1. SYNCOPE Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS Cardiology – San Francisco General Hospital UCSF Disclosures: None

2. SCOPE OF THE PROBLEM Cumulative lifetime incidence in general population up to 35% 1% of all hospital admissions 3% of all ER visits; up to 65% are vasovagal 6% incidence in institutionalized elderly Prevalence: 7 - 47% in young, healthy subjects; unknown in elderly Up to 30% of patients may have no diagnosis established at hospital discharge 6% annual mortality if no cause established 12 - 25% recurrence

3. Kapoor Medicine 69:1990 N = 433 Sudden death: 37% Mortality % 50 40 30 20 10 0 Cardiac Noncardiac Unknown Yr. of FU:012345 No. at risk:43338034929517944

4. SURVIVAL IN SYNCOPAL PATIENTS Follow-up (yr) Soteriades et al NEJM 2002;347:878 (Framingham) N = 822/7814 0510152025 Probability of survival 1.0.8.6.4.2 0 No syncope Vasovagal & other causes (OH, med Rx) Unknown cause Neurologic cause Cardiac cause

5. PREVALENCE OF SYNCOPE BY AGE 50 40 30 20 10 0 Ganzeboom et al AJC 4.15.03 Prevalence (%) Age (yrs) Males Females 071421

6. YOUNGER ADULTSELDERLY 15% 40% 30% 25% 15% 30% Vasovagal Undetermined Cardiogenic Other causes OH, situational, seizures, drugs 1° arrhythmia OH, CSS, situational, seizures, drugs 1° arrhythmia, LV obstruction

7. ETIOLOGY OF FIRST SYNCOPE IN PATIENTS > 65 YEARS % Reflex-mediated (VVS, CSS, situational)13-30% Orthostatic12 Cardiac Arrhythmic8 Nonarrhythmic3 Drug-induced8 CNS6 Unexplained49 Roussanov et al, Am J Geriatric Cardiol 2007;16:249 N=304 (VA patients)

8. FEATURES OF UNEXPLAINED SYNCOPE IN OLDER PATIENTS High incidence of comorbid conditions 24% recurrence rate Concurrent BP and HF Rx increases susceptibility to + HUT Only 9% had an etiology established during follow-up Lower diagnostic yield of history and tests compared in younger patients Roussanov et al, Am J Geriatric Cardiol 2007;16:249 N=304 (VA patients)

9. PROGNOSIS IN UNEXPLAINED SYNCOPE IN PATIENTS > 65 Proportion of pts alive 1.0.75.50.25 0 0123 Yrs FU Roussanov et al Am J Geriatric Cardiol 2007; 16:249 N = 304 VA pts Control Syncope

10. EVALUATION OF SYNCOPE: PERTINENT HISTORY Precipitating factors - Posture changes (orthostatic hypotension) - Cough, swallowing, micturition, defecation (“situational” syncope) - Exercise (consider aortic stenosis, HOCM, VT) - Head turning, Valsalva (suggests carotid sinus syndrome) Prodromal symptoms Speed of onset and recovery (prolonged recovery suggests vasovagal syncope) Aura (suggests seizure) Hx heart disease (predicts cardiac syncope: 95% specificity )

11. NATURAL HISTORY OF AORTIC STENOSIS % Survival 100 75 50 25 0 Onset of Sx With AVR Without AVR Asx stage CHF Angina Syncope 102030 Years

12. EVALUATION OF SYNCOPE: PERTINENT HISTORY Drugs - Diuretics (  hypokalemia, hypomagnesemia) - Digitalis (AVB, VT-classically bidirectional) - Antihypertensives - Antiarrhythmic agents (  proarrhythmia) - Ophthalmic  -blockers - Antianginal medications (preload and afterload reduction) - QT prolonging drugs (www.torsades.org)www.torsades.org - OTC drugs - Herbs - Illicit drugs, alcohol - β-blockers Family history of sudden death (congenital long QT syndrome, hypertrophic obstructive cardiomyopathy) Known rhythm abnormality (e.g., WPW)

13. Exercise-induced RVOT VT

14. Tussive bradycardia

16. Deglutition bradycardia Continuous strips

17. CONGENITAL LQTS 1:10,000 is a gene carrier 3-4,000 sudden deaths/yr, mostly young patients 10% sudden deaths in untreated patients 30% of sudden or aborted sudden deaths occur as 1st event Female gender About 10% have normal QT C ; about 30% have borderline QT C

19. CLUES TO ETIOLOGY OF SYNCOPE FROM PHYSICAL EXAMINATION Left ventricular impulse abnormalities suggesting past myocardial infarction Ventricular hypertrophy (need for AV synchrony) Ventricular gallops Murmurs (aortic stenosis, hypertrophic obstructive cardiomyopathy) Pulmonary hypertension Mitral valve prolapse (PSVT, VT, autonomic dysfunction) Carotid sinus massage indicating CSH

20. Generally accepted contraindications - Carotid bruits - Prior endarterectomy - Prior TIA or CVA - Known cerebrovascular disease Responses to CSM - Bradycardia / asystole usually abrupt - Hypotension often not abrupt, and outlasts the CSM - Complications (< 1%): TIA, transient paresis, visual disturbances CAROTID SINUS MASSAGE

21. CLUES TO ETIOLOGY OF SYNCOPE FROM 12-LEAD ECG Long QT interval Prior MI (substrate for VT) Epsilon wave, anterior (V 1-3 ) T inversion, QRS duration V 1-3 / V 4-6 > 1.2, suggesting RV dysplasia Brugada pattern Short QT interval (with tall symmetric T waves) Ectopy Bradycardia AV conduction delay / block Bifascicular block Ventricular hypertrophy (need for AV synchrony)

22. Epsilon wave of RV dysplasia Marcus, Fontaine PACE 6.95 V1V1 V2V2 V3V3

23. RV DYSPLASIA Young pt Can present as syncope or aborted sudden death ECG: - Anterior T inversion V 1-3 - Prominent anterior forces - RIVCD - Delayed S wave V 1-2 MRI is usually (but not always) diagnostic (fat replacement)

24. RV dysplasia

26. BRUGADA SYNDROME

28. OUTCOME IN PTS WITH BRUGADA ECG Free of events (SD, VF) 1.0.8.6.4.2 0 Brugada et al Circulation 2002; 105:73 N = 334, all EPS 63% of syncopal pts had VT induced Asymptomatic (57%) Syncope (22%) Sudden death (21%) p = 0.00001 0100200300 Mos

29. Follow-up (mos) Antzelevitch et al Circulation 2005; 111:659 N=258 (Registry) PROGNOSIS OF SYNCOPE IN BRUGADA SYNDROME Free of Appropriate ICD Rx 1.0.8.6.4.2 0 Asymptomatic Syncope Sudden death 01224364860

30. ROLE OF ECHOCARDIOGRAPHY IN SYNCOPE Aortic stenosis Hypertrophic cardiomyopathy (especially obstructive) Regional wall-motion disorders (substrate for VT) Right ventricular dysplasia Calcified mitral / aortic annulus ( AV block incidence) Intracardiac tumor Mitral valve prolapse Repaired congenital heart disease Normal echo

31. NONARRHYTHMIC CARDIAC SYNCOPE: OBSTRUCTION TO FLOW Aortic stenosis - LV baroceptor stimulation with reflex peripheral vasodilation - Ventricular arrhythmias - Transmural ischemic injury with LV dysfunction Hypertrophic obstructive cardiomyopathy Tumor Primary pulmonary hypertension, pulmonic stenosis Pulmonary embolism

32. Syncope in aortic stenosis Recorded during syncopal spell. BP unobtainable.

33. Syncope in aortic stenosis Lead III: During syncopal spell

34. SYNCOPE IN HYPERTROPHIC CARDIOMYOPATHY - 1 Causes - SVT (especially AF) - VT - LV outflow tract gradient - Abnormal baroreceptor reflexes - Ischemia EP studies unreliable  -blockers, disopyramide and Ca ++ channel blockers do not reduce incidence of SD

35. SYNCOPE IN HYPERTROPHIC CARDIOMYOPATHY - 2 ICD indicated for high risk patients -Family hx syncope/sudden death -LVH > 3 cm -Aborted sudden death -Nonsustained VT on Holter

36. SYNCOPE IN PULMONARY HYPERTENSION Usually exertional or immediately post-exercise “Fixed” right sided obstruction due to high pulmonary vascular resistance Inability to increase CO in response to SVR Decreased cerebral perfusion

37. SYNCOPE IN SYSTOLIC HEART FAILURE In patients with syncope, heart failure is an independent predictor of mortality Syncopal patients with ICDs have appropriate therapies delivered SCD-HeFT: -Predictors of syncope: QRSd > 120 ms, NYHA III, no beta blocker -Not predictors: EF, NSVT, AF, other HF Rx -16% with ICD had syncope; 41% had appropriate shock (vs 12% with no syncope) -Syncope was predictor of total and CV mortality, but not sudden death and did not differ among ICD, amio, or placebo pts -ICDs did not reduce mortality in syncope patients

38. NEUROCARDIOGENIC (VASOVAGAL) SYNCOPE Occurs at all ages 17 - 35% suffer significant injury 5 - 7% have fractures Up to 4% of pts diagnosed with VVS may have cardiac syncope

39. FEATURES OF HISTORY IN VVS Usually occurs in upright position Rare during exercise 3 phases: prodrome, loss of consciousness, postsyncopal period May have specific triggers: pain, trauma, stress, “situational” (swallow, micturition, defecation) Peri-event amnesia common Association with chronic fatigue syndrome, depression, somatic disorders May run in families  frequency around menses

40. Male<.001 Age > 54 <.001 SupineNS UprightNS Precipitant<.001 No presyncopeNS WarningNS Diaphoresis<.001 VASOVAGAL vs ARRHYTHMIC* SYNCOPE *VT + AVB Calkins et al AJM 98:1995 020406080100 P VV (%)Arrhythmic (%)

41. VASOVAGAL vs ARRHYTHMIC* SYNCOPE Fatigue Post<.001 ConfusionNS PalpitationsNS Incontinence.02 InjuryNS Major InjuryNS Recovery > 0”<.001 020406080100 P VV (%)Arrhythmic (%) *VT + AVB Calkins et al AJM 98:1995

42. NEUROCARDIOGENIC SYNCOPE  LV volume  Venous return Peripheral venous pooling HEAD UP TILT Peripheral vasodilation Hypotension   adrenergic tone  LV contractility Mechanoreceptor stimulation (myocardial C fibers) Vasomotor center  Vagal tone Bradycardia or asytole

43. * Watch for urinary retention, torsades de pointes VT VVS: PHARMACOLOGIC THERAPY Anticholinergic agents - Disopyramide* (effect vs placebo is controversial) - Scopolamine Negative inotropic agents - Disopyramide* Fludrocortisone Vasopressin Alpha-adrenergic agonists - Ephedrine - Etilephrine - Theophylline - Dexedrine - Midodrine Serotonin reuptake inhibitors

44. VVS: PACEMAKER THERAPY Effect vs placebo is controversial and not supported in RCTs - Dual chamber - Rate-drop response or other algorithm which detects heart rate, then tachypaces while periodically searching for spontaneous rhythm

45. VVS: PACING vs  -BLOCKADE (SYDIT) % syncope free pts 1.0 0.9 0.8 0.7 0.6 Ammirati et al Circulation 2001; 104:52 N = 93 02004006008001000 Days Pacemaker Atenolol P = 0.0031

46. “ORTHOSTATIC TRAINING” FOR REFRACTORY NEUROCARDIOGENIC SYNCOPE N = 47, mean age 16 5 in hospital training sessions 40 min BID standing against wall at home Results: (FU 18 ± 5 mos) 96%had – HUT(Control 26%) 0%had syncope(Control 57%) Girolamo et al Circulation 1999;100:1798

47. LEG CROSSING AND MUSCLE TENSING TO ABORT / MITIGATE VASOVAGAL SYNCOPE N = 21 At onset of sx, leg crossing with tensing of abdominal, leg and buttock muscles BP and HR stabilized in all pts in 3 - 6" 5 / 20 aborted syncope 15 / 20 had delayed onset of syncope by 0.5 - 11' At 10 mo FU, 16 / 19 benefited from maneuver Similar benefit for cardiac pacing Krediet at al, Circulation 2002;106:1684

49. ISOMETRIC ARM EXERCISE TO ABORT VASOVAGAL SYNCOPE Control2 min handgrip Brignole et al JACC 2002;40:2053 N = 19 Asx 11% Syncope 47% Asx 63% Syncope 5% HR 112 90 68 45 BP 178 156 133 111 89 67 44

50. FALLS: SCOPE OF THE PROBLEM 30% of pts > 65 fall / yr 60% of pts in long-term care facilities fall / yr 10 - 20% result in injury 2 - 6% result in fractures Usually unwitnessed 30% have LOC with CSM; 80% had amnesia Kenny et al SAFEPACE JACC 2001;38 N = 175

51. SAFE-PACE TRIAL* *Syncope and Falls in the Elderly Pacing and Carotid Sinus Evaluation Prospective randomized, controlled trial of 175 patients > 50 y.o. with cardioinhibitory carotid sinus hypersensitivity and unexplained falls Randomized to pacing (with rate-drop response) vs. no pacing Follow-up one year Odds-ratio of falls in nonpaced patients 4:1, 0. 35 in paced patients Kenny et al JACC 2001;38

52. DDD PACING FOR CAROTID SINUS SYNDROME WITH FALLS, DIZZINESS AND SYNCOPE Crilley et al Postgrad Med J 73:1997 N = 42 100 80 60 40 20 0 SyncopeFallsDizziness BeforeAfter

53. SYNCOPE WORKUP ECG Holter (overall yield 2-35%) Event Monitor (patient cannot be syncopal) Head-up tilt table testing Electrophysiologic study (predictive value variable) Implantable loop recorder

54. TILT-TABLE TESTING FOR EVALUATION OF SYNCOPE: SUMMARY OF PRINCIPAL INDICATIONS Tilt-table testing warranted Recurrent syncope or single syncopal episode in a high risk patient, whether or not the medical history is suggestive of neurally mediated (vasovagal) origin and: 1. No evidence of structural cardiovascular disease, or 2. Structural cardiovascular disease is present, but other causes of syncope have been excluded by appropriate testing Benditt et al JACC July 1996

55. Tilt-table testing warranted Further evaluation of patients in whom an apparent cause has been established (e.g., asystole, atrioventricular block), but in whom demonstration of susceptibility to neurally mediated syncope would affect treatment plans Part of the evaluation of exercise-induced or exercise-associated syncope

56. Reasonable differences of opinion exist regarding utility of tilt-table testing Differentiating convulsive syncope from seizures Evaluating patients (especially the elderly) with recurrent unexplained falls Assessing recurrent dizziness or presyncope Evaluating unexplained syncope in the setting of peripheral neuropathies or dysautonomias Follow-up evaluation to assess therapy of neurally mediated syncope

57. Tilt-table testing not warranted Single syncopal episode, without injury and not in a high risk setting, with clear-cut vasovagal features Syncope in which an alternative specific cause has been established and in which additional demonstration of a neurally mediated susceptibility would not alter Rx

58. DIAGNOSTIC YIELD OF AMBULATORY ELECTROCARDIOGRAPHIC MONITORING (AECG) IN SYMPTOMATIC PATIENTS Sx w/o AECGNo Sx with AECG arrhythmia (%)arrhythmia (%) No. +–+– Zeldis3713343023 Clark983394117 Jonas358401680 Kala108771669 Gibson1,5122151079 Boudoulas11926132734 Diamond854420433 TOTAL2,65121 48 Overall yield 2% DiMarco and Philbrick, Ann Intern Med 6/90

62. PATIENT PRESENTING WITH SYNCOPE AND SEIZURE

63. ADVANTAGES AND LIMITATIONS OF IMPLANTABLE LOOP RECORDERS Advantages Prolonged ECG recording capability (to 2 yrs) Memory - allows activation after syncopal event Automatic recording, allowing automatic acquisition of ECG events which fall outside programmable boundaries Elimination of technical factors which impair good quality surface ECG recording during sx High sx-ECG correlation yield: Dx made in 25-50% of pts, and suggested in an additional 15-25% Benditt et al

64. ADVANTAGES AND LIMITATIONS OF IMPLANTABLE LOOP RECORDERS Limitations Surgical implantation Does not record other potentially important parameters (e.g., BP) Sx - ECG correlation not available when automatic recordings are obtained Does not distinguish vasovagal episodes from conduction system disease Benditt et al

65. RECOMMENDATIONS FOR IMPLANTABLE CARDIOVERTER DEFIBRILLATORS IN SYNCOPAL PATIENTS Class I Syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at EPS Class IIa Reasonable for patients with unexplained syncope, significant LV dysfunction, and nonischemic dilated cardiomyopathy Reasonable for patients with Brugada syndrome who have had syncope. ACC/AHA/HRS Guidelines 2008

66. ACC/AHA/ESC 2006 Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death EP Testing in Patients with Syncope Class I Patients with syncope of unknown cause with impaired LV function or structural heart disease Class IIa Can be useful in patients with syncope when brady- or tachyarrhythmias are suspected, and in whom noninvasive diagnostic studies are not conclusive.

67. RECOMMENDATIONS FOR ICDS IN SYNCOPAL PATIENTS Class IIb May be consideered in patients with syncope and advanced structural heart disease in whom thorough invasive and noninvasive investigations have failed to define a cause. Class III Syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural heart disease. ACC/AHA/HRS Guidelines 2008

68. ESC GUIDELINES ON SYNCOPE For Dx: Strongly recommended Suspected or known significant heart disease ECG abnormalities suggestive of arrhythmic syncope Syncope during exercise Syncope causing severe injury Strong family history of sudden death Europace 2004;6: 467-537 Hospital Admission for Syncope Management

69. ESC GUIDELINES ON SYNCOPE May need to be admitted Patients with or without heart disease but with: Sudden palpitations shortly before syncope Syncope in supine position Worrisome family history Significant physical injury Patients with minimal or mild heart disease when there is high suspicion for cardiac syncope Suspected pacemaker or ICD problem Europace 2004;6: 467-537

70. For Rx: Cardiac arrhythmias as cause Syncope due to cardiac ischemia Syncope due to structural cardiac or pulmonary disease Stroke or focal neurologic disorders Cardioinhibitory neurally mediated syncope when pacemaker implant is planned Europace 2004;6: 467 - 537 Hospital Admission for Syncope Management ESC GUIDELINES ON SYNCOPE

71. INDICATIONS TO REFER SYNCOPAL PT TO ELECTROPHYSIOLOGIST Neurocardiogenic syncope, especially if refractory to avoidance of triggers and drug Rx, or associated with prolonged pauses in cardiac rhythm Arrhythmia identified during evaluation: - VT due to any cause - Bradyarrhythmia caused by Rx that cannot be withheld or changed - Supraventricular tachycardia, esp. with WPW conduction

72. INDICATIONS TO REFER SYNCOPAL PT TO ELECTROPHYSIOLOGIST Congenital long QT syndrome Brugada syndrome Structural heart disease Syncope in athletes Syncope during exercise Short QT syndrome Origin of syncope remains unknown and prolonged arrhythmia monitoring by implantable loop recorder is being considered