Dario DiFrancesco

Bio: Dario DiFrancesco is an academic researcher from University of Milan. The author has contributed to research in topics: Pacemaker potential & Sinoatrial node. The author has an hindex of 66, co-authored 176 publications receiving 15835 citations. Previous affiliations of Dario DiFrancesco include Columbia University & University of Oxford.

Pacemaker Mechanisms in Cardiac Tissue

Abstract: The heartbeat is a sign of life, and not surprisingly it has attracted much interest and curiosity since the early stages of scientific investigation. Even Leonardo da Vinci, in his anatomical studies, realized that rhythmic, restless activity was an intrinsic property of cardiac muscle (92), "As to the heart: it moves itself, and doth never stop, except it be for eternity." In fact, a search for the basis of spontaneous cardiac activity could only be undertaken several centuries after these primitive observations with the development of techniques that allowed the study of the electrical properties of excitable tissues and particularly of cardiac muscle (18, 71,77,23). Cardiac pacemaker activity originates in specialized myocytes located in restricted areas of the heart that are characterized by the ability to beat spontaneously even when separated from the rest of the cardiac muscle (24, 106, 103, 11, 81). Voltage-clamp investigation of pacemaker tissue opened the way to a better understanding of the ionic mechanisms promoting rhythmicity in pacemaker tissue (64, 6). In pacemaker cells of the mammalian sino-atrial (SA) node, spontaneous activity results from a typical phase of their action potential, the slow diastolic depolarization. The concept that a slow depolarization is an inherent property of spontaneously active myocar­ dium is an old one that has been actively investigated since the first recordings of cardiac electrical activity revealed the existence of a slow depolarizing phase preceding the action potential onset in beating tissue (for a review, see 105). During this phase, corresponding to diastole of the cardiac contraction cycle, the membrane slowly depolarizes following termination of an action potential, until threshold for a new action potential is reached. Thus, the

A Model of Cardiac Electrical Activity Incorporating Ionic Pumps and Concentration Changes

Abstract: Equations have been developed to describe cardiac action potentials and pacemaker activity. The model takes account of extensive developments in experimental work since the formulation of the M.N.T. (R. E. McAllister, D. Noble and R. W. Tsien, J. Physiol., Lond. 251, 1-59 (1975)) and B.R. (G. W. Beeler and H. Reuter, J. Physiol., Lond. 268, 177-210 (1977)) equations. The current mechanism i $\_{K2}$ has been replaced by the hyperpolarizing-activated current, i $\_f$ . Depletion and accumulation of potassium ions in the extracellular space are represented either by partial differential equations for diffusion in cylindrical or spherical preparations or, when such accuracy is not essential, by a three-compartment model in which the extracellular concentration in the intercellular space is uniform. The description of the delayed K current, i $\_K$ , remains based on the work of D. Noble and R. W. Tsien (J. Physiol., Lond. 200, 205-231 (1969a)). The instantaneous inward-rectifier, i $\_{K1}$ , is based on S. Hagiwara and K. Takahashi's equation (J. Membrane Biol. 18, 61-80 (1974)) and on the patch clamp studies of B. Sakmann and G. Trube (J. Physiol., Lond. 347, 641-658 (1984)) and of Y. Momose, G. Szabo and W. R. Giles (Biophys. J. 41, 311a (1983)). The equations successfully account for all the properties formerly attributed to i $\_{K2}$ , as well as giving more complete descriptions of i $\_{K1}$ and i $\_K$ . The sodium current equations are based on experimental data of T. J. Colatsky (J. Physiol., Lond. 305, 215-234 (1980)) and A. M. Brown, K. S. Lee and T. Powell (J. Physiol., Lond. 318, 479-500 (1981)). The equations correctly reproduce the range and magnitude of the sodium \`window' current. The second inward current is based in part on the data of H. Reuter and H. Scholz (J. Physiol., Lond. 264, 17-47 (1977)) and K. S. Lee and R. W. Tsien (Nature, Lond. 297, 498-501 (1982)) so far as the ion selectivity is concerned. However, the activation and inactivation gating kinetics have been greatly speeded up to reproduce the very much faster currents recorded in recent work. A major consequence of this change is that Ca current inactivation mostly occurs very early in the action potential plateau. The sodium-potassium exchange pump equations are based on data reported by D. C. Gadsby (Proc. natn. Acad. Sci. U.S.A. 77, 4035-4039 (1980)) and by D. A. Eisner and W. J. Lederer (J. Physiol., Lond. 303, 441-474 (1980)). The sodium-calcium exchange current is based on L. J. Mullins' equations (J. gen. Physiol. 70, 681-695 (1977)). Intracellular calcium sequestration is represented by simple equations for uptake into a reticulum store which then reprimes a release store. The repriming equations use the data of W. R. Gibbons & H. A. Fozzard (J. gen. Physiol. 65, 367-384 (1975b)). Following Fabiato & Fabiato's work (J. Physiol., Lond. 249, 469-495 (1975)), Ca release is assumed to be triggered by intracellular free calcium. The equations reproduce the essential features of intracellular free calcium transients as measured with aequorin. The explanatory range of the model entirely includes and greatly extends that of the M.N.T. equations. Despite the major changes made, the overall time-course of the conductance changes to potassium ions strongly resembles that of the M.N.T. model. There are however important differences in the time courses of Na and Ca conductance changes. The Na conductance now includes a component due to the hyperpolarizing-activated current, i $\_f$ , which slowly increases during the pacemaker depolarization. The Ca conductance changes are very much faster than in the M.N.T. model so that in action potentials longer than about 50 ms the primary contribution of the fast gated calcium channel to the plateau is due to a steady-state \`window' current or non-inactivated component. Slower calcium or Ca-activated currents, such as the Na-Ca exchange current, or Ca-gated currents, or a much slower Ca channel must then play the dynamic role previously attributed to the kinetics of a single type of calcium channel. This feature of the model in turn means that the repolarization process should be related to the inotropic state, as indicated by experimental work. The model successfully reproduces intracellular sodium concentration changes produced by variations in [Na] $\_o$ , or Na-K pump block. The sodium dependence of the overshoot potential is well reproduced despite the fact that steady state intracellular Na is proportional to extracellular Na, as in the experimental results of D. Ellis J. Physiol., Lond. 274, 211-240 (1977)). The model reproduces the responses to current pulses applied during the plateau and pacemaker phases. In particular, a substantial net decrease in conductance is predicted during the pacemaker depolarization despite the fact that the controlling process is an increase in conductance for the hyperpolarizing-activated current. The immediate effects of changing extracellular [K] are reproduced, including: (i) the shortening of action potential duration and suppression of pacemaker activity at high [K]; (ii) the increased automaticity at moderately low [K]; and (iii) the depolarization to the plateau range with premature depolarizations and low voltage oscillations at very low [K]. The ionic currents attributed to changes in Na-K pump activity are well reproduced. It is shown that the apparent K $\_m$ for K activation of the pump depends strongly on the size of the restricted extracellular space. With a 30% space (as in canine Purkinje fibres) the apparent K $\_m$ is close to the assumed real value of 1 mM. When the extracellular space is reduced to below 5%, the apparent K $\_m$ increases by up to an order of magnitude. A substantial part of the pump is then not available for inhibition by low [K] $\_b$ . These results can explain the apparent discrepancies in the literature concerning the K $\_m$ for pump activation.

Direct activation of cardiac pacemaker channels by intracellular cyclic AMP

Abstract: CYCLIC AMP acts as a second messenger in the modulation of several ion channels1–9 that are typically controlled by a phosphorylation process10. In cardiac pacemaker cells, adrenaline and acetylcholine regulate the hyperpolarization-activated current (if), but in opposite ways; this current is involved in the generation and modulation of pacemaker activity11. These actions are mediated by cAMP and underlie control of spontaneous rate by neurotransmitters12–17. Whether the cAMP modulation of if is mediated by channel phosphorylation is, however, still unknown. Here we investigate the action of cAMP on if in excised patches of cardiac pacemaker cells and find that cAMP activates if by a mechanism independent of phosphorylation, involving a direct interaction with the channels at their cytoplasmic side. Cyclic AMP activates if by shifting its activation curve to more positive voltages, in agreement with whole-cell results. This is the first evidence of an ion channel whose gating is dually regulated by voltage and direct cAMP binding.

How does adrenaline accelerate the heart

Abstract: THE way in which adrenaline acts on the sinoatrial (SA) node to accelerate the heart rate has hitherto been obscure. However, in various other parts of the heart adrenaline increases the slow inward (Ca2+/Na+) current1–4, and voltage-recording experiments have indicated that adrenaline also has this action in the sinus region5–7. In the voltage-clamp experiments reported here, we find that adrenaline does indeed increase the slow inward current in the SA node of the rabbit, but that it also augments the outward current which would tend to decelerate pacemaker depolarisation. We find that an additional current, if, is activated within the range of voltage where the pacemaker depolarisation occurs: this could be important both in normal pacemaking and in adrenaline-induced acceleration.

The Role of the Funny Current in Pacemaker Activity

Abstract: Pacemaking is a basic physiological process, and the cellular mechanisms involved in this function have always attracted the keen attention of investigators The “funny” ( I f) current, originally described in sinoatrial node myocytes as an inward current activated on hyperpolarization to the diastolic range of voltages, has properties suitable for generating repetitive activity and for modulating spontaneous rate The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing Because I f is controlled by intracellular cAMP and is thus activated and inhibited by β-adrenergic and muscarinic M2 receptor stimulation, respectively, it represents a basic physiological mechanism mediating autonomic regulation of heart rate Given the complexity of the cellular processes involved in rhythmic activity, an exact quantification of the extent to which I f and other mechanisms contribute to pacemaking is still a debated issue; nonetheless, a wealth of information collected since the current was first described more than 30 years ago clearly agrees to identify I f as a major player in both generation of spontaneous activity and rate control I f- dependent pacemaking has recently advanced from a basic, physiologically relevant concept, as originally described, to a practical concept that has several potentially useful clinical applications and can be valuable in therapeutically relevant conditions Typically, given their exclusive role in pacemaking, f-channels are ideal targets of drugs aiming to pharmacological control of cardiac rate Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects Indeed a selective f-channel inhibitor, ivabradine, is today commercially available as a tool in the treatment of stable chronic angina Also, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known today to cause rhythm disturbances, such as for example inherited sinus bradycardia Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biological pacemakers eventually able to replace electronic devices This article is the introduction of a new thematic series on Mechanisms of Pacemaking in the Heart , which includes the following articles: Be Still, My Beating Heart – Never! [2010;106:238–239] Development of the Pacemaker Tissues of The Heart [2010;106:240–254] Mapping Cardiac Pacemaker Circuits: Methodological Puzzles of the Sinoatrial Node Optical Mapping [2010;106:255–271] The Role of The Funny Current in Pacemaker Activity Ca2+ Cycling in the Mechanism of Pacemaking Cardiac Pacemaking: Historical Overview and Future Directions Dennis Noble Guest Editor and Brian O'Rourke Editor

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.

Abstract: Jeffrey L. Anderson, MD, FACC, FAHA, Chair Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair 2009–2011 [§§][1] Sidney C. Smith, Jr, MD, FACC, FAHA, Past Chair 2006–2008 [§§][1] Cynthia D. Adams, MSN, APRN-BC, FAHA[§§][1] Nancy M

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Abstract: T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through L...