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      Cardiac efficiency and Starling's Law of the Heart

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          Abstract

          Abstract

          The formulation by Starling of The Law of the Heart states that ‘the [mechanical] energy of contraction, however measured, is a function of the length of the muscle fibre’. Starling later also stated that ‘the oxygen consumption of the isolated heart … is determined by its diastolic volume, and therefore by the initial length of its muscular fibres’. This phrasing has motivated us to extend Starling's Law of the Heart to include consideration of the efficiency of contraction. In this study, we assessed both mechanical efficiency and crossbridge efficiency by studying the heat output of isolated rat ventricular trabeculae performing force–length work‐loops over ranges of preload and afterload. The combination of preload and afterload allowed us, using our modelling frameworks for the end‐systolic zone and the heat–force zone, to simulate cases by recreating physiologically feasible loading conditions. We found that across all cases examined, both work output and change of enthalpy increased with initial muscle length; hence it can only be that the former increases more than the latter to yield increased mechanical efficiency. In contrast, crossbridge efficiency increased with initial muscle length in cases where the extent of muscle shortening varied greatly with preload. We conclude that the efficiency of cardiac contraction increases with increasing initial muscle length and preload. An implication of our conclusion is that the length‐dependent activation mechanism underlying the cellular basis of Starling's Law of the Heart is an energetically favourable process that increases the efficiency of cardiac contraction.

          Key points

          • Ernest Starling in 1914 formulated the Law of the Heart to describe the mechanical property of cardiac muscle whereby force of contraction increases with muscle length.

          • He subsequently, in 1927, showed that the oxygen consumption of the heart is also a function of the length of the muscle fibre, but left the field unclear as to whether cardiac efficiency follows the same dependence.

          • A century later, the field has gained an improved understanding of the factors, including the distinct effects of preload and afterload, that affect cardiac efficiency. This understanding presents an opportunity for us to investigate the elusive length‐dependence of cardiac efficiency.

          • We found that, by simulating physiologically feasible loading conditions using a mechano‐energetics framework, cardiac efficiency increased with initial muscle length.

          • A broader physiological importance of our findings is that the underlying cellular basis of Starling's Law of the Heart is an energetically favourable process that yields increased efficiency.

          Abstract

          Abstract figure legend When the length of cardiac muscle is increased from L 1 to L 2, the muscle produces greater mechanical force. This is the Law of the Heart, formulated by Ernest Starling over a century ago. We studied the energetics consequences of the length‐dependent increase of force. We found that mechanical work output (the area of the force–length work‐loop) and change of enthalpy (i.e. energy expenditure) both increase with increasing length. The former increases more than the latter, leading to increasing efficiency of contraction with increasing length.

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          Most cited references104

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          The Heat of Shortening and the Dynamic Constants of Muscle

          A V Hill (1938)
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            Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats.

            Ventricular pressure-volume relationships have become well established as the most rigorous and comprehensive ways to assess intact heart function. Thanks to advances in miniature sensor technology, this approach has been successfully translated to small rodents, allowing for detailed characterization of cardiovascular function in genetically engineered mice, testing effects of pharmacotherapies and studying disease conditions. This method is unique for providing measures of left ventricular (LV) performance that are more specific to the heart and less affected by vascular loading conditions. Here we present descriptions and movies for procedures employing this method (anesthesia, intubation and surgical techniques, calibrations). We also provide examples of hemodynamics measurements obtained from normal mice/rats, and from animals with cardiac hypertrophy/heart failure, and describe values for various useful load-dependent and load-independent indexes of LV function obtained using different types of anesthesia. The completion of the protocol takes 1-4 h (depending on the experimental design/end points).
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              Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.

              Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.
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                Author and article information

                Contributors
                j.han@auckland.ac.nz
                Journal
                J Physiol
                J Physiol
                10.1111/(ISSN)1469-7793
                TJP
                jphysiol
                The Journal of Physiology
                John Wiley and Sons Inc. (Hoboken )
                0022-3751
                1469-7793
                10 September 2022
                01 October 2022
                10 September 2022
                : 600
                : 19 ( doiID: 10.1113/tjp.v600.19 )
                : 4265-4285
                Affiliations
                [ 1 ] Auckland Bioengineering Institute University of Auckland Auckland New Zealand
                [ 2 ] Department of Engineering Science University of Auckland Auckland New Zealand
                [ 3 ] Department of Physiology University of Auckland Auckland New Zealand
                Author notes
                [*] [* ] Corresponding author J.‐C. Han: Auckland Bioengineering Institute, University of Auckland, 70 Symonds Street, Auckland, New Zealand. Email: j.han@ 123456auckland.ac.nz

                Author information
                https://orcid.org/0000-0002-6396-7628
                https://orcid.org/0000-0002-0452-0308
                https://orcid.org/0000-0002-6928-4019
                https://orcid.org/0000-0002-8651-3557
                Article
                TJP15240
                10.1113/JP283632
                9826111
                35998082
                1e226224-0084-4936-89b0-400ebc6acc14
                © 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 28 July 2022
                : 18 August 2022
                Page count
                Figures: 13, Tables: 0, Pages: 21, Words: 12750
                Funding
                Funded by: Royal Society Te Apārangi (Royal Society of New Zealand)
                Award ID: James Cook Research Fellowship
                Funded by: Royal Society of New Zealand | Marsden Fund (Royal Society of New Zealand Marsden Fund): Marsden Fast‐Start grants
                Award ID: UOA1504
                Award ID: UOA1703
                Funded by: Manatu Hauora | Health Research Council of New Zealand (HRC): Sir Charles Hercus Health Research Fellowships
                Award ID: 20/011
                Award ID: 21/116
                Categories
                Research Article
                Cardiovascular
                Custom metadata
                2.0
                1 October 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:08.01.2023

                Human biology
                cardiac energetics,force–length relation,frank–starling mechanism,mechanical efficiency

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