Andersons pediatric cardiology 1739

Cellular Physiology of the Cardiac Myocyte Before discussing the cellular mechanisms associated with the development of myocardial failure, it is necessary to examine the structure and function of the normal cardiomyocyte This section examines some of the principles related to this topic, although it will not provide a comprehensive review of the multitude of intracellular and intercellular messengers; these have been considered in some excellent specialist reviews.17–19 Cardiac myofibers are composed of groups of muscle cells (cardiac myocytes) connected in series and surrounded by connective tissue Each cardiomyocyte is bounded by a thin bilayer of lipid (the sarcolemma) and contains bundles of myofibrils arranged along its long axis These myofibrils, in turn, are formed of repeating sarcomeres, the basic contractile units of the cell, composed of thick and thin filaments, which provide the myocyte with its characteristic striated pattern The thick filaments consist of interdigitating molecules of myosin and the myosin-binding proteins, while the thin filaments consist of monomers of α-actin as well as the regulatory proteins α-tropomyosin and troponins T, I, and C A third filament within the myofibril is the giant protein titin Cardiac myocytes are joined at each end to adjacent myocytes at the intercalated disc This disc contains gap junctions (containing connexins) that mediate electrical conduction between cells and mechanical junctions, composed of adherens junctions and desmosomes The myocyte also contains an extensive and complex network of proteins linking the sarcomere with the sarcolemma and, in turn, with the extracellular matrix This highly organized cytoskeleton provides support for subcellular structures and transmits mechanical and chemical signals within and between cells by activating phosphorylation cascades.20–22 Myocardial activation is dependent on excitation-contraction coupling This is mediated through the release of calcium into the myocyte from the extracellular space but more importantly from intracellular stores, particularly from an intracellular network of membranes, the sarcoplasmic reticulum It appears that the generation of an action potential facilitates the influx of calcium from the extracellular space through the so-called L-type calcium channels, which are particularly concentrated in specialized areas of the sarcolemma (transverse tubules) and invaginate into the cell to reach its interior, close to receptors on the surface of the sarcoplasmic reticulum (the so-called ryanodine receptors) The increase in the intracellular concentration of calcium, which results from its influx from the extracellular space, triggers further release of calcium from the sarcoplasmic reticulum The calcium activates myocardial contraction through its interaction with regulatory proteins on the myofibrils Conversely, diastole is heralded by the reuptake of calcium into the sarcoplasmic reticulum through the activation of an energy-dependent mechanism residing with the so-called sarcoplasmic reticulum calcium ATPase, which itself is regulated by a number of stimulatory and inhibitory proteins, in particular the inhibitory protein phospholamban The ambient level of myocardial activation is modulated by the actions of catecholamines through their interaction with specific receptors on the surface on the myocyte Stimulation of these receptors invokes a series of complex intracellular phosphorylation cascades that modulate not only the rate of influx of calcium from the extracellular space but also the release and reuptake of calcium from the sarcoplasmic reticulum and the affinity of the myofibrillar proteins for calcium Central to the function and homeostasis of the cardiomyocyte is the mitochondrion As the heart is the organ in the body with the highest rate of oxygen uptake and an enormous demand for the continuous synthesis of adenosine triphosphate by oxidative phosphorylation, cardiac myocytes have a very high density of mitochondria This central role for the mitochondrion as the power source for the cell and its position as the major site for the transformation of energy within the myocyte has been well established Energy is stored in the form of high-energy phosphate bonds in adenosine triphosphate The free energy necessary for the formation of the adenosine triphosphate by the phosphorylation of adenosine diphosphate is derived from the oxidation of nicotinamide adenine dinucleotide by the electron transport chain In addition to playing a central role in the metabolism of oxygen, it is now recognized that the mitochondrion plays a crucial role in both apoptosis and necrosis through its so-called permeability transition pores The mitochondrion contains all the necessary machinery for apoptosis and is now acknowledged to be a key determinant of whether a myocyte will live or die after a pathologic insult.23 Central to this determination is the role of reactive oxygen species, generated by the diversion of electrons from the electron transport chain Although it has long been established that excessive levels of superoxide may result in damage to biologic molecules―for example the sarcolemma and intracellular proteins―it is also established that reactive oxygen species play a central signaling role within the cell, which may not only regulate the key metabolic pathways within the cell but also prevent apoptosis and cellular necrosis It is clear, therefore, that the mitochondrion and reactive oxygen species play a central role as executioner or savior in determining the viability of the cardiomyocyte.24,25 Cardiac Myocyte in Heart Failure Having considered the basic physiology of the cardiac myocyte, it is of interest to consider that any of these elements―the myofibrils, the sarcolemma, the gap junctions, the cytoskeleton, the mechanism of excitation-contraction coupling, the adrenergic receptors, or the mitochondria―may contribute to the pathogenesis of heart failure This role may be a primary one; for example, the abnormality of the mitochondrion seen in a patient with a so-called mitochondrial cardiomyopathy26; the abnormality of the key component of the cytoskeleton, dystrophin, in the patient with muscular dystrophy27; or the mutation in a sarcomeric protein in a patient with hypertrophic cardiomyopathy.28 Abnormalities of these elements may also occur secondary to a primary insult originating outside the myocyte They may thus represent the final common pathway in the development of heart failure29,30 and the maladaptive myocardial response to a host of primary external insults Thus the development of heart failure secondary to ischemia-reperfusion injury may be associated with abnormalities of the myocardial mitochondrion in association with alterations in the expression and function of the adrenergic receptors In patients with viral myocarditis, changes in the function of the mitochondrion may herald the onset of apoptosis, whereas enteroviral proteases may cleave dystrophin, leading to a secondary impairment of the mitochondrion's function.29