Preface: cardiac control pathways: signaling and transport phenomena.

Signaling is part of a complex system of communication that governs basic cellular functions and coordinates cellular activity. Transfer of ions and signaling molecules and their interactions with appropriate receptors, transmembrane transport, and the consequent intracellular interactions and functional cellular response represent a complex system of interwoven phenomena of transport, signaling, conformational changes, chemical activation, and/or genetic expression. The well-being of the cell thus depends on a harmonic orchestration of all these events and the existence of control mechanisms that assure the normal behavior of the various parameters involved and their orderly expression. The ability of cells to sustain life by perceiving and responding correctly to their microenvironment is the basis for development, tissue repair, and immunity, as well as normal tissue homeostasis. Natural deviations, or human-induced interference in the signaling pathways and/or inter- and intracellular transport and information transfer, are responsible for the generation, modulation, and control of diseases. The present overview aims to highlight some major topics of the highly complex cellular information transfer processes and their control mechanisms. Our goal is to contribute to the understanding of the normal and pathophysiological phenomena associated with cardiac functions so that more efficient therapeutic modalities can be developed. Our objective in this volume is to identify and enhance the study of some basic passive and active physical and chemical transport phenomena, physiological signaling pathways, and their biological consequences.

The challenge of cardiac modeling--interaction and integration.

The goal of clinical cardiology is to obtain an integrated picture of the interacting parameters of muscle and vessel mechanics, blood circulation and myocardial perfusion, oxygen consumption and energy metabolism, and electrical activation and heart rate, thus relating to the true physiological and pathophysiological characteristics of the heart. Scientific insight into the cardiac physiology and performance is achieved by utilizing life sciences, for example, molecular biology, genetics and related intra- and intercellular phenomena, as well as the exact sciences, for example, mathematics, computer science, and related imaging and visualization techniques. The tools to achieve these goals are based on the intimate interactions between engineering science and medicine and the developments of modern, medically oriented technology. Most significant is the beneficiary effect of the globalization of science, the Internet, and the unprecedented international interaction and scientific cooperation in facing difficult multidisciplined challenges. This meeting aims to explore some important interactions in the cardiac system and relate to the integration of spatial and temporal interacting system parameters, so as to gain better insight into the structure and function of the cardiac system, thus leading to better therapeutic modalities.

Preface: the cellular communications maze.

Inter- and intracellular ionic and molecular communications are indispensable to the preservation of life and all organic functions. The cell constantly responds to a myriad of extracellular ionic and molecular signals, and cell behavior in single-cell or multicellular organisms is coordinated by these signals moving into, inside, or between the cells. The signals pass through the cell's phospholipidic plasma membrane by diffusion and, mostly, via protein transporters: gates, receptors, and/or ion pumps imbedded in the membrane. Each signaling pathway is a complex cause and effect chain of events involving intricate networks of interactions. For example, the extracellular signals, which are monitored by the cell's membrane cognate receptors, form ligand-receptor complexes. These are typically amplified by interaction with a coupling protein, mostly a G protein, and are diversified via intracellular signal transductions, either directly or via the activation of intracellular second messengers. The present volume focuses on signal-induced interactions that trigger specific responses of the effector system. Highlighting the cellular communication framework and the major parameters encountered in these complex interactive phenomena may help to familiarize the uninitiated with the complex phenomena involved in sustaining life.

Cardiac engineering--deciphering the cardiome.

Two monumental phenomena have shaped science and medicine in the last century and practically changed the world we live in. The first relates to the intimate interaction between engineering science and medicine-for example, technology and cardiology. The second relates to the globalization of science, the proliferation of the internet, and the unprecedented international interaction and scientific cooperation in facing difficult multidisciplinary challenges. The beneficial combination of these two megaphenomena, accompanied by significant environmental and sanitary changes, has greatly improved the quality of life and increased longevity around the globe. This conference, and the volume issuing from it, aims to explore the application of new developments in the microworld of cells and genes to gain better insight into the structure and function of the cardiac system, and hence to lead to better therapeutic modalities This multinational gathering of outstanding scientists from the various fields of the cardiac sciences is a living testimonial to human ingenuity and the spirit of international cooperation.

The adaptive intracellular control of cardiac muscle function.

This study explores the mechanisms dominating the regulation of the biochemical energy consumption and the mechanical output of the actin-myosin motor units, the crossbridges (Xbs), in the cardiac sarcomere. Our analytical model, which couples Xbs cycling dynamics with the kinetics of the free Ca(2+) binding to troponin-C (Tn-C), includes two feedback mechanisms: (1) a cooperativity mechanism, whereby the amount of force generating Xbs determines the affinity of calcium binding to the regulatory protein and the force-length relationship (FLR); and (2) a mechanical (negative) feedback, whereby the filament shortening velocity affects the rate of Xb turnover from the force- to the nonforce-generating state, allows the analytical solution for the muscle force-velocity relationship (FVR), and the linear relation between energy consumption and the generated mechanical energy. Our experimental and analytical studies of the force response to large-amplitude sarcomere length (SL) oscillations at various frequencies and constant [Ca(2+)] in the isolated tetanized rat trabeculae reveal that the generated force depends on the history of contraction and establishes the validity of these two feedbacks. The cooperativity mechanism generates counterclockwise (CCW) hystereses, where the muscle generates external work; while at higher frequencies the mechanical feedback produces clockwise (CW) hystereses, where the muscle behaves as a damper. The cooperativity provides the adaptive control of the cardiac response to short-term changes in the load by modulating Xb recruitment. The cardiac efficiency, defined as the ratio of the generated mechanical energy (i.e., external work and pseudo-potential energy) to the sarcomere energy consumption, 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 and is constant and load independent.

Augmentation of dilated failing left ventricular stroke work by a physiological cardiac assist device.

A novel physiological cardiac assist device (PCAD), otherwise known as the LEVRAM assist device, which is synchronized with the heartbeat, was developed to assist the left ventricle (LV) in chronic heart failure (CHF). The PCAD utilizes a single cannula, which is inserted in less than 15 s through the apex of the beating LV by means of a specially designed device. Blood is withdrawn from the LV into the PCAD in diastole and is injected back to the LV, through the same cannula, during the systolic ejection phase, thereby augmenting stroke volume (SV) and stroke work (SW). CHF with dilated LV was induced in sheep by successive intracoronary injections of 100-microm beads. The sheep (92.2 +/- 25.9 kg, n = 5) developed stable CHF with increased LV end-diastolic diameter (69.4 +/- 3.3 mm) and end-diastolic volume (LVEDV = 239 +/- 32 mL), with severely reduced ejection fraction (23.8 +/- 7.6%), as well as mild-to-moderate mitral regurgitation. The sheep were anesthetized, and the heart was exposed by left thoracotomy. Pressure was measured in the LV and aorta (Millar). The SV was measured by flow meters and the LV volume by sonocrystals. Assist was provided every 10 regular beats, and the assisted beats were compared with the preceding unassisted beats, at the same LVEDV. The PCAD displaced 13.6 +/- 3.4 mL, less than 8% of LVEDV. Added SW was calculated from the assisted and control pressure-volume loops. The efficiency, defined as an increase in SW divided by the mechanical work of the PCAD, was 85.4 +/- 16.9%. We conclude that the PCAD, working with a small displaced blood volume in synchrony with the heartbeat, efficiently augments the SW of the dilated failing LV. The PCAD is suggested for use as a permanent implantable device in CHF.

Molecular motion and cardiac muscle motor dynamics.

This paper reports on the kinetics of molecular motion in cardiac (and skeletal) muscles, studied by image analysis of the motility assay of an isolated actin filament sliding over isolated myosin heads that perform as linear motors. Image analysis allows us to study the dynamics of the crossbridges (Xbs) formed by the interactions between the actin molecule and the myosin heads, and to explore the rate kinetics of the interactions between the two. A most significant result pertains to the identification and characterization of two kinds of kinetics involved in Xb dynamics. The analysis of the acquired images suggests that Xb dynamics is determined by two distinctive kinetic mechanisms: fast physical kinetics that relates to the actin-myosin Xb attachment and detachment cycle and a process that is orders of magnitude slower in biochemical kinetics that relates to the reactions of nucleotide binding and dissociation.