Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III
1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 5 Linguagem: Inglês
10.1161/01.cir.99.5.674
ISSN1524-4539
AutoresSilvia G. Priori, Jacques Barhanin, Richard N.W. Hauer, Wilhelm Haverkamp, Habo J. Jongsma, André G. Kléber, William J. McKenna, Dan M. Roden, Yoram Rudy, Ketty Schwartz, Peter J. Schwartz, Jeffrey A. Towbin, Arthur M. Wilde,
Tópico(s)Cardiac pacing and defibrillation studies
ResumoHomeCirculationVol. 99, No. 5Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III1 2 Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBGenetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III1 2 Silvia G. Priori, Jacques Barhanin, Richard N. W. Hauer, Wilhelm Haverkamp, Habo J. Jongsma, André G. Kleber, William J. McKenna, Dan M. Roden, Yoram Rudy, Ketty Schwartz, Peter J. Schwartz, Jeffrey A. Towbin and Arthur M. Wilde Silvia G. PrioriSilvia G. Priori From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Jacques BarhaninJacques Barhanin From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Richard N. W. HauerRichard N. W. Hauer From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Wilhelm HaverkampWilhelm Haverkamp From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Habo J. JongsmaHabo J. Jongsma From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , André G. KleberAndré G. Kleber From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , William J. McKennaWilliam J. McKenna From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Dan M. RodenDan M. Roden From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Yoram RudyYoram Rudy From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Ketty SchwartzKetty Schwartz From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Peter J. SchwartzPeter J. Schwartz From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. , Jeffrey A. TowbinJeffrey A. Towbin From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. and Arthur M. WildeArthur M. Wilde From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands. Originally published9 Feb 1999https://doi.org/10.1161/01.CIR.99.5.674Circulation. 1999;99:674–681Part III: Molecular Basis of Cardiac Electrophysiology and ArrhythmiasIn Parts I and II of this article,* we discussed monogenic arrhythmic disorders. These are determined or favored by an inborn alteration and for the most part are characterized by a single genetic alteration. This has allowed the use of "paradigms"; namely, diseases, such as the long-QT syndrome (LQTS), in which it has been possible to trace specific mutations on ion channel genes to their electrophysiological consequences in the patient. Unfortunately for the practicing cardiologist, these "simple" diseases constitute only a small part of the clinical conditions associated with cardiac arrhythmias. The majority of cases affect patients in whom the arrhythmogenic substrate is complex. Indeed, the expression of the molecular systems responsible for normal and abnormal electrical activity vary significantly, depending on a variety of factors, including age, regional factors (type of cells, myocardial perfusion), and such underlying chronic diseases as cardiac hypertrophy, myocardial infarction, and heart failure.The study of this complex system of interacting molecular functions requires an approach somewhat different from that required to consider monogenic disease. Accordingly, in this section we discuss broader themes that are essential to understand the integration of gene expression, ion channel function, and cell coupling in multicellular networks as a first step toward the comprehension of more frequent and more complex arrhythmogenic conditions.Diversity of Gene Expression in the HeartUnderstanding cell-to-cell variability in the cardiac action potential shape and the mechanisms underlying impulse propagation is the key to understanding normal and abnormal cardiac electrophysiology. Much of this variability can be attributed to variability in the characteristics of individual ion currents whose integrated behavior determines the shape and duration of action potentials in individual cardiac cells, as well as to variability in cell-to-cell communications. Ion currents are now recognized to flow through specific pore-forming membrane proteins called ion channels. The first gene encoding an ion channel protein was cloned in 1984,95 and the succeeding decade and a half has seen the cloning of genes encoding most ion channels expressed in heart and in many other tissues.969798 Many of the proteins these genes encode share common structures and can be viewed as members of the same superfamily. For example, Figure 3* shows the tremendous diversity of mammalian genes that make up the family of potassium channel genes. Because potassium channels are made up of 4 ion channel α-subunit proteins, which are not necessarily identical, the potential for diversity in potassium currents is even greater than shown. This is further compounded by the identification of ancillary subunits (the products of different genes) that can assemble with potassium channel tetramers to modulate their function.99100101 Figure 4 illustrates the major ion currents in heart and the genes whose protein products are thought to form their structural basis. The dramatic increase in molecular genetic information underlying cardiac function is not confined to ion channels but rather has extended to multiple other genes, including those controlling cell-to-cell communication (the connexins, Cx), the contractile apparatus, and cardiac development, to name a few. With this cloning effort have come important advances not only in understanding mechanisms of normal cardiac function but also in new insights into the mechanisms underlying common cardiac diseases and their therapy.A common method of studying individual cardiac ion channel gene function is to express the gene of interest in noncardiac (heterologous) study systems, such as mammalian cell lines or the eggs of the African clawed toad, Xenopus laevis. In some cases, expression of a single gene in such heterologous systems is sufficient to reproduce the physiological and pharmacological characteristics of a specific cardiac ion current; HERG expression to recapitulate IKr is an example,102 although coexpression of the minK subunit may increase IKr amplitude.103104 The systems have been especially valuable in delineating the functional consequences of ion channel gene mutations, although it should be recognized that mechanisms other than a simple dominant negative effect on channel gating (eg, altered trafficking) may also play a role.In other cases, faithful recapitulation of a specific cardiac ion current requires coexpression of >1 gene. Heterotetramers of Kv4.2 and Kv4.3 may determine the Ito in some species.105 Other examples include coexpression of a structural gene and an ancillary subunit; one good example is the finding that coexpression of KvLQT1, a member of the potassium channel family shown in Figure 3, with the minK gene is required to recapitulate IKs.13,14Another example is the α-β1 interaction during the development of an adult sodium current as described below. In yet other cases, a gene product (eg, Kv2.1) can be detected in heart without a recognized counterpart among the known ion currents, and ion currents (If) remain for which no corresponding gene has yet been identified. One very important observation is that ion channel genes are virtually never expressed exclusively in the heart. Thus, mutations or blocking drugs may affect not only cardiac function but also function in other organs. The best-described example to date is the deafness displayed by patients with the recessive (Jervell and Lange-Nielsen) form of LQTS.4 This arises because the 2 genes involved in the disease, KvLQT119,20 and minK,16,106 are expressed not only in the heart but also in the inner ear, where together they control endolymph homeostasis.107 It is not yet known whether parent carriers, who have mild, usually but not always asymptomatic mutations in KvLQT120 or minK,15 display subtle defects in hearing. This is but one example of the potential for a molecular genetic explanation for a diversity of symptoms through common mutations affecting function in multiple organs.DevelopmentOne well-recognized form of variability in cardiac function is the stereotypical changes that are observed during development. Much of the information has been gathered in small rodents and may not be directly applicable to humans, but it may be important because a common form of cardiac response to injury is regression to a fetal phenotype. Whether, for example, the electrophysiological changes associated with hypertrophy (eg, in patients with hypertension or heart failure) represent such a patterned response is an important consideration. Understanding the mechanisms underlying such a change in phenotype may be an important step in the prevention of arrhythmias in these common acquired disorders of cardiac function.The earliest stage at which ion currents have been recorded from heart tissue is embryonic (postcoital, pc) day 11 in mouse (normal gestation period, 20.5 days). At this stage, the predominant inward current is L-type calcium current [ICa(L)], and the predominant outward current is the rapidly activating component of the delayed rectifier, IKr.108109 Sodium current (INa) appears later and increases markedly just before birth.109 There are important differences between sodium current recorded in neonatal animals and those recorded in adult animals110111 : INa in neonates is smaller; it activates, inactivates, and recovers from inactivation more slowly than that in adults; and it has a more positive voltage dependence of inactivation than that in adults. Some data suggest that this difference between neonatal and adult sodium current may reflect expression of a β1-subunit and/or α-β1-assembly to produce the "mature" phenotype112113 and that this change may reflect the sympathetic innervation of the heart that occurs around the time of birth. This may be but one example of a more general influence of sympathetic innervation as a modulator of cardiac electrophysiology.114 It is likely that multiple mechanisms will be identified. The possibility that regional cardiac denervation may play a role in acquired diseases (eg, myocardial infarction) is an obvious one that requires further study.115 Another intriguing observation during development is the consistent embryotoxicity of specific IKr blockers, such as dofetilide or almokalant, in the rat.116 Because IKr is the predominant (if not the sole) repolarizing current at this stage,108 it has been postulated that embryotoxicity is due to failure of cardiac repolarization, with death due to arrhythmias secondary to triggered activity (which have been demonstrated under these experimental conditions) or simply membrane depolarization. Whether similar considerations apply to humans has not been determined.The pattern of expression of the connexins, which form the gap junction channels and belong to one gene family, also varies during development. Cx43 mRNA is detectable in mouse heart from day 9.5 pc. Initially, it is expressed only in ventricle, but later it spreads throughout the whole heart. Two weeks after birth, the message starts to diminish again to a steady level that is maintained during adulthood.117 Cx40 is detected from 9.5 days pc. The message is initially confined to atrium and left ventricle, but during development it spreads throughout the whole heart.118 After 14 days pc, Cx40 message starts to diminish in the ventricles from epicardial to endocardial until in the adult, Cx40 is restricted to both atria and the proximal conduction system.117 Cx45 mRNA is expressed from day 11 pc at a constant level throughout the whole heart until week 3 postpartum, when it starts to decrease until in adulthood, only low-level expression in the proximal conduction system is detected.117Regional Diversity in Cardiac ElectrophysiologyAlthough heterogeneity of cardiac electrophysiology is increasingly recognized as a contributor to cardiac arrhythmias, it should also be recognized that there is substantial heterogeneity in the electrophysiological properties of individual cells even under physiological conditions. A trivial example is the differences among the electrophysiological properties of sinoatrial node, atrium, AV node, conducting system, and ventricular myocardium. These differences presumably reflect variability in expression and/or function of the repertoire of ion channels, whose integrated activity determines the distinctive action potentials in each of these regions. More recently, it is increasingly recognized that there is considerable potential for cell-to-cell variability in action potentials and gene expression within such specified regions. For example, a survey of atrial myocytes revealed a consistent Ito only in ≈60% of cells, a consistent IK in ≈15% of cells, and both currents in 30% of cells.119 Studies of mRNA expression have also demonstrated striking cell-to-cell variability in expression of individual ion channel genes.120 Two LQTS genes, HERG and KvLQT1, were identified in a majority of cells in most regions. In contrast, minK was most abundant in sinoatrial node (in ≈33% of cells) but was much less abundant in ventricular muscle cells (10% to 29%). This is consistent with a more recent report that, at least in the mouse, minK expression appears to be restricted largely to the conducting system.121 Similarly, M cells, which as described below appear to play a role in the genesis of arrhythmias related to a long QT interval, have distinctively long action potentials that prolong markedly at slow heart rates,122 a characteristic also seen in Purkinje cells.122124 One report suggests that this distinctive action potential behavior is paralleled by a reduction in IKs (compared with endocardial and epicardial cells).125Electrophysiological studies have identified Kv4.2 and/or 4.3 (depending on the species) as the ion channel gene whose expression in heterologous systems results in a current most closely resembling human Ito.126 One of the important features of human Ito is its usually rapid recovery from inactivation.127 It was this observation that first raised the suggestion that Kv1.4, an initial leading candidate for Ito, might not, in fact, encode this current, because Kv1.4 recovers very slowly from inactivation.128 Interestingly, the human endocardium also displays an Ito, but one that, unlike that recorded in epicardium, recovers from inactivation very slowly and is therefore not regularly observed in endocardia
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