Υπερτροφική Μυοκαρδιοπάθεια (YMK)

Υπερτροφική Μυοκαρδιοπάθεια (YMK) Διαστρωµάτωση κινδύνου Γεώργιος Κ Ευθυµιάδης Α Kαρδιολογική κλινική, ΑΠΘ Conflict of interest: nothing to declare

Figure 1. Contemporary Insights and Strategies for Risk Stratification and Prevention of Sudden Death in Hypertrophic Cardiomyopathy. Maron, Barry Circulation. 121(3):445-456, January 26, 2010. DOI: 10.1161/CIRCULATIONAHA.109.878579 Figure 1. SD and age in HCM. Top, SD is most common before [almost equal to]25 years of age, whereas heart failure and stroke generally occur later in life. From Maron et al.11 Used with permission from the American Heart Association, copyright (C) 2000. Bottom, Single most frequent cause of SD in young competitive athletes in the United States. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; AS, aortic valve stenosis; CHD, congenital heart disease; LAD, left anterior descending; MVP, mitral valve prolapse; and WPW, Wolff- Parkinson-White. *Regarded as possible (but not definitive) evidence for HCM at autopsy with mildly increased LV wall thickness and heart weight (447+/-76 g). +Includes Kawasaki disease, sickle cell trait, and sarcoid. 2010 American Heart Association, Inc. Published by American Heart Association. 2

Αιφνίδιος θάνατος στην ΥΜΚ n < 1% ανά έτος n Σε επιλεγµένη οµάδα ασθενών (15-20%) 4-6% ανά έτος

Αιφνίδιος θάνατος στην ΥΜΚ επιδηµιολογία n n n n n Μπορεί να είναι η πρώτη εκδήλωση της νόσου 50% του συνόλου των θανάτων στην ΥΜΚ Ασυµπτωµατικά ή ελάχιστα συµπτωµατικά άτοµα (70%) Συµβαίνει σε -συνηθισµένες δραστηριότητες (βάδιση, ηρεµία, οδήγηση, ύπνος) 85% -έντονη άσκηση Κύριο αίτιο θανάτου σε άτοµα <35 ετών και σε αθλητές

Μηχανισµοί ΑΚΘ στην ΥΜΚ n n Maron BJ, et. al Efficacy of Implantable Cardioverter Defibrillators for the Prevention of Sudden Death in Patients with Hypertrophic Cardiomyopathy. N Engl J Med 2000; 342:365-373 In all 21 patients with stored electrographic data and appropriate interventions, the interventions were triggered by ventricular tachycardia or fibrillation.

Εκτίµηση κινδύνου αιφνιδίου θανάτου

Risk factors for SD in HCM n n n Major risk factors Risk factors Possible (arbitrators) risk factors

Major Risk Factors for SD in HCM Prior aborted cardiac arrest Spontaneous sustained ventricular tachycardia n 7-year mortality rate of 33% n 5-year SCD or ICD discharge rate of 41% Cecchi F. J Am Coll Cardiol 1989;13:1283-8. Elliott PM. J Am Coll Cardiol 1999;33:1596-601.

Prognosis of Unexplained Syncope in HCM Figure 1. Kaplan-Meier estimates of the proportion of patients with sudden death in subgroups with different temporal proximity of unexplained syncopal events to initial evaluation and in patients without unexplained syncope. Spirito P et al. Circulation 2009;119:1703-1710 Copyright American Heart Association

Figure 2. Risk of sudden death in relation to age and temporal proximity of unexplained syncope to initial evaluation. Spirito P et al. Circulation 2009;119:1703-1710 Copyright American Heart Association

Υπερτροφία > 30 χιλιοστά

Οικογενειακό ιστορικό αιφνιδίου θανάτου n Maron BJ, Lipson LC, Roberts WC, Savage DD, Epstein SE. "Malignant" hypertrophic cardiomyopathy: identification of a subgroup of families with unusually frequent premature death. Am J Cardiol. 1978 Jun;41(7):1133-40. n McKenna W, Deanfield J, Faruqui A, England D, Oakley C, Goodwin J. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol. 1981 Mar;47(3):532-8.

Οικογενειακό ιστορικό αιφνιδίου θανάτου n n Θεωρείται θετικό, όταν συµβεί σε συγγενή πρώτου βαθµού <40 ετών όταν δεν υπάρχει διαγνωσµένη νόσος Σε οποιαδήποτε ηλικία όταν τεκµηριώνεται νεκροτοµικά η ΥΜΚ ως αιτία θανάτου

From: Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients J Am Coll Cardiol. 2003;42(5):873-879. doi:10.1016/s0735-1097(03)00827-1 Figure Legend: Number of runs of non-sustained ventricular tachycardia (NSVT) in 48 h in 104 patients with hypertrophic cardiomyopathy and NSVT. Date of download: 6/2/2013 Copyright The American College of Cardiology. All rights reserved.

From: Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients J Am Coll Cardiol. 2003;42(5):873-879. doi:10.1016/s0735-1097(03)00827-1 Figure Legend: Kaplan-Meier survival curves for sudden death in patients older (A) and younger (B) than 30 with and without non-sustained ventricular tachycardia (NSVT). Dotted lines = yes; solid lines = no. Date of download: 6/2/2013 Copyright The American College of Cardiology. All rights reserved.

Ανώµαλη απάντηση της πίεσης στην κόπωση Edwards RH, Kristinsson A, Warrell DA, Goodwin JF. Effects of propranolol on response to exercise in hypertrophic obstructive cardiomyopathy. Br Heart J. 1970 Mar;32(2):219-25

Kaplan-Meier survival curve for two groups: normal BPR and abnormal BPR (ABPR). Sadoul N et al. Circulation 1997;96:2987-2991 Copyright American Heart Association

Cardiovasc Ultrasound. 2009; 7: 37.

End-stage HCM Μυοκαρδιακή ισχαιµία

Apical aneurysms

Flow diagram summarizing the clinical course of 28 HCM patients with LV apical aneurysms Maron, M. S. et al. Circulation 2008;118:1541-1549 Copyright 2008 American Heart Association

Mid-LV obstruction

Probability of Sudden Death among 224 Patients with a Left Ventricular Ouflow Tract Gradient of at Least 30 mm Hg and 770 Patients without Obstruction Maron M et al. N Engl J Med 2003;348:295-303

Kaplan Meier estimates of the proportions of patients surviving from sudden cardiac death, appropriate ICD discharge, or resuscitated ventricular fibrillation in relation to LVOTO. Elliott P M et al. Eur Heart J 2006;27:1933-1941 The European Society of Cardiology 2006. All rights reserved. For Permissions, please e- mail: journals.permissions@oxfordjournals.org

Efthimiadis GK, Parcharidou DG, Giannakoulas G, Pagourelias ED, Charalampidis P, Savvopoulos G, Ziakas A, Karvounis H, Styliadis IH, Parcharidis GE. Left ventricular outflow tract obstruction as a risk factor for sudden cardiac death in hypertrophi cardiomyopathy. Am J Cardiol. 2009 Sep 1;104(5):695-9.

Role of genetics in prognosis

Πρόληψη αιφνιδίου θανάτου µε χορήγηση φαρµάκων n n Β-αναστολείς, βεραπαµίλη, δισοπυραµίδη, κινιδίνη, µεξιλετίνη Καµµία δράση Αµιοδαρόνη Υπό προϋποθέσεις

Indications for ICDs in HCM. *SCD risk modifiers include established risk factors and emerging risk modifiers (Section 9.4.2). Writing Committee Members et al. Circulation 2011;124:2761-2796 Copyright American Heart Association

Η µεγάλη ηλικία προστατεύει από τον αιφνίδιο θάνατο? q q ΥΠΕΡ 1/3 των ΑΘ <35 ετών Θερµές φάσεις σε νεαρή ηλικία (ισχαιµίααρρυθµίες) ΚΑΤΑ q Δεν προλαβαίνουν οι ασθενείς να φθάσουν σε µεγάλη ηλικία, γιατί πεθαίνουν αιφνίδια q Μέγιστο πάχος >30 χιλ µόνο το 3% >65 ετών

Προοπτικές n Έναρξη θεραπείας στο προκλινικό στάδιο της νόσου n Genotype (+)/Phenotype (-) n A-MEA, AT-inhibitors, spironolactone, diltiazem, b-blockers

ICD implantation in 37 pts with HCM for primary prevention (AHEPA Hospital) n Appropriate ICD intervention in 10 out of 37 (27.02%) primary prevention patients n Cumulative probability of ICD intervention at five years was 29.2% (± 7.4%) n First appropriate intervention rate was 7.18% per year (95% CI: 3.44-13.20)

n n Inappropriate discharge: AF: 4 pts SVT: 2 pts ST: 1 pt Infection-lead fraction 4/34 pts

Mid-ventricular hypertrophy

Perspectives n n n n AIM: reversal or prevention of hypertrophy and fibrosis experimental therapies: beneficial small clinical trials in overt HCM: no benefit beneficial effect when applied in the preclinical phase? ongoing trial : diltiazem in preventing phenotypes, in preclinical HCM

Annual HCM-related mortality depicted prospectively from age at study entry (initial evaluation). Maron B J et al. Circulation 2000;102:858-864 Copyright American Heart Association

Clinical profile of sudden death. Maron B J et al. Circulation 2000;102:858-864 Copyright American Heart Association

Importance of hypertrophy pattern in sudden death risk stratification among patients suffering from hypertrophic cardiomyopathy. E Pagourelias, GK. Efthimiadis, DG. Parcharidou, TD. Gossios, H. Karvounis, IH. Styliadis. (presented in ESC congress, Munchen 2012)

From: Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy J Am Coll Cardiol. 2003;41(2):315-321. doi:10.1016/s0735-1097(02)02713-4 Figure Legend: Distribution of maximum left ventricular (LV) thickness among 237 patients with hypertrophic cardiomyopathy (HCM), according to age. The stacks in each bar represent the percentage of patients in each age group and LV thickness class at the time of the first diagnosis of HCM. Date of download: 6/3/2013 Copyright The American College of Cardiology. All rights reserved.

From: Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy J Am Coll Cardiol. 2003;41(2):315-321. doi:10.1016/s0735-1097(02)02713-4 Figure Legend: Annual rates of cardiovascular mortality according to maximum left ventricular (LV) thickness at diagnosis. Solid bars = total cardiovascular mortality; shaded bars = sudden death; open bars = congestive heart failure/stroke-related death. Date of download: 6/3/2013 Copyright The American College of Cardiology. All rights reserved.

From: Maximum left ventricular thickness and risk of sudden death in patients with hypertrophic cardiomyopathy J Am Coll Cardiol. 2003;41(2):315-321. doi:10.1016/s0735-1097(02)02713-4 Figure Legend: Kaplan-Meier curves showing cumulative survival according to maximum left ventricular (LV) thickness. Survival free of cardiovascular mortality is shown for four different thickness classes. Because no event occurred in patients with maximum LV thickness 15 mm, this particular subgroup was excluded from the analysis, for added clarity. A comparison of survival curves showed that there was no trend toward increasing mortality for increasing values of maximum LV wall thickness. Date of download: 6/3/2013 Copyright The American College of Cardiology. All rights reserved.

Apical 5-chamber long-axis view at rest showing mitral valve at end diastole (SAM was absent in systole) (A) with normal continuous-wave Doppler velocity through the LV outflow tract (C) Maron, M. S. et al. Circulation 2006;114:2232-2239 Copyright 2006 American Heart Association

Prevalence of LV outflow tract obstruction in the overall study group of 320 HCM patients Maron, M. S. et al. Circulation 2006;114:2232-2239 Copyright 2006 American Heart Association

Γιατί προσέρχεται για έλεγχο ο ασθενής 1. Εµφάνιση συµπτωµάτων (Δύσπνοια, στηθάγχη, αίσθηµα παλµών) 2. Εµφάνιση συµβαµάτων (συγκοπή, εγκεφαλικό επεισόδιο, κολπική µαρµαρυγή) 3. Διερεύνηση φυσήµατος ή παθολογικού ΗΚΓ σε προληπτικό έλεγχο 4. Ύπαρξη οικογενειακού ιστορικού ΥΜΚ 5. Αιφνίδιος θάνατος στην οικογένεια σε µικρή ηλικία

From: Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients J Am Coll Cardiol. 2003;42(5):873-879. doi:10.1016/s0735-1097(03)00827-1 Figure Legend: Relation of age to the presence of non-sustained ventricular tachycardia (NSVT) during Holter monitoring. The incidence of NSVT increases with age (p = 0.008). Date of download: 6/2/2013 Copyright The American College of Cardiology. All rights reserved.

Figure 4. Evolution to ES in a male HCM patient (patient 26), shown at end diastole in parasternal long-axis (A and C) and short-axis (B and D) echocardiographic crosssectional planes. Harris K M et al. Circulation 2006;114:216-225 Copyright American Heart Association

Figure 1 Source: The Lancet 2001; 357:420-424 (DOI:10.1016/S0140-6736(00)04005-8) Terms and Conditions

Hazard ratios for sudden cardiac death (filled square) or cardiovascular death (filled circle) for non-sustained ventricular tachycardia. Christiaans I et al. Europace 2010;12:313-321 Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.

Hazard ratios for sudden cardiac death (filled circle) or cardiovascular death (filled circle) for abnormal blood pressure response. Christiaans I et al. Europace 2010;12:313-321 Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.

Apical aneurysm

Correlation of % LGAD and Risk Factors for SCD (AHEPA registry, unpublished data) Family history (SCD) Yes No Syncope Yes No Max wall thickness >30mm Yes No NSVT Yes No ABPR Yes No 13.5 (9.5) 9.48 (12.1) 17.1 (10.4) 8.7 (11.5) 16.38 (5.7) 9.5 (12) 13.4 (8.54) 9.6 (12.14) 12.1 (13.4) 9.15 (10.7) Late Gadolinium Enhancement (%) p value 0.238 0.031 0.024 0.014 0.228

LGAD)enhancement Efthimiadis GK, et al. Hypertrophic cardiomyopathy involving the right ventricular apex Can J Cardiol. 2007; 23(14): 1162.

HCM with apical aneurysms n 2% n 40% <=50 years of age. n 70% mid-lv obstruction n 30% apical HCM n myocardial scarring (late gadolinium enhancement) n recognized by echocardiography in 60% n By MRI in 100% Maron MS, et al. Circulation 2008;118:1541-1549

Atrial fibrillation in HCM

From: Dilated-Hypokinetic Evolution of Hypertrophic Cardiomyopathy: Title and subtitle BreakPrevalence, Incidence, Risk Factors, and Prognostic Implications in Pediatric and Adult Patients J Am Coll Cardiol. 2005;46(8):1543-1550. doi:10.1016/j.jacc.2005.04.062 Figure Legend: A representative example of evolution to dilated-hypokinetic hypertrophic cardiomyopathy (HCM) in a female pediatric patient. (A) The basal echocardiogram (at age 13 years) shows HCM with massive left ventricular (LV) hypertrophy involving the intraventricular septum and the left posterior wall, accompanied by diminutive LV cavity size. (B) Three years later (at age 16 years), the LV cavity has become enlarged and the walls have thinned in the context of severe heart failure, requiring heart transplantation. Date of download: 10/16/2012 Copyright The American College of Cardiology. All rights reserved.

O'Mahony C, Tome-Esteban M, Lambiase PD, Pantazis A Dickie S, McKenna WJ, Elliott PM. Heart. 2013 Jan 22 Median f/u 6.6 years SCD/appropriate ICD shock per/year q 20/660 pts (3%): 0 RF (0.45%) q 31/636 pts (4.8%): 1 RF (0.65%) q 27/249 pts (10.8%):2 RF (1.3%) q 7 /51 pts (13.7%): 3 RF (1.9%) q 4/10 pts (40%): 4 RF (5.0%)

Figure 9. Contemporary Insights and Strategies for Risk Stratification and Prevention of Sudden Death in Hypertrophic Cardiomyopathy. Maron, Barry Circulation. 121(3):445-456, January 26, 2010. DOI: 10.1161/CIRCULATIONAHA.109.878579 Figure 9. Number of risk factors. Top, Appropriate ICD intervention rates (per 100 person-years) are not significantly different with respect to 1, 2, or >=3 risk factors. Center, Cumulative rates for first appropriate device intervention in patients with 1, 2, or >=3 risk factors. Reprinted from Maron et al.8 Used with permission from the American Medical Association, copyright (C) 2007. Bottom, ICD intervention rates in those patients with only 1 risk factor. LVH indicates LV hypertrophy; NSVT, nonsustained VT. 2010 American Heart Association, Inc. Published by American Heart Association. 2

SD in HCM n n n n n Family history of premature SD (<40-y) Unexplained syncope (<6 months) Huge hypertrophy (> 30 mm) Non-sustained VT (especially <30-y) Abnormal blood pressure response on exercise (<40-y)