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      Exploring cardiac biophysical properties

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          Abstract

          The heart is subject to multiple sources of stress. To maintain its normal function, and successfully overcome these stresses, heart muscle is equipped with fine-tuned regulatory mechanisms. Some of these mechanisms are inherent within the myocardium itself and are known as intrinsic mechanisms. Over a century ago, Otto Frank and Ernest Starling described an intrinsic mechanism by which the heart, even ex vivo, regulates its function on a beat-to-beat basis. According to this phenomenon, the higher the ventricular filling is, the bigger the stroke volume. Thus, the Frank-Starling law establishes a direct relationship between the diastolic and systolic function of the heart. To observe this biophysical phenomenon and to investigate it, technologic development has been a pre-requisite to scientific knowledge. It allowed for example to observe, at the cellular level, a Frank-Starling like mechanism and has been termed: Length Dependent Activation (LDA).

          In this review, we summarize some experimental systems that have been developed and are currently still in use to investigate cardiac biophysical properties from the whole heart down to the single myofibril. As a scientific support, investigation of the Frank-Starling mechanism will be used as a case study.

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          The cellular basis of the length-tension relation in cardiac muscle.

          The relation between muscle length or sarcomere length and developed tension for lengths up to the optimal for contraction (Lmax) is much steeper in cardiac muscle than in skeletal muscle. The steepness of the cardiac length--tension relation arises because the degree of activation of the cardiac myofibrils by calcium increases as muscle length is increased. Two processes contribute to this length-dependence of activation: (i) the calcium sensitivity of the myofibrils increases with muscle length and (ii) the amount of calcium supplied to the myofibrils during systole increases with muscle length. Of these two, the change in calcium sensitivity is the most clearly defined and is responsible for a large part of the rapid change in developed tension when muscle length is altered. It is likely that this change in calcium sensitivity is due to a change in the affinity of troponin for calcium but the underlying mechanism has not been identified. There is good evidence that changes in the calcium supply to the myofibrils can account for the slow changes in tension that follow an alteration in length; there may also be rapid changes in calcium supply but this is less clearly established at present.
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            Myofilament length dependent activation.

            The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca(2+) ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the "Frank-Starling law of the heart" constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development. Copyright (c) 2009 Elsevier Ltd. All rights reserved.
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              Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate.

              We investigate acute effects of axial stretch, applied by carbon fibers (CFs), on diastolic Ca2+ spark rate in rat isolated cardiomyocytes. CFs were attached either to both cell ends (to maximize the stretched region), or to the center and one end of the cell (to compare responses in stretched and nonstretched half-cells). Sarcomere length was increased by 8.01+/-0.94% in the stretched cell fraction, and time series of XY confocal images were recorded to monitor diastolic Ca2+ spark frequency and dynamics. Whole-cell stretch causes an acute increase of Ca2+ spark rate (to 130.7+/-6.4%) within 5 seconds, followed by a return to near background levels (to 104.4+/-5.1%) within 1 minute of sustained distension. Spark rate increased only in the stretched cell region, without significant differences in spark amplitude, time to peak, and decay time constants of sparks in stretched and nonstretched areas. Block of stretch-activated ion channels (2 micromol/L GsMTx-4), perfusion with Na+/Ca2+-free solution, and block of nitric oxide synthesis (1 mmol/L L-NAME) all had no effect on the stretch-induced acute increase in Ca2+ spark rate. Conversely, interference with cytoskeletal integrity (2 hours of 10 micromol/L colchicine) abolished the response. Subsequent electron microscopic tomography confirmed the close approximation of microtubules with the T-tubular-sarcoplasmic reticulum complex (to within approximately 10(-8)m). In conclusion, axial stretch of rat cardiomyocytes acutely and transiently increases sarcoplasmic reticulum Ca2+ spark rate via a mechanism that is independent of sarcolemmal stretch-activated ion channels, nitric oxide synthesis, or availability of extracellular calcium but that requires cytoskeletal integrity. The potential of microtubule-mediated modulation of ryanodine receptor function warrants further investigation.
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                Author and article information

                Journal
                Glob Cardiol Sci Pract
                Glob Cardiol Sci Pract
                GCSP
                GCSP
                Global Cardiology Science & Practice
                Bloomsbury Qatar Foundation Journals (Qatar )
                2305-7823
                2015
                10 April 2015
                : 2015
                : 10
                Affiliations
                [1] 1Qatar Cardiovascular Research Center, Qatar Foundation, Doha, Qatar
                [2] 2U1046 INSERM – UMR9214 CNRS– Université de Montpellier, Montpellier, France
                [3] 3Department of Cell and Molecular Physiology, Heath Science Division, Loyola University Chicago, Maywood, Illinois 60153
                Author notes
                Article
                gcsp.2015.10
                10.5339/gcsp.2015.10
                4448074
                26779498
                241da6e1-9669-4538-9a53-fe5cc245e0fa
                © 2015 Ait Mou, Bollensdorff, Cazorla, Magdi, de Tombe, licensee Bloomsbury Qatar Foundation Journals.

                This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 December 2014
                : 26 February 2015
                Categories
                Review Article

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