The mechanism of the cardiac arrhythmias Norbert Jost, PhD

Transcription

1 The mechanism of the cardiac arrhythmias Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences Szeged, Hungary

2 When the pulse strikes out in long beats and smoothly for a long time and then the beats of the pulse become smaller and hard on their own account, then a quick death will occur and no cure can be effected. Huang Ti Nei Ching Su Wen, China ~ 240 B.C.

3 Nomotop activity Treshold potential Spontaneous diastolic depolarization Maximal diastolic potential Patologic depolarization!!!!!!!!!!!

4 General schema representing aritmia mechanisms and the role of remodeling Cardiac arrhythmia

5 Abnormal automaticity EAD = Early AfterDepolarization Disorder of the automaticity I. early afterdepolarization OK: Extrem repolarization lengthening a, hypokalaemia b, extrem bradicardia c, genetic mallfunction d, K-channel blockers (ex. terfenadine, erythromycin, sotalol) Treatment a, serum K + elevation b, magnesium (Mg 2+ ) c, drugs that facilitate repolarization (ex. mexiletine, verapamil)

6 The demonstration of the arrhythmogen effect of the early afterdepolarization (EAD) in canine heart preparations Control Purkinje fibre Ventricular muscle Ventricular muscle Purkinje fibre

7 Abnormal automaticity DAD = Delayed AfterDepolarization Disorder of the automaticity II. OK: CALCIUM OVERLOAD a, ischaemia b, digitalis intoxication delayed afterdepolarization Treatment decrease of the intracellular calcium level a) b-receptor blockers (propanolol) b) calcium antagonists (verapamil) c) Na-channel blockers (difedan, lidocaine)

8 Principal mechanisms for arrhythmogenesis

9 Symmetrical injury of impulse conduction in heart muscle I.

10 Asymmetrical injury impulse conduction in heart muscle II.

11 A 1 2 The re-entry arrhythmias 1 2 B C 1 2 Antiarrhythmic mechanisms 1 2 D E 1 2 Proarrhythmic mechanisms 1 2 F

12 CAST (1989) Cardiac Arrhythmia Suppresion Trial Flecainide Encainide Aim: To test the hypothesis how supression of ventricular extrasystoles by pure CLASS I drugs flecainide and encainide which decrease impulse conduction can improve arrhythmia related postinfarction mortality N Engl J Med, 321, , 1989.

13 Selective fast I Na block Flecainide, Encainide, Propafenone Rate dependent block of the impulse propagation by inhibition of the fast I Na in the damaged tissue during sustained arrhythmia but proarrhytmia due to: Inhibition of the impulse propagation in the damaged tissue during asymptomatic (arrhythmia free) periods

14 SWORD (1995) Survival With ORal D-sotalol d-sotalol Aim: To test the hypothesis how a pure CLASS III drug - d-sotalol - which drug prolongs ventricular repolarization can improve arrhythmia related postinfartion mortaly

15 Selective I Kr (HERG) BLOCK Sotalol, Dofetilide, Ibutilide Lenghten both atrial and ventricular APD (ERP) EAD but proarrhythmia due to: Reverse rate dependent APD prolongation Increased dispersion of repolarization (substrate) EAD provocation (trigger) ES Torsades de pointes ventricular tachycardia The risk of the sudden cardiac death increases

16 Proarrhythmia -definition Proarrhythmia is a new or more frequent occurrence of pre-existing arrhythmias, paradoxically precipitated by antiarrhythmic therapy, which means it is a side effect associated with the administration of some existing antiarrhythmic drugs, as well as drugs for other indications. In other words, it is a tendency of antiarrhythmic drugs to facilitate emergence of new arrhythmias.

17 Torsades de pointes QT interval prolongation, with the potential for fatal arrhythmias, has been the single most common cause of withdrawal or relabeling of marketed drugs in the last decade (Roden et al. J.Clin.Invest. 115: ; 2005) RARE: with terfenadine 1/50000 Developmental cost Withdrawal cost: ~ 800 million USD ~ 500 -? million USD Withdrawn drugs Terfenadine Astemizole Grepafloxacin Cisapride None approval or suspended development several Complicated approval Moxifloxacin Ziprasidone Approved with QT cautions in labeling numerous Re-labeling Thioridazine Droperidol

18 Repolarization inhomogeneity based dog arrhythmia model substrate Akar et al. Circulation. 2002;105:

19 Repolarization inhomogeneity based simplified arrhythmia model Varro and Backó Pflugers Arch - Eur J Physiol (2010) 460:31 40

20 Atrial fibrillation

21 Atrial fibrillation - AF Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age but becomes extremely common in the elderly, with a prevalence approaching 20% in patients 85 years of age. AF is characterized by disorganized, high-rate ( /min) atrial electrical activity and it is associated with shorter action potential duration (APD) and effective refractory period and a loss of rate-dependent APD adaptation that involve concomitant alterations in ion current activity. In some cases AF episodes can be asymptomatic but they are often associated with symptoms like palpitations, dizziness, fatigue, angina, dyspnea and hemodynamic impairment (reduced cardiac output, decreased exercise tolerance due to the loss of atrial contribution to ventricular filling and rapid, irregular ventricular contractions. These problems lead to tachycardia-induced cardiomyopathy and other serious complications. Although AF itself is not a life threatening arrhythmia it can increase the risk of thromboembolic events (five-fold increase in the risk of stroke), the mortality of congestive heart failure (CHF, two-fold increase in mortality, AF occurs in 10-30% of patients with CHF), and is also a frequent complication of cardiac surgery occurring in up to 40% of patients leading to prolonged hospitalization.

22 WL (Wavelength) = ERP x conduction velocity Principal mechanisms that can produce AF. Reentry involves a vulnerable substrate, which requires a trigger for reentry initiation. Ischemia, inflammation, and dilation make atria more vulnerable to AF. AF that results from any mechanism causes tachycardia-induced remodeling. Even if AF is initially maintained by ectopic activity or singlecircuit reentry in a given patient, ATR-induced spatially heterogeneous refractoriness abbreviation creates conditions favorable to multiple-circuit reentry, which may then become the AF-maintaining mechanism. Thus, multiple circuit reentry may be a final common pathway AF mechanism in many patients.

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24 The role of pulmonary veins The muscular sleeves of the pulmonary veins contains in large amount (40 %) myoycytes able for spontaneous diastolic depolarization (ectopic foci). The originating atrial systoles are the triggers of AFs. This can be suppressed by ablation. There were often observed spontaneous DADs or chatecholamine induced EADs. This PV-automaticity may be a therapeutically relevant observation

25 ERP 146 ms 95 ms Wijffels et al. Circulation 1995, 92:

26 Atrial fibrillation remodelling AF is a progredient disease (paroxysmal persistent permanent) (all changes, which are involved to initiate and maintain the AF) Sarcolemmal ion channels Signal transduction and working proteins Gap-junctions, ECM Tachycardia (ATR) 1. Electrical remodelling 2. Contractile remodelling Neurohormonal systems, 3. Structural remodelling Autonomic nervous system (RAAS) Congestive heart failure Circulus vitiosus, which promote the initiation, renewal, stabilization and maintaing of the AF The legendary hydra of Hercules Lloyd and Langberg (J Cardiov Electrophysiol, 2006; 17: 236) etc.

27 !!! AF - electrical remodelling

28 Contractile remodelling Representative recordings of cell-shortenings (right) and calcium transients (left) obtained from a Ctl, a P7, and a P42 cells Sun et al. Circulation 1998, 98: The loss of contractile force of the myocardium, mainly due to I CaL reduction (as a protective mechanism against Ca 2+ overload) and consequently by the damage of the Ca 2+ -homeostasis. Hipocontractility will increase the wall stretch, and thereby, causes atrial dilation (LAV ). Electrical and contractile remodelling go hand in hand!!!

29 Structural remodelling (ASR) A paradigm shift in treatment af atrial fibrillation: from electrical to structural therapy? (Heidbüchel, Eur Heart J, 2003; 24: ) The importance of upstream/non channel treatment of AF!!! The structural remodelling is the main cause for the progredient behaviour of the AF (paroxysmal persistent permanent). In long lasting AF the following low flow ischaemia type structural changes occur: increase in cell size perinuclear accumulation of glycogen central loss of sarcomeres (myolysis) alterations in connexin expression (gap-junctions) changes in mitochondrial shape fragmentation of sarcoplasmic reticulum homogeneous distribution of nuclear chromatin changes in quantity and localization of structural cellular proteins fibrosis!!!

30 The positive feedback correlation between the three types of atrial remodellings Allessie et al. Cardiovasc Res, 2002, 54: Electrical and contractile remodelling may occur in minutes, hours and days reversible after conversion Structural remodelling develops within 3-4 months, and is hardly or even nonreversible

31 The four main repolarizing K + currents under the action potential shape

32 I Ks and repolarization reserve in human and dog ventricular preparations a+b <c Jost et al, J Physiol, 591, , 2013.

33 50 mv I K1 and repolarization reserve in human and dog ventricular preparations APD 90 change (%) APD 90 change (%) 50 mv A 0 mv HUMAN B APD 90 =58.8±5.0 % (n=6) APD 90 =44.1±4.3 % (n=6) Human (n=6) * BaCl 2 (a) a+b <c * DOF (b) N.S. (a)+(b) * BaCl + 2 DOF (c) Control 10 µm BaCl 2 50 nm dofetilide (DOF) 10 µm BaCl nm DOF DOG 0 mv Dog (n=5) EAD # p<0.05 * 0 mv 20 * * APD 90 =24.8±2.0 % (n=5) ms APD 90 =16.0±2.1 % (n=5) BaCl 2 (a) DOF (b) 200 ms (a)+(b) BaCl + 2 CL = 3000 ms DOF (c) Jost et al, J Physiol, 591, , 2013.

34 Specific conclusion considering the role of repolarization reserve In the mammalian (human, dog and rabbit) ventricular muscle when only one type of potassium channels is inhibited, excessive APD lengthening is not likely to occur. This is probably due to the capability of the various potassium channels to substitute and/or supplement each other. Human and dog ventricular myocytes seem to repolarize with a strong safety margin ( repolarization reserve ). When this normal repolarization reserve is attenuated (due to drugs, increased sympathetic activity, remodelling or genetic disorders), the otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular action potential duration. Multiple K + channel block can result excessive repolarization lengthening by eliminating the repolarization reserve and therefore it can associate with increased proarrhythmic risk.

35 SUMMARY In pathological settings, when repolarization reserve is impaired, the relatively mild block of additional K + current can cause marked APD/QT interval prolongation. Congenital ion channel defects, ion channel remodeling due to myocardial infarction, heart failure, diabetes mellitus, etc. - can lead to impaired repolarization reserve Administration of I Kr -blockers (cardiac and non-cardiac drugs) in the setting of decreased repolarization reserve can increase Torsade de Pointes (TdP) incidence QT interval measurements: not reliable in arrhythmic risk prediction repolarization reserve impairment: no measurable prolongation of ventricular repolarization in significant number of cases We should re-evaluate our safety pharmacology concept related to possible QT lengthening effect of drugs to apply tests in preparations where the repolarization reserve is impaired instead of using preparations where this reserve is normal

36 General conclusion!!! Without the thorough investigation and understanding the physiological, biophysical and pathophysiological phenomenons, ie. without basic science there is no chance for sucesful applied (R&D) science for example drug development

37 Thanks for your attention!!

38 T-Tubule RyR ARRHYTHMIA IN HEART FAILURE REPOLARIZATION RESERVE Increased sympathetic tone SL Ca 2+ pump Upregulated NCX NaCaX Forward Reverse 3Na + Ca 2+ I Na Na + Na + NHE Na + pump 2K + trigger substrate b-ar AC camp ATP Na CaX Na CaX Na HX ATP Ca 2+ I Ca ATP Ca 2+ SR PKA PDE P PLB AMP SERCA ATP Ca 2+ Ca 2+ 3Na + Ca 2+ H + 3Na + K + K + I k1 I Ks Ca 2+ DAD Myofilaments EAD Mitochondria K + K + Cl - I to I Kr I Cl extra beat DAD I spont. f extra beat Na +

39 INHIBITION OF NCX ABOLISHES EAD AND DAD trigger Jost et al, British Journal of Pharmacology, 2013

40 I f REMODELLING trigger E. Cerbai et al. J Mol Cell Cardiol 33, (2001)