The Silent Killers Sudden Cardiac Death In The Absence Of Apparent Structural Heart Disease

1. The Silent Killers Sudden Cardiac Death In The Absence Of Apparent Structural Heart Disease M Sherif Mokhtar, MD Cairo University

3. In the truly normal heart SCD, is an uncommon occurrence. • The majority do not actually have "normal" hearts, but our diagnostic tools limit identification of structural or functional derangement. Myerburg, 1997 Wever et al., 2004

4. Epidemiology • The most common underlying disorders: • Hypertrophic Cardiomyopathy (36 percent) • An Anomalous Coronary Artery (13 %), and • Myocarditis (7 percent). “An autopsy series from the USA in (286 competitive athletes under age 35)” Maron et al., 2003

5. Electrolyte Abnormalities, such as: Hypokalemia and Hypomagnesemia, Can precipitate SCD in susceptible subjects. Siscovick et al., 1998

6. Identified Causes I. Familial II. Commotio Cordis III. Idiopathic VF

7. Familial Causes of SCD • WPW and other forms of SVT • The long QT syndrome • Polymorphic VT with normal QT • BRUGADA syndrome • Congenital short QT syndrome

8. A. WPW and other forms of SVT: • SVT associated with the WPW syndrome can cause SCD in 2.1%. • AF with a rapid ventricular response: is the most common. • Atrioventricular Nodal Reentrant Tachycardia (AVNRT) or AF with a rapid ventricular response may deteriorate into VF in 2.4 percent . Wang et al., 1991

9. Familial Causes of SCD • WPW and other forms of SVT • The long QT syndrome • Polymorphic VT with normal QT • BRUGADA syndrome • Congenital short QT syndrome

10. The Long QT Syndrome Mechanistic Model: • An imbalance in sympathetic cardiac innervation could lead to prolongation of the QT interval and risk of arrhythmia.

11. The Long QT Syndrome Cellular Model: The trigger for early afterdepolarizations is Reopening of Cardiac L-type Calcium Channels during the prolonged plateau phase of the cardiac action potential. The beneficial effect of b- adrenergic blockers may be caused by a blunting of the increase in L-type calcium current by sympathetic nerve stimulation.

12. LQTS Genes: • The recognition that LQTS is actually a group of ion channel diseases with a similar phenotype has led to the new terminology for mutations: • (1) LQT1 on KvLQT1, (2) LQT2 on HERG, • (3) LQT3 on SCN5A, and (4) LQT5 on mink.

13. Congenital Long QT Syndrome Gene Mutations: LQT2 is caused by mutations in the HERG (human ether-a-go-go-related gene), a potassium channel generesponsible for the rapid component of Delayed Rectifier Potassium Current Ikr in ventricular myocytes.

14. Mutations in LQTS Genes Functional Consequences of Mutations: • When mutations in KvLQT1, KCNE1, or HERG are expressed alone or with wild-type alleles they exhibit “Loss of Function”, ie, the total current carried by the defective channel complexes is reduced.

15. Mutations in LQTS Genes Functional Consequences of Mutations: 2. Mutations in the SCN5A channels cause a “Gain of Function”. These mutations produce a persistent late INa that is not present physiologically and that is due to defective inactivation. In most described mutations, the INa is increased because of lateReopenings of the Channels.

16. Mutations in LQTS Genes Functional Consequences of Mutations: 3. Most HERG mutations, however, are MISSENSE Mutations that have a dominant-negative effect on HERG function. “lead to the synthesis of HERG subunits that are usually nonfunctional when they are expressed alone”.

17. LQTS Genes Functional Consequences of Mutations: It is generally difficult to develop specific therapies for loss of function (eg, the K+ channel defects). By contrast, the gain of abnormal function exhibited by mutant SCN5A gene products raises the possibility that a cure could be accomplished by pharamcological agents that inhibit the gained function, ie, block the late INa. (mexiletine or lidocaine?).

18. The Long QT Syndrome Therapeutic Implications: • A mechanistic understanding of long QT syndrome may enable treatment. Historically, patients with LQT have been treated with • Beta-adrenergic antagonists, • Left Cervical Sympathectomy, or • Implantation of permanent pacing devices and • Automatic defibrillators.

19. The Long QT Syndrome Therapeutic Implications: The putative role of IKs in cardiac physiology suggests an especially favorable effect of beta blockade and the avoidance of vigorous increase in heart rate (ie., competitive sports) in LQT1 and LQT5. These examples demonstrate that Gene-Specific Therapy may be feasible in LQTS.

20. Drug-Induced LQTS Drug-induced LQTS might represent a genetically mediated “forme fruste” of LQTS. Recent studies have identified relatively large numbers of individuals who carry “silent” mutations on LQTS genes.

21. Genetic Testing for LQTS: • Genetic testing could be useful, because depending on the gene (and ultimately even the specific mutation), modifications in management may be suggested: • The addition of mexiletine in LQT3 or • Lifestyle modifications such as limitation of strenuous or competitive exercise in LQT1.

22. Familial Causes of SCD • WPW and other forms of SVT • The long QT syndrome • Polymorphic VT with normal QT • BRUGADA syndrome • Congenital short QT syndrome

23. Polymorphic VT with Normal QT interval • Affected patients typically present with life-threatening VT or VF occurring during emotional or physical stress, (syncope often being the first manifestation of the disease). • Although sporadic cases occur, this is primarily a Familial Disease (also called Catecholaminergic VT).

24. Occurrence of polymorphic ventricular tachycardia after exercise testing

25. Polymorphic VT with Normal QT interval • Some cases are due to mutations in the Cardiac Ryanodine Receptor, (the Cardiac Sarcoplasmic Calcium Release Channel). • May account for at least one in every seven cases of sudden unexplained death). Tester et al., 2004

26. Familial Causes of SCD • WPW and other forms of SVT • The long QT syndrome • Polymorphic VT with normal QT • BRUGADA syndrome • Congenital short QT syndrome

27. Brugada Syndrome • Characterized by the electrocardiographic findings of: • (RBBB) and • ST-segment elevation in leads V1 to V3, and • An increased risk of sudden death. • Brugada syndrome may represent either a: • Functional abnormality in the electrical activity of the heart i.e (primary electrical disease,channelopathy) or • An early subclinical manifestation of arrhythmogenic right ventricular dysplasia (ARVD).

28. Variation in the precordial lead ST and T waves in a patient with Brugada syndrome.

29. Brugada Syndrome Electrophysiological Basis and Genetics : • Additional features include: • (1) unmasking of the characteristic ECG changes by sodium channel-blocking drugs such as ajmaline, flecainide, and procainamide.

30. Brugada Syndrome Electrophysiological Basis and Genetics : (2)Autosomal dominant pattern of inheritance, but with marked male predominance; and (3) usual presentation in the fourth decade of life despite the presence of the underlying defect(s) at birth. Antzelevitch et al 2003

31. Brugada Syndrome Basic Electrophysiology : Regional Heterogeneities in Action Potential Characteristics between the right and left ventricles, and the epicardium, midmyocardium and endocardium. Antzelevitch et al 2002

32. Brugada Syndrome Basic Electrophysiology : The presence of three dominant cell types, epicardial, M, and endo­cardial cells is a basis for the action potential variations. The three cell types display quantitative differences in the density of the various ionic currents that contribute to the generation of the normal action potential.

33. Heterogeneity of action potential characteristic's across ventricu­lar wall: Pemel (A) shows typical action potentials recorded from epicardial and endocardial cells. The epicanlud action potential has a prominent notch durinr; phase I and a "spike and dome" configuration. The NI-cell also has a prominent phase 1 and the longest duration of action potentials across the ventricular wall. Phase 1 is relatively prominent in endocardial cells. Panels (B) and (C) show the membrane currents recorded from each cell type. Epicandial cells have a transient outward potassium current while this current is diminutive in endocardial cells. The slow component of the de­layed rectifier current is diminished in M-cells.25 Reprinted with permission from Blackwell Publishing.

34. Brugada Syndrome Basic Electrophysiology : This sets up a voltage gradient between epicardium and endocardium that is evident on the ECG as ST-segment elevation. Current from the endocardium to the epicardium can result in closely coupled extrasystoles and the initiation of ventricular fibrillation. (phase 2 reentry).

35. Familial Causes of SCD • WPW and other forms of SVT • The long QT syndrome • Polymorphic VT with normal QT • BRUGADA syndrome • Congenital short QT syndrome

36. Congenital Short QT Syndrome • A Familial Syndrome characterized by an abnormally short QT interval: (Corrected QT interval “QTc” < 0.30 sec) and • Associated with an increased risk of SCD. • All Family members had histories of syncope, palpitations, AF, and, in one case, resuscitated SCD. • On electrophysiologic evaluation, all had short atrial and ventricular refractory periods, and frequently had inducible VF. Gussak et al 2000

37. A. Schematic representation of the normal action potential and the flux of ions. B. With gain-of-function mutations in any of 3 different potassium channels, the cardiac action potential shortens and the QT interval decreases.

38. Short QT syndrome Pharmacologic Therapy Because shortening of the QT interval is likely due to an increase in the outward current, blocking the current with class III antiarrhythmic drugs (which are known to increase the QT interval) may be a therapeutic approach for treating short QT syndrome. No large randomized trials have been conducted to date on drug therapies for the syndrome. The current evidence is derived from small studies.

39. Electrocardiogram of a patient with short QT syndrome. Observe the tall peaked T waves.

40. Short QT syndrome Therapeutic Options: The first line of therapy, especially in people recovered from sudden cardiac death or with a history of syncopal episodes, is the implantation of Cardioverter Defibrillator. Schimpf et al., 2003

41. Identified Causes I. Familial II. Commotio Cordis III. Idiopathic VF

42. Commotio cordis • Most often occurs in Young Athletes who have been struck in the precordium with a projectile object such as a baseball, hockey puck, or fist. • Mostly during organized or recreational sporting activities,an during routine daily activities. • Usually accidental, although some have resulted in criminal liability Maron et al., 2002

43. Commotio cordis • An animal model was developed in which low-energy blows to the chest wall would produce: • VF if delivered during repolarization, just before the peak of the T wave, produced VF, • Transient Complete Heart Block followed by ST segment elevation if delivered during depolarization, and during the QRS complex. • The frequency of VF was related to the hardness of the projectile and impact speed. Link et al., 2003

44. Identified Causes I. Familial II. Commotio Cordis III. Idiopathic VF

45. Idiopathic VF • If the above disorders are excluded and the heart is structurally normal, the diagnosis of idiopathic VF (also called primary electrical disease) is made. • Estimated to account for 5 percent of cases of SCD. • The mean age was 36 years with a • Male-to-female ratio of 2.5:1. • A history of syncope preceded the episode of VF in 25 percent. Viskin & Belhassen, 1990

46. Idiopathic VF Electrophysiologic Basis Relatively localized areas of abnormal myocardium with functional activation delay, while other regions were minimally abnormal or normal (heterogeneous disease). Saumarez et al., 2003

47. Idiopathic VF Prognosis: Among survivors of SCD due to idiopathic VF, the reported rate of recurrent VF ranges between 22 and 37 percent at two to four years. Marcus 1997

48. Idiopathic VF Management 1. Because they have no structural heart disease, these pts have an excellent prognosis for long-term survival if VF is prevented. As a result, such patients are best treated with an ICD. Meissner et al., 1993

49. Idiopathic VF Management • Another possible therapeutic approach is Mapping and Radiofrequency Ablation. • Triggering premature beats were elicited from the Purkinje system and less frequently from the right ventricular outflow tract in four. At a mean follow-up of two years after local RF ablation, 24 pts (89 percent) had no recurrence of VF. Haissaguere et al., 2002

50. Minor cardiac abnormalities not associated with SCD