady transport to and from the cells and the intracellular conversion of biochemical energy to mechanical energy and heat.. The conversion involves molecular translocation and reversible biochemical reactions, modulated by complex nano-scale protein motoric machines. This cellular exchange of substances with their surroundings proceeds with the singular objective of preserving constant steady state homeostasis conditions. It is achieved by normal transport (diffusion and convection), but mainly by facilitated and active transport through the cells' membranes. The energy needed for the active transport as well as for motion and contractility is obtained by the chemo-mechanical transformation of chemical metabolic energy, and usually involves linear and rotary molecular motors utilizing the intracellular high-energy phosphate cycle of ATP<->ADP +P and proton transfer, respectively. The cellular control mechanisms determine the consequent heartbeat and the cyclic cardiac contraction in response to different loads. It must be noted that two levels of control mechanisms operate simultaneously to assure organ viability: The essenssially macro scale maintenance of homeostasis and the basically micro-scale dynamic control and response to transient urgent demands. Understanding the micro and macro scale cardiac characteristics and physiological function requires studying the interactions between the major governing parameters by utilizing integrated models and experimental verifications.
The proper identification of the actual geometry of the heart is crucial for the correct analysis of the state of the heart. The heart's normal and pathological geometry and function can be quantified from the three-dimensional (3D) shape of the heart obtained from cine CT or MRI scans. A simple reconstruction procedure allows visualizing the shape of the heart and determining global deformities, local wall thickness and regional motion. Defining local deviation from normalcy leads to better application of therapeutic modalities and design of surgical manipulations.
Understanding cardiac performance, and its deviation from normal function, requires knowledge of the interactions between the various major parameters involved in maintaining the beating heart. Since many of these variables are difficult, or impossible, to measure, we must rely on logical models, which serve to analyze global or local variations under different operating conditions. The results of the analysis must then be verified against measurable properties. As an example, we consider the interaction between transmural cellular-sarcomere mechanics, blood perfusion across the wall and the local metabolic energy consumption. Comparing the calculated temperature profile across the wall to experimental data validates the assumptions of the model. An interesting application relates to open-heart surgery. The theoretical relationship between blood flow and energetic metabolism and heat production allows determining the coronary blood flow in open-heart surgery by utilizing infrared (IR) thermography.
Another model, which highlights cardiac function, involves the bi-directional interaction between tissue mechanics and capillary blood flow in the myocardium. The model accounts for the three-phase (fiber-blood-interstitium) structure and composition and the fluid and mass transport between them. Simulations show the effects of load and perfusion pressure on cardiac function and, particularly, the effects of edema on cardiac mechanics. Noteworthy are the rather new attempts of resynchronization which aim to improve the ventricular function by proper placing of the pacing electrodes.
Muscle contraction is produced by the sliding of the actin filaments over the myosin filaments due to the work generated by acto-myosin crossbridges (Xbs) in the sarcomere. Understanding the cardiac muscle contraction phenomena depends on having a reasonable description of the intracellular relationship between calcium binding to the cellular 'troponin complex, and the actin-myosin Xb cycling kinetics. A novel model utilizing four physiological / energetic states of the Xbs in the beating heart cycle allows to analyze, describe and understand the contraction phenomena, wherein energy is consumed to generate power with the ability to respond to internal, pathologically dictated , and external, environmentally dictated loads.
The contraction of the cardiac muscle is characterized by: 1) A linear relationship between energy consumption by the sarcomere and the generated mechanical energy, and 2)The sarcomere / Xb ability to modulate the generated mechanical energy, and the energy consumption, in response to various loading conditions. The analytical model, which couples Xbs cycling dynamics with the kinetics of the free Ca2+ binding to troponin-C, includes two feedback mechanisms: i) A positive cooperativity mechanism, whereby the number of force generating Xbs determines the affinity of calcium binding to the regulatory protein and the Force-Length relationship (FLR), and ii) A mechanical negative feedback, whereby the filament shortening velocity affects the rate of Xb turnover from the force to the non-force generating state. The model yields the analytical solution for the muscle Force-Velocity Relationship (FVR), and the linear relation between energy consumption and the generated mechanical energy, as well as the proper definitions of efficiency and economy of power generation. Our experimental and analytical studies of the force response to large amplitude sarcomere length oscillations at various frequencies and constant [Ca2+] reveal that the generated force depends on the history of contraction, and establish the validity of these two feedbacks. The cooperativity provides the adaptive control of the cardiac response to short term changes in the load by modulating Xb recruitment. The cardiac efficiency on the other hand is determined by the mechanical feedback , reflecting an inherent property of the single Xb. The efficiency is thus independent of the number of strong Xbs, is constant and load independent. The combined effects of these two feedback mechanisms regulate sarcomere's dynamics and response characteristics.
A wide range of intracellular motoric activity and cellular motility depends on millions of linear and rotary molecular protein motors of nanometer scale , which propel (bacteria, sperms), transport (messengers in neural network, cell division) generate high-energy metabolites (ATPsynthase) and perpetuate motion (muscle shortening).. Of particular interest here are the mitochondrial rotary ATPsynthase motors which upgrade the biochemical fuel (ATP]) and the linear motors of actin-myosin Xbs which perpetuate motion i.e. sarcomeres shortening and muscle filaments contraction and expansion. These linear molecular motors are energized by ATP hydrolysis, and actuate muscle contraction by the relative motion of the actin-myosin filaments sliding one over the other. The muscle is made of millions of actin-myosin nano-scale linear molecular motors. Each cubic mm of muscle tissue contains 40.1012 motor units. The Xb is 19nm long and 5nm thick, and create a unitary force of ~ 2pN and a single stroke step of 5nm. Image analysis shows the actin-myosin Xb attachment/detachment rate ~2000s-1 cycle compared to ~10s-1 biochemical kinetics of nucleotide binding and dissociation, corresponding to the energy (ATP) consumption rate by the cycling Xbs.
Unlike the linear motors, the rotary engines in flagellar bacteria as well as ATP synthase are proton driven, with a fixed stoichiometry of protons per revolution, by trans-membrane chemical (DpH) and/or electrical potential. Both are equally effective: the protons generate torque regardless of the original energy form. The ATPsynthase motor consists of a rotor and a stator and has a proton driven mechanism (Fo) which drives another mechanism (F1) to catalyze the conversion of ADP to ATP. The same Protein motor can work in reverse, utilizing ATP , to pump ions against the electro-chemical gradient. The Fo rotary motor is about 10nm in diameter and works with a very high efficiency since energy conversion proceeds close to equilibrium. Rotary motors are capable of generating more power than the linear / track motors, and are therefore more feasible as power sources in nano-devices by, say, integration with NEMS
Nanotechnology, and specifically Nanomedicine, is the study of physiology, pharmacy and biosensors at the cellular level, all aimed at manipulating and affecting natural cellular and intracellular phenomena in order to achieve unique useful therapeutic devices. Specific goals are: 1) Maintain and improve human health on the molecular scale by targeted medical procedures, 2) Identify and define diseases by genomic analysis, 3) Improve diagnosis and therapy, including aging, 4) Discover new drugs.. To achieve these goals we must understand the nature of the nano-scale and pico-second intracellular phenomena and develop some unique capabilities to manipulate this molecular world with precision. This involves the ability to construct objects with 3D positional control of molecular structures, manipulate atoms with atomic scale control, avoid harmful mistakes in pico-second constructions, identify and continuously correct unavoidable errors.. Future developments may yield:
A salient feature of the present seminar series is its integrated presentation of interdisciplinary topics; Cell biology concepts and analytic and kinetic modelling are coupled with mechanistic biological and engineering perspectives. The succinct presentations, rich in information and structural in organization, are valuable tools for future research efforts. The lectures distill the essence of the complex cardiac system and highlight pertinent approaches for better understanding and improved insight into potential therapeutic modalities