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• W4383556496 abstract "Learning objectivesBy reading this article, you should be able to:•Recall the principal ion channels and currents involved in the cardiac action potential.•Describe the mechanisms underlying excitation-contraction coupling.•Relate the structure of myofilaments to their function in health and disease.•Discuss the metabolic pathways that provide energy for cardiac muscle contraction.Key points•Resting membrane potential arises from ionic concentration gradients across the cell membrane coupled with varying membrane permeability to each ion. Potassium concentration has dominant influence because of its high membrane permeability.•The characteristic shape of the cardiac action potential is a result of distinct sodium, calcium and potassium channels. Genetic variants affecting these channels have been linked to numerous congenital arrhythmia syndromes.•Type 2 ryanodine receptor plays a central role in calcium-induced calcium release and the activation of excitation-contraction coupling.•Abnormalities in cellular calcium handling and myofilament structure have been identified as important underlying mechanisms in cardiomyopathies and heart failure.•An understanding of metabolic remodelling and cellular energetics in heart failure may provide future therapeutic options. By reading this article, you should be able to:•Recall the principal ion channels and currents involved in the cardiac action potential.•Describe the mechanisms underlying excitation-contraction coupling.•Relate the structure of myofilaments to their function in health and disease.•Discuss the metabolic pathways that provide energy for cardiac muscle contraction. •Resting membrane potential arises from ionic concentration gradients across the cell membrane coupled with varying membrane permeability to each ion. Potassium concentration has dominant influence because of its high membrane permeability.•The characteristic shape of the cardiac action potential is a result of distinct sodium, calcium and potassium channels. Genetic variants affecting these channels have been linked to numerous congenital arrhythmia syndromes.•Type 2 ryanodine receptor plays a central role in calcium-induced calcium release and the activation of excitation-contraction coupling.•Abnormalities in cellular calcium handling and myofilament structure have been identified as important underlying mechanisms in cardiomyopathies and heart failure.•An understanding of metabolic remodelling and cellular energetics in heart failure may provide future therapeutic options. The heart is a biomechanical pump at the centre of our circulatory system. It contracts rhythmically from approximately 6 weeks of gestational age until death.1Valenti O. Di Prima F.A.F. Renda E. et al.Fetal cardiac function during the first trimester of pregnancy.J Prenat Med. 2011; 5: 59-62Google Scholar Contractions are initiated by action potentials, arising from pacemaker cells, transmitted to individual cardiomyocytes via specialised conduction pathways, through intercalated discs and gap junctions between cells.2Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Google Scholar The arrival of this electrical signal results in excitation-contraction coupling, sarcomere and cellular shortening and ejection of blood.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar In this article we describe the cellular processes involved in the activation and mechanics of cardiac muscle contraction and the metabolism fuelling this activity. Cardiomyocytes are excitable cells, with a resting membrane potential in non-pacemaker cells of approximately -90mV.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar This is primarily the result of the electrochemical gradient of ions inside and outside the cell and the variable permeability of the membrane to these ions.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar The most important are K+, Na+, Ca2+ and Cl−. The Nernst equation (Eqn. 1) describes the equilibrium potential for each ion individually given a specific intracellular and extracellular concentration.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar,6Hopkins P.M. Skeletal muscle physiology.Contin Educ Anaesth Crit Care Pain. 2006; 6: 1-6Google Scholar Whereas the Goldman-Hodgkin-Katz constant field equation (Eqn. 2) combines the products of the equilibrium potential and relative permeability (P′) of major ions to calculate the membrane potential.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google ScholarEx=RTzFln[X]out[X]in(1) Equation 1 EX: equilibrium or Nernst potential for ion X; [X]out: extracellular concentration of X; [X]in: intracellular concentration of X; R: universal gas constant; T: absolute temperature; z: valency of ion; F: Faraday constant.Em=PNaPTENa+PKPTEK+PCaPTECa+PClPTEClEm=P′NaENa+P′KEK+P′CaECa+P′ClEClEm=PNa′(+52mV)+PK′(−96mV)+PCa′(+134mV)+P′Cl(−90mV)(2) Equation 2 Goldman-Hodgkin-Katz equation. Em: membrane potential; P: ion permeability of the membrane; P’: ion permeability relative to total membrane permeability to all ions (PT); EX: equilibrium potential for specific ion “x”. At rest, P’Na, P’Ca and P’Cl are very low while P’K is relatively high, therefore Em is closest to the equilibrium potential of K+.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar Under these conditions K+ is moving out of the cell while Na+ and Ca2+ are diffusing in, down their electrochemical gradients (Table 1). The ionic gradients are maintained by a series of ion-exchange mechanisms. The Na/K-ATPase transports 3 Na+ ions out of the cell and 2 K+ ions in, contributing to the negative resting transmembrane potential as well as the differential ion concentrations.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar There is also a Na–Ca exchanger (NCX) which exchanges 3 Na+ ions for 1 Ca2+ generating a small current and may operate in either direction, depending on the concentration gradients of Na+ and Ca2+ and the phase of the action potential (favouring cellular efflux of Ca2+ during diastole and Ca2+ influx when the membrane potential is more positive than – 20 mV).Table 1Intracellular and extracellular concentrations of the principal ions involved in generating the membrane potential.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google ScholarIonIntracellular concentration (mmol L-1)Extracellular concentration (mmol L-1)K+1504Na+20145Ca2+0.00012.5Cl-4120 Open table in a new tab The cardiac action potential originates from cells with pacemaker function, which is the ability to generate regular, spontaneous action potentials. Cells in the sinoatrial (SA) node (70–80 beats min−1), atrioventricular (AV) node (40–60 beats min−1), the bundle of His and Purkinje fibres (15–40 beats min−1) are all capable of generating spontaneous electrical activity.7Guyton A.C. Hall J.E. Rhythmical excitation of the heart.in: Guyton A.C. Hall J.E. Textbook of Medical Physiology. 11th ed. Elsevier Saunders, Philadelphia2006: 116-122Google Scholar However, in the normal myocardium, SA node cells have the highest rate of spontaneous discharge and therefore dictate the beating rate of the heart. In pathological conditions where SA node discharge or action potential conduction fails, other pacemaker cells can take over, but this may result in an abnormally low heart rate, which may require the patient to have a temporary or permanent artificial pacemaker device fitted. In contrast to contractile cardiomyocytes, pacemaker cells do not have a stable resting membrane potential, instead there is a slow diastolic depolarisation that results in the activation of voltage-gated L-type Ca2+ channels resulting in Ca2+ influx (ICa,L) and more rapid depolarisation.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar The origin of this slow, spontaneous depolarisation is thought to be caused by a hyperpolarisation-activated inward current of Na+ and K+, also known as If or ‘funny current’, but more recently other currents and a complex interaction between membrane proteins and sarcoplasmic reticulum (SR) Ca2+ cycling, known as the ‘calcium clock’ have been implicated.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar,8Lakatta E.G. DiFrancesco D. JMCC point-counterpoint.J Mol Cell Cardiol. 2009; 47: 157-170Google Scholar Depolarisation spreads from the SA node to the AV node through atrial muscle cells and via some preferential inter-nodal conduction pathways. In health, the AV node is the only avenue of conduction from the atria to the ventricles. It has a complex structure including faster and slower pathways with differential expression of connexin (gap junction membrane channels) isoforms responsible for impulse conduction from cell to cell.9Temple I.P. Inada S. Dobrzynski H. Boyett M.R. Connexins and the atrioventricular node.Heart Rhythm. 2013; 10: 297-304Google Scholar From here the signal passes through the bundle of His and down the fast-conducting, non-contractile Purkinje fibres to the ventricular myocardium. Purkinje fibres have very fast depolarisation and impulse conduction (2–3 m s−1), because of the high expression of voltage-gated Na+ channels (Nav1.5 isoform) and Cx40 connexins (rather than the slower Cx43 isoform found in myocardial cells) in their gap junctions, respectively.10Ideker R.E. Kong W. Pogwizd S. Purkinje fibers and arrhythmias.Pacing Clin Electrophysiol PACE. 2009; 32: 283-285Google Scholar Contractile myocardial cells have a characteristic action potential (AP) with a flat baseline and a plateau phase, though some differences exist between regions within the heart (Fig. 1): mid-myocardial cells having the longest AP duration, followed by endocardial, then epicardial cells.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar Classically, the cardiac AP is considered to have 5 distinct phases, based on a “typical” ventricular myocardial cell AP. Phase 0 is the fast depolarisation of the cell caused by a rapid increase in Na+ conductivity primarily through the opening of Nav1. Voltage-gated Na+ channels in response to an incoming wave of depolarisation from adjacent cells, resulting in the current INa.4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar This Nav1.5 channel is the predominant isoform in the myocardium and is encoded by the SCN5A gene.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar A loss-of-function variant in SCN5A leads to reduced peak INa and slowing of AP conduction and is implicated in around 20% of patients with Brugada syndrome, while a gain-of-function variant plays a role in congenital LQT3 syndrome.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar,11Levy D. Bigham C. Tomlinson D. Anaesthesia for patients with hereditary arrhythmias part I: Brugada syndrome.BJA Educ. 2018; 18: 159-165Google Scholar These fast Na+ channels open when a threshold voltage of about -70 to -55 mV is reached, resulting in a large increase in P’Na and the membrane potential rapidly reaching +30mV.2Nerbonne J.M. Kass R.S. Molecular physiology of cardiac repolarization.Physiol Rev. 2005; 85: 1205-1253Google Scholar,4Klabunde R.E. Cardiac electrophysiology: normal and ischemic ionic currents and the ECG.Adv Physiol Educ. 2017; 41: 29-37Google Scholar Cardioplegia solution given during cardiac surgery has a particularly high [K+], typically between 16-20 mmol L−1. This shifts the membrane potential towards -50 mV, causing deactivation of Nav1.5 and a diastolic arrest providing a motionless target for the surgeons.12Chambers D.J. Fallouh H.B. Cardioplegia and cardiac surgery: pharmacological arrest and cardioprotection during global ischemia and reperfusion.Pharmacol Ther. 2010; 127: 41-52Google Scholar In Phase 1 fast Na+ channels rapidly inactivate and there is a transient outward K+ current, Ito, through Kv4.3 ion channels resulting in a degree of repolarisation.13Grant A.O. Cardiac ion channels.Circ Arrhythm Electrophysiol. 2009; 2: 185-194Google Scholar This Ito is downregulated in heart failure, hypertrophic cardiomyopathy and in diabetes, prolonging repolarisation and increasing arrhythmia potential.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar Phase 2 is a prolonged plateau of around 200 ms where multiple opposing currents are active in maintaining a depolarised membrane potential. The main inward current is ICa,L, an inward Ca2+ current through L-type calcium channels (Cav1.2) activated by membrane depolarisation to above -45mV.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar,13Grant A.O. Cardiac ion channels.Circ Arrhythm Electrophysiol. 2009; 2: 185-194Google Scholar These Ca2+ channels have much slower kinetics than Nav1.5 and remain open for longer contributing not only to the plateau phase but also to excitation-contraction coupling.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar The reversed NCX is active generating a further inward current.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar Compensatory outward currents are provided by voltage-gated delayed rectifier K+ channels that can be separated into rapid (IKr) and slow (IKs) components conducted by different ion channels.13Grant A.O. Cardiac ion channels.Circ Arrhythm Electrophysiol. 2009; 2: 185-194Google Scholar IKr is conducted by Kv11.1, whose α subunit is encoded by the KCNH2 gene (formerly known as HERG or “human ether-a-go-go related gene”). Loss of function variants in KCNH2 can cause congenital long QT syndromes, whereas gain of function variants result in short QT syndromes.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar Multiple drugs inhibit IKr and therefore assessment of the inhibition of this current is a mandatory part of cardiac safety testing of new drugs.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar IKs and other outward K+ currents also contribute to the maintenance of Phase 2 and with the closure of L-type calcium channels, to the Phase 3 repolarisation. The existence of multiple redundant currents provides a “repolarisation reserve” that is protective against QT prolongation in case of genetic variants or drug effects.14Roden D.M. Long QT syndrome: reduced repolarization reserve and the genetic link.J Intern Med. 2006; 259: 59-69Google Scholar Phase 4 represents the resting membrane potential, during which inward rectifying K+ channels open (IK1), resulting in a large inward current on hyperpolarisation and small outward current on depolarisation, maintaining a stable baseline potential.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar,13Grant A.O. Cardiac ion channels.Circ Arrhythm Electrophysiol. 2009; 2: 185-194Google Scholar Figure 2 summarises the principal ionic currents underpinning the atrial, Purkinje fibre (conducting tissue) and ventricular myocyte action potentials, along with physiological modulators of the ionic currents and their pharmacology (therapeutic and experimental). As mentioned, regional differences in AP duration exist within the myocardium, for example between endocardium and epicardium (Fig 1), resulting from differential expression of K+ channels, especially Kv4.3 responsible for Ito.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar,13Grant A.O. Cardiac ion channels.Circ Arrhythm Electrophysiol. 2009; 2: 185-194Google Scholar In health, this ensures one-way conduction of depolarisation preventing re-entrant circuits. In disease, changes in impulse propagation and AP duration and therefore refractory period duration can give rise to formation of an arrhythmia substrate, that combined with a trigger can result in dangerous re-entry tachycardia.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar Such triggers may be ectopic beats resulting from early or delayed after-depolarisations, most commonly caused by reactivation of L-type calcium channels during prolonged AP duration, or spontaneous diastolic SR Ca2+ release leading to a depolarising NCX current respectively.5Varró A. Tomek J. Nagy N. et al.Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior.Physiol Rev. 2021; 153: 111-122Google Scholar When an action potential reaches a cardiomyocyte, a rapid increase in intracellular [Ca2+] is triggered, which results in activation of the contractile proteins, actin and myosin (Fig. 3), resulting in sarcomeric and thus cellular shortening. The force of cardiac muscle contraction, or inotropy, for a given muscle mass depends on the increase in intracellular [Ca2+] and the sensitivity of the myofilaments to Ca2+.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar Thus mechanisms that control inotropy either regulate calcium handling or affect actin-myosin interaction.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar Numerous T-tubule invaginations of the sarcolemma ensure complete and synchronous action potential propagation into the core of the cell and their loss in heart failure contributes to contractile dysfunction.15Eisner D.A. Caldwell J.L. Kistamás K. Trafford A.W. Calcium and excitation-contraction coupling in the heart.Circ Res. 2017; 121: 181-195Google Scholar L-type calcium channels within the t-tubules are in close apposition to multiple type 2 ryanodine receptors (RyR2s) located within the junctional SR membrane.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar These units are called ‘couplons’, with a RyR2 to L-type calcium channel ratio of approximately 4:1 resulting in signal amplification.16Meissner G. The structural basis of ryanodine receptor ion channel function.J Gen Physiol. 2017; 149: 1065-1089Google Scholar Ca2+ entry via ICa triggers opening of RyR2s resulting in further Ca2+ release from the SR, a process called calcium-induced calcium release (CICR).3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar L-type calcium channels are inactivated by the rising intracellular [Ca2+], while RyR2s are closed by intrinsic inactivation and a decrease in SR [Ca2+], which decreases by 50–75% during contraction.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar,15Eisner D.A. Caldwell J.L. Kistamás K. Trafford A.W. Calcium and excitation-contraction coupling in the heart.Circ Res. 2017; 121: 181-195Google Scholar In fact SR [Ca2+] is a major determinant of the amplitude of Ca2+ release and abnormalities in this flux have been identified in multiple pathologies.15Eisner D.A. Caldwell J.L. Kistamás K. Trafford A.W. Calcium and excitation-contraction coupling in the heart.Circ Res. 2017; 121: 181-195Google Scholar Increased Ca2+ leak from the SR caused by protein kinase A (PKA)-mediated RyR2 hyperphosphorylation in heart failure may contribute to the reported decrease in SR [Ca2+] and the amplitude of calcium release during contraction.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar,15Eisner D.A. Caldwell J.L. Kistamás K. Trafford A.W. Calcium and excitation-contraction coupling in the heart.Circ Res. 2017; 121: 181-195Google Scholar In general, increased diastolic Ca2+ leak via RyR2 promotes spontaneous SR Ca2+ waves, which induce a transient inward current associated with Ca2+ extrusion via electrogenic NCX. If the resulting delayed after-depolarisations reach threshold, this may trigger ventricular arrhythmias, as seen in catecholaminergic polymorphic ventricular tachycardia and heart failure.15Eisner D.A. Caldwell J.L. Kistamás K. Trafford A.W. Calcium and excitation-contraction coupling in the heart.Circ Res. 2017; 121: 181-195Google Scholar,17Kuo I. Ehrlich B. Signaling in muscle contraction.Cold Spring Harb Perspect Biol. 2015; 7Google Scholar In health, when SR [Ca2+] decreases, there is reduced inactivation of ICa leading to increased calcium entry to the cell and replenishment of SR stores.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar During diastole, cytosolic Ca2+ must decrease to allow relaxation. In humans, the majority (approx. 70%) of Ca2+ is removed by the SERCA (sarco-endoplasmic Ca2+ ATPase), while the rest is mainly extracted by NCX.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar In heart failure there is reduced expression of SERCA and the contribution of NCX is increased, also contributing to Ca2+ depletion.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar In neonates the immature SR contributes less to systolic calcium flux and there is an increased reliance on extracellular calcium entry, mainly through L-type calcium channels and NCX, to maintain contractility.18Baum V.C. Palmisano B.W. The immature heart and anesthesia.Anesthesiology. 1997; 87: 1529-1548Google Scholar Sympathetic stimulation results in enhanced inotropy and lusitropy via increased cAMP production and PKA activation. There is phosphorylation of phospholamban, L-type Ca channels, RyR2, cardiac troponin I (cTnI) and myosin binding protein C. Phosphorylation of phospholamban is the most important for lusitropic effect.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar This protein normally inhibits SERCA but when phosphorylated, inhibition is removed and SERCA activity is increased leading to an increase in SR Ca2+ content, systolic Ca2+ release and contractility. Phospholamban genetic knockout results in a hyperdynamic heart in rats.3Bers D.M. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Google Scholar Striated muscle contraction is the result of interaction between thick and thin filaments within the sarcomere (Fig. 3). When intracellular [Ca2+] rises, Ca2+ binds troponin C of the troponin complex; this leads to displacement of tropomyosin from myosin-binding sites on actin.6Hopkins P.M. Skeletal muscle physiology.Contin Educ Anaesth Crit Care Pain. 2006; 6: 1-6Google Scholar Myosin heads complexed with ADP and inorganic phosphate (Pi) in the high energy position bind to actin (Fig. 4), which induces a conformational change resulting in dissociation of ADP and Pi, pivoting of the myosin head and sliding of the filaments.6Hopkins P.M. Skeletal muscle physiology.Contin Educ Anaesth Crit Care Pain. 2006; 6: 1-6Google Scholar Following this, ATP binds the myosin head, resulting in detachment from actin, ATP hydrolysis and a return to its high energy position.6Hopkins P.M. Skeletal muscle physiology.Contin Educ Anaesth Crit Care Pain. 2006; 6: 1-6Google Scholar Each cycle generates a force of approximately 3.5 × 10−12 N, and 11 nm of displacement.19Yu H. Chakravorty S. Song W. Ferenczi M.A. Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives.Eur Biophys J. 2016; 45: 779-805Google Scholar Myosin is a hexameric protein molecule, consisting of two heavy chains, and four light chains.20Finer J.T. Simmons R.M. Spudich J.A. Single myosin molecule mechanics: piconewton forces and nanometre steps.Nature. 1994; 368: 113-119Google Scholar Heavy chains are the molecular motors of contraction with a long tail segment, a lever arm region and the cross-bridge forming head.21Chang A.N. Kamm K.E. Stull J.T. Role of myosin light chain phosphatase in cardiac physiology and pathophysiology.J Mol Cell Cardiol. 2016; 101: 35-43Google Scholar Two heavy chains are intertwined at their tail ends with an essential and a regulatory light chain binding each lever arm.20Finer J.T. Simmons R.M. Spudich J.A. Single myosin molecule mechanics: piconewton forces and nanometre steps.Nature. 1994; 368: 113-119Google Scholar There are two main isoforms of myosin heavy chains in mammalian hearts, α and β, the former possessing nearly three times higher ATPase activity.19Yu H. Chakravorty S. Song W. Ferenczi M.A. Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives.Eur Biophys J. 2016; 45: 779-805Google Scholar This leads to increased velocity of contraction but at the expense of higher ATP consumption. Relative expression of α and β heavy chains in health and disease is an active area of research.21Chang A.N. Kamm K.E. Stull J.T. Role of myosin light chain phosphatase in cardiac physiology and pathophysiology.J Mol Cell Cardiol. 2016; 101: 35-43Google Scholar Β-myosin heavy chain is the predominant isoform in human hearts and variants in its encoding gene (MYH7) together with variants in the cardiac myosin binding protein-C gene (MYBPC3) account for almost 70% of inherited hypertrophic cardiomyopathies.22Suay-Corredera C. Alegre-Cebollada J. The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP-C.FEBS Lett. 2022; 596: 703-746Google Scholar,23McNally E.M. Barefield D.Y. Puckelwartz M.J. The genetic landscape of cardiomyopathy and its role in heart failure.Cell Metab. 2015; 21: 174-182Google Scholar Cardiac myosin binding protein-C (cMyBP-C) regulates cross-bridge formation between myosin head and actin, serving as a brake in its dephosphorylated state.24Flashman E. Redwood C. Moolman-Smook J. Watkins H. Cardiac myosin binding protein C.Circ Res. 2004; 94: 1279-1289Google Scholar When phosphorylated by PKA, it facilitates the binding of the myosin head with actin, thereby modulating cardiac contractility.24Flashman E. Redwood C. Moolman-Smook J. Watkins H. Cardiac myosin binding protein C.Circ Res. 2004; 94: 1279-1289Google Scholar At rest some myosin heads are available for actin binding, protruding from the thick filament in their “on” configuration, while some lie parallel to the their tail segment in the “off” configuration.21Chang A.N. Kamm K.E. Stull J.T. Role of myosin light chain phosphatase in cardiac physiology and pathophysiology.J Mol Cell Cardiol. 2016; 101: 35-43Google Scholar Regulatory myosin light chains (RLCs) bind the lever arm region of the heavy chains, and through their phosphorylation status, influence the configuration of the head.20Finer J.T. Simmons R.M. Spudich J.A. Single myosin molecule mechanics: piconewton forces and nanometre steps.Nature. 1994; 368: 113-119Google Scholar,21Chang A.N. Kamm K.E. Stull J.T. Role of myosin light chain phosphatase in cardiac physiology and pathophysiology.J Mol Cell Cardiol. 2016; 101: 35-43Google Scholar (Fig. 5) When RLC is phosphorylated by myosin light-chain kinase (MLCK), it stabilises the myosin head in the “on” configuration, making it available for actin binding, enhancing contractility. In health, approximately 40% of RLCs are phosphorylated within the sarcomere, suggesting significant contractile reserve through this tuning mechanism and it has been shown that RLC phosphorylation is reduced in human heart failure.21Chang A.N. Kamm K.E. Stull J.T. Role of myosin light chain phosphatase in cardiac physiology and pathophysiology.J Mol Cell Cardiol. 2016; 101: 35-43Google Scholar Another mechanism of fine tuning cardiac muscle contraction is through phosphorylation of cTnI at serines 23/24 (cTnI-Ser23/24) by PKA, which reduces Ca2+ sensitivity, leading to increased relaxation or lusitropy.25Wijnker P.J.M. Murphy A.M. Stienen G.J.M. van der Velden J. Troponin I phosphorylation in human myocardium in health and disease.Neth Heart J. 2014; 22: 463-469Google Scholar Loss of β-adrenergic sensitivity leads to reduced PKA activity and reduced cTnI phosphorylation which has been demonstrated in a wide variety of heart failure aetiologies, including patients with diastolic dysfunction.25Wijnker P.J.M. Murphy A.M. Stienen G.J.M. van der Velden J. Troponin I phosphorylation in human myocardium in health and disease.Neth Heart J. 2014; 22: 463-469Google Scholar Phosphorylation of cTnI-Ser23/24 may also play a role in Frank-Starling's law of length-dependent activation of myofilaments.25Wijnker P.J.M. Murphy A.M. Stienen G.J.M. van der Velden J. Troponin I phosphorylation in human myocardium in health and disease.Neth Heart J. 2014; 22: 463-469Google Scholar Genetic studies have highlighted the importance of the structural proteins that maintain the normal alignment and spatial orientation of the thin and thick filaments within the cardiomyocyte sarcomeres. Of particular note is titin, a giant protein that extends between the Z- and M-lines to support the thick filaments. Variants in TTN, the gene encoding titin, are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy type 9, early onset atrial fibrillation and heart failure.26Jurgens S.J. Choi S.H. Morrill V.N. et al.Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.Nat Genet. 2022; 54: 240-250Google Scholar The heart requires vast amounts of energy to power its contractile and basic cellular functions. It has the highest oxygen extraction of any tissue and the average adult heart turns over approximately 6 kg ATP in a day.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar Mitochondria occupy a third of the cellular volume, as >95% of ATP is generated by oxidative phosphorylation, glycolysis making up a meagre, but important 5%.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar,28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Energy in the heart is stored as ATP and creatine phosphate, their conversion being catalysed by creatine kinase (CK). However ATP and creatine phosphate stores are limited and ischaemia rapidly results in overt ATP depletion and contractile dysfunction. Some energy is stored as glycogen but myocardial stores are much lower than in skeletal muscle.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar The heart is ‘omnivorous’, but under usual conditions, 70–90% of ATP is generated from fatty acid oxidation, the rest from glucose, lactate and ketone bodies.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Fatty acid and glucose pathways are closely interlinked and reciprocally inhibit each other's metabolism via the Randle cycle.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Lactate and ketone bodies can become an important fuel source during exercise and fasting respectively.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar Cellular fatty acid uptake is facilitated by fatty acid translocase (CD36), whereas glucose enters via glucose transporters GLUT1 and GLUT4.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar GLUT1 is constitutively active and is the main transporter in the fetal heart, whereas GLUT4 is insulin regulated and is predominant in the adult heart.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Fatty acids require specialised transport to enter the mitochondria, through the carnitine shuttle, where they undergo β-oxidation, to yield NADH, FADH and acetyl CoA.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Carnitine palmitoyltransferase I (CPT1) is inhibited by high glucose levels, whereas excess cytosolic fatty acids reduce the activity of pyruvate dehydrogenase (PDH) a crucial regulator of glucose metabolic flux.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar Oxidation of fatty acids yields more ATP per mol of substance than glucose but at the expense of higher O2 consumption.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar Many metabolic intermediates have signal transducing roles, that extend to the control of metabolism, mitochondrial biogenesis and beyond, therefore modulating metabolic pathways can have far-reaching and complex effects.28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Under ischaemic conditions there is an accumulation of excess lipids and metabolites which uncouple oxidative phosphorylation, reducing ATP synthesis and stimulating cytochrome c release and apoptosis as well as interacting with sarcolemmal ion channels to increase arrhythmia potential.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar In hypertrophy and heart failure there is a switch from fatty acids to glucose as the primary fuel, similar to the fetal heart, resulting in improved efficiency but eventually reduced overall ATP generation.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar Whether this is adaptive or maladaptive is still a matter of debate but with disease progression there is worsening mitochondrial dysfunction, inefficient transduction of energy from ATP to myofilaments and contractile dysfunction.27Kolwicz S. Purohit S. Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616Google Scholar,28Doenst T. Nguyen T. Abel E. Cardiac metabolism in heart failure.Circ Res Am Heart Assoc. 2013; 113: 709-724Google Scholar Manipulation of this metabolic balance has been a matter of great interest in the search for effective therapies for hypertrophy and heart failure. Glucose-insulin-potassium (GIK) infusion is one such therapy that has been studied extensively over the past 50 years.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar GIK increases glycolytic flux and ATP generation, reduces fatty acid uptake and metabolism and attenuates ischaemia-reperfusion damage in animal models.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar Human trials have had mixed results but when GIK is given close to the time of ischaemic insult, outcomes are more promising.29Grossman A. Opie L. Beshansky J. Ingwall J. Rackley C. Selker H. Glucose-insulin-potassium revived.Circ Am Heart Assoc. 2013; 127: 1040-1048Google Scholar Studies in cardiac surgery have shown reduced incidence of low cardiac output syndrome and inotrope use and improved systolic and diastolic function.30Licker M. Reynaud T. Garofano N. Sologashvili T. Diaper J. Ellenberger C. Pretreatment with glucose-insulin-potassium improves ventricular performances after coronary artery bypass surgery: a randomized controlled trial.J Clin Monit Comput. 2020; 34: 29-40Google Scholar,31Howell N.J. Ashrafian H. Drury N.E. et al.Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) trial.Circulation. 2011; 123: 170-177Google Scholar The IMMEDIATE trial compared early infusion of GIK with placebo in patients with suspected acute coronary syndrome. Although there was no benefit shown for the primary outcome of conversion of acute coronary syndrome to myocardial infarction, results of secondary outcomes suggested a reduction in the composite outcome of cardiac arrest and in-hospital death, with lower risk of serious adverse cardiovascular events at 1 year.32Selker H.P. Udelson J.E. Massaro J.M. et al.One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement during Initial Assessment and Treatment in Emergency Care] Trial).Am J Cardiol. 2014; 113: 1599-1605Google Scholar Cardiomyocytes are uniquely adapted to fulfil their purpose at the centre of the circulatory system. Our understanding of the myriad pathways and mechanisms that characterise their function in health and disease is constantly growing. With an increasing elderly population, anaesthetists increasingly encounter patients with chronic heart disease. Our interventions in operating theatres and the ICU can have a profound effect on the circulation, therefore understanding cardiac physiology remains core knowledge for our practice." @default.
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