Icke ischemisk VT senaste nytt Carina Blomström Lundqvist, Jonas Schwieler
Etiologi till VT Varje år, i Sverige, dör ca 30 Genomgången hjärtinfarkt vanligaste orsaken individer < 30 års ålder av hjärtsjk DCMP associerade med plötslig död. Idiopatiska VT Benign RVOT LVOT Fascikel VT Ärftliga hjärtsjk associerade med SCD Kardiomyopatier HCMP vanligaste orsaken till plötslig död hos unga, ffa. idrottare ARVC Jonkanal sjk Brugada LQTS, SQTS CPVT (Catecholaminkänslig polymorf VT) Proarytmi
Hypertrof Cardiomyopati (HCMP) Medfödd hjärtmuskelsjukdom Autosomal dominant med mutation i sarcomere i 60% Prevalence av fenotypen 0.2% (1:500) Heterogen sjukdom Debut i alla åldrar Flesta individer sannolikt normal överlevnad En del sjukdoms progress el plötslig död
HCM diagnos Criteria Adult pat Wall thickness 15 mm in one or more LV myocardial segments any imaging technique; echo, MR, CT not explained solely by loading conditions. Genetic and non genetic disorders can present with lesser degrees of wall thickening (13 14 mm) HCM diagnosis requires evaluation of other features family history, non cardiac symptoms and signs, ECG abnormalities, lab tests, multimodality cardiac imaging First degree relatives of pats with unequivocal disease (LVH 15 mm) Unexplained increased LV wall thickness 13 mm in one or more LV myocardial segments any cardiac imaging technique; echo, MR, CT Elliott, EHJ 2014
Clinical features differential diagnosis of hypertensive heart disease and HCM Clinical features favouring hypertension only Normal 12 lead ECG or isolated increased voltage without repolarisation abnormality Regression of LVH over 6 12 months tight systolic blood pressure control (<130 mm Hg) Clinical features favouring HCM Family history of HCM RV hypertrophy Late gadolinium enhancement at the RV insertion points or localized to segments of maximum LV thickening on CMR Maximum LV wall thickness 15 mm (Caucasian); 20 mm (black) Severe diastolic dysfunction Marked repolarisation abnormalities, conduction disease or Q waves on 12 lead ECG Elliott, EHJ 2014
Prognos profiler vid HCM 3 prognos profiler Icke predikterbara VA, vanligen unga asymptomatiska pat < 35 år Kan ske progress till slutsstadie med extensiv myokard ärrbildning FF; PAF el persist. FF Varierande grad av hjärtsvikt ökad stroke risk
Plötslig död och ålder vid HCMP Plötslig död vanligast före 25 års ålder. Hjärtsvikt och stroke vanligare hos äldre. Maron, Circul J 2010
Heart Rhythm, Dec 2011
Elliott, EHJ 2014
Bakomliggande etiologi vid HCM Elliott, EHJ 2014
HCM utredning komplex utredning Signs and symptoms suggestive of specific diagnoses ECG abnormalities suggesting specific diagnoses or morphological variants Elliott, EHJ 2014
HCM utredning Elliott, EHJ 2014
Elliott, EHJ 2014
Genetics Elliott, EHJ 2014
Genetics Recommendations for genetic and clinical testing of adult relatives Elliott, EHJ 2014
Genetisk testning Autosomal dominant mutation i gener kodande för sarkomer proteiner el associerade proteiner i 60% Har >1,000 mutationer i 11 gener. Class I (rekommenderas) Riktad genetisk testning (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) rekommenderas för pat med klinisk HCMP diagnos enligt klinisk anamnes, familje historia, och EKG/ eko fenotyp. Mutations specifik genetisk testning för anhöriga när sjukdoms alstrande mutation identifierats hos index pat. MYBPC3 11p11.2 Cardiac myosin-binding protein C 20% 45% MYH7 14q11.2-q12 Myosin heavy chain 15% 20% TNNT2 1q32 Cardiac troponin T type 2 1% 7% TNNI3 19q13.4 Cardiac troponin I type 3 1% 7% Ackerman, Heart Rhythm, 2011
Elliott, EHJ 2014
HCMP risk stratifiering för plötslig död Risk factors Recom. Evidence 1. Family history of SCD HCM Class IIa B 2. Syncope (exertion, in young) Class IIa B 3. Extreme LVH ( 30 mm max. wall thickness) Class IIa B 4. Hypotens. BP response to exercise Class IIa B a fall or sustained failure to rise 20 mmhg, exercise or recovery, < 50 years old 5. Nonsustained VT (Holter) Class IIa B 6. Sust VT, VF Christiaans, Europace 2010
Systematic review of recommended major and possible clinical risk markers for SCD in HCM. Medline, Embase, Cochrane databases publications 1971 2007. HCM pats with follow up data on SCD survival analysis. 30 studies passed quality assessment. Use of 6 major risk factors in risk stratification for SCD as recommended by guidelines was supported by literature. Christiaans, Europace 2010
HCMP Primär prevention av plötslig död Relativt stor andel av HCMP pat har en eller flera riskfaktorer för plötslig död Marion, Circulation 2003, Elliot JACC 2000
HCMP ICD behandling Cumulative rates for 1st appropriate ICD intervention: Secondary preventive ICD (n=123) Primary preventive (n=383) Maron, Circul J 2010
New Model for estimating SCD risk Multicentre, retrospective, longitudinal cohort study of 3675 pats; new SCD risk prediction model. 73 HCM Risk SCD predictor variables associated with increased risk of SCD in at least one published multivariable analysis. excludes abnormal BP response as a risk marker. provides individualized 5 year risk estimates Elliott, EHJ 2014
Risk Factor Age Major clinical features associated with increased risk of SCD in adults Comment Higher risk for SCD if nsvt, LVH, unexplained syncope Non sustained VT Maximum LV wall thickness Family history of SCD at young age Syncope Left atrial diameter LV OT obstruction Exercise BP response Elliott, EHJ 2014 20 30 % of pats during Holter, independent predictor of SCD. Greatest risk of SCD in pats with max wall thickness of 30 mm 1 2 first degree relative SCD < age 40 yrs or if SCD any relative with HCM Syncope is common in pats with HCM but is challenging to assess as it has multiple causes Positive association between LA size and SCD Association with SCD Failure to increase systolic BP by at least 20 mm Hg from rest to peak exercise or a fall of >20 mm Hg from peak pressure Higher risk of SCD in pats aged 40 years
New Model for estimating SCD risk Prognostic index = [0.15939858 x maximal wall thickness (mm)] [0.00294271 x maximal wall thickness 2 (mm2)] + [0.0259082 x LA diameter (mm)] + [0.00446131 x maximal (rest/valsalva) LVOT gradient (mm Hg)] + [0.4583082 x family history SCD] + [0.82639195 x NSVT] + [0.71650361 x unexplained syncope] [0.01799934 x age at clinical evaluation (yrs)] Elliott, EHJ 2014
Recommendations on prevention of SCD Elliott, EHJ 2014
Elliott, EHJ 2014
Recommendations on AF / AFL Elliott, EHJ 2014
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Recommendations on routine follow up Elliott, EHJ 2014
N= 239 HCM pats; syncope + previous surgical myectomy mean age 48 + 17 yrs; 56% men. age-matched pats with HCM + syncope treated medically Median FU 4.7 yrs Syncope recurrence 11% in myectomy vs 40% in medical group (p <0.0001). Survival free of all-cause mortality greater for myectomy pats than medically treated pats (10-year estimate 82 + 4% vs 69 + 4%; p <0.01). Conclusion, surgical myectomy in pats with HC and a history of syncope - reduction in recurrent syncope and increased survival. Am J Cardiol 2013
Arytmogen högerkammar CMP ARVC Progressiv förlust av myocyter Fibros + fett omvandling RV myokard Structur/ funktion Arytmier VES VT VF Plötslig död LV RV RV dilatation Abnorm väggrörelse Vägg förtunning Sacculationer RVEF sänkt starkare prediktor för plötslig död än LP. LV påverkan
ARVC Prevalens 1:1,000 1:10,000 Familiär i 50 65 % av fallen Symtomdebut: 33 ±14 år (8 73 år) Autosomal dominant nedärvning med ofullständig penetrans (majoriteten). Recessiva former ofta associerade med hudsjukdom. Heterogen olika fenotyper 90 % desmosomala gener 10 % icke desmosomala gener
ARVC 12 ARVC relaterade gener kodar för: (majoriteten av patogena mutationer har identifierats i gener som kodar för desmosomala proteiner) 5 desmosomal proteiner Plakophilin 2 PKP2 * Desmoplakin DSP, Desmoglein 2 DSG2, Desmocollin 2 Dsc2 Junction plakoglobin (PG) JUP * 25-40% 15-20% av ARVC fall. PKP2 genen vanligast Hos 50% med strikta ARVC-kriterier Hos 70% med familjär ARVC Saknas vid icke familjär ARVC 7 icke desmosomal proteiner Desmin DES Transmembranprotein 43 TMEM43 Transform. tillväxtfaktor β 3 TGFB3 Lamin A/C LMNA Titin TTN Phosfolamban PLN αt katenin CTNNA3. (Mutation i ryanodine genen (RyR2) klassats som ARVC phenokopia, men ä ej ARVC). ARVC2 -juvenil SCD, ansträngn utlöst polymorp VT. Liknar typ 1 CPVT sannolikt en CPVT phenotyp kopia o inte ARVC.
Gentest Class I (rekommenderas) Mutations-specifik genetisk testning för anhöriga när sjukdoms alstrande ARVC mutation identifierats hos index pat Class IIa (kan vara användbart) Riktad genetisk testning (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) för pat som uppfyller nya ARVC kriterierna. Class IIb (kan övervägas) Genetisk testning för pat med möjlig ARVC (med 1 major eller 2 minor av nya ARVC kriterierna). Class III (rekommenderas inte) Genetisk testning för pat med endast en minor kriterie. Ackerman, Heart Rhythm 2011
STATE OF GENETIC TESTING FOR ARVC Approximate 50 % yield of current generation genetic test 16 % frequency of rare variants in these same genes among healthy volunteer Possible that up to 1/3 of rare missense variants during genetic testing are false positives. 3 previously reported missense variants occur in 0.5% 1.4% of healthy controls. Many PKP2 variants are not sufficient per se for clinical disease. Doubt regarding pathogenicity of certain genetic variants in DSG2, identified in healthy control subjects in 0.5% 13.9% Extreme caution regarding obtaining ARVC genetic test and interpreting its significance!! Better refer pat with a questionable diagnosis of ARVC to a specialty center rather than order genetic test.
Kliniska arytmier VT från höger kammare LBBB morfologi: 96 % Ansträngningsutlöst: 43-75 % Multipla QRS morfologier (>2): 41% Tonet, AJC -91; Leclercq, EHJ -89 Berder, AJC -94; B-Lundqvist, -87
ARVC Kliniska fynd Fysikaliskt status Oftast normalt EKG fynd % T vågs neg. V1-V3 70-92 Inkompl./kompl. RBBB 10-33 RV hypertrofi 5-15 Low voltage 0-19 T vågs inversion V1 V3: Normalt hos barn <12 år, Kan vara sekundärt till RBBB el. RV belastning Metzger, AJC -93; Lemery, JACC -89, Lascault, Circul -88; B Lundqvist -87
Epsilon waves Signal medelvärdesbildat EKG Small amplitude potentials after the QRS complex Right precordial leads *Turrini, AJC-99; Hermida, AJC-97; Mehta JACC-96; Kinoshita, Circul -95; Leclercq, EHJ-93; B-Lundqvist, EHJ -88;
Imaging: RV + LV MR CT RV angiography Echocardiography (RV projections) Dimensions Wall thickness Wall motion abnormalities Sacculations RVEF LV involvement? 2D echo: 36 % Macroscopically or histologically in 76 % of autopsy or transplant SD hearts Corrado D, JACC 1997, Pinamonti, AHJ 1992
Diagnostic criteria for ARVC Major 1. Global or regional dysfunction and structural alterations by echo, MR, RV angio 2. Tissue characterization of wall Residual myocytes <60%, + fibrous replacement of RV free wall >1 sample 3. Repolarization abnormalities T inversions V1 V3 4. Depolarization/conduction abnormalities Epsilon waves V1 3 5. Arrhythmias VT nonsust or sust of LBBB + superior axis. 6. Family history; 1st, TF criteria, autopsy, genetic Minor 1. Same but milder changes. 2. Tissue characterization of wall As major but 60 75% 3. Repolarization abnormalities V1 V2 or V4 V6 at age > 14 yrs 4. Depolarization/conduction abnormalities Late potentials by SAECG in >1/3 parameters (absence of QRSd > 110ms) on standard ECG. Terminal activation duration QRS >55 ms V1 3 5. Arrhythmias VT RVOT or >500 VES on 24 h Holter 6. Family; 2nd ARVC, 1st SCD <35yr Diagnos: 2 major / 1 major + 2 minor criteria / 4 minor from different categories; Borderline: 1 major + 1 minor / 3 minor criteria from different categories Possible: 1 major / 2 minor criteria from different categories. Cox, Circul Arrhythm Electrophysiol. 2010
Right ventricular tachycardias A. Exclude other structural heart diseases with RV involvement congenital heart disease repaired tetralogy of Fallot, Ebstein anomaly, ASD acquired disease TV disease, PH, RV infarction; dilated CMP, Sarcoidosis B. Differentiate from: Idiopathic RVOT tachycardia
Differentiate IRVOT VT vs ARVC IRVA ARVC Inducibility of VT by PES + >2 ECG morphology during VT + Fragmented diast. potentials, VT + Re entry + Triggered automatic basis + Niroomand F, Heart. 2002 Jan;87(1):41-7, O'Donnell D, Eur Heart J. 2003 May;24(9):801-10
Freedom from VT recurrence post ablation in pats with ARVC vs RVOT VT IRVOT ARVC Idiopathic RV arrhythmias responsive to medical and ablative treatment benign prognosis O'Donnella, European Heart Journal (2003) 24, 801 810
VT ablation in ARVC Survival Free of VT Recurrence Dalal, JACC 2007
2010 diagnostic criteria for ARVC limited discrimination in distinguishing ARVC vs sarcoidosis. Suspect sarcoidosis if: Older age of symptom onset, Presence of CV comorbidities, Non familial pattern, PR prolongation, high grade AV block, Significant LV dysfunction, myocardial delayed enhancement of septum, Mediastinal lymphadenopathy Philips, Circul Arrhythm Electro2014
Aktuell överlevnad vs frihet från ICD terapi pga VF/V fladder Actual survival VF/VFl-free survival 132 ARVC pat med ICD, CA 10%, VT 62%, Syncope, el annat 28% Vid 36 mån.: Aktuell överlevnad vs. VF/VFl fri överlevnad 96% vs 72%, P<0.001. PES begränsat värde för risk värdering av VA Corrado D, Circulation. 2003;108:3084-3091
ARVC risk stratification for SCD Useful/likely useful risk factors Level of evidence Extensive RV disease Class IIa C LV involvement Class IIa C Family member with SCD, Class IIa C or undiagnosed syncope Zipes, EHJ 2006
Predictors of occurrence of a first arrhythmic event among ARVC associated desmosomal mutation carriers; Sex, pedigree, family history of SCD and ARVC, Nature of presentation, syncope, Precordial T wave inversions, depolarization abnormalities, LV dysfunction, and RV structural abnormality Cox regression model (n= 215 pats (88 probands,127 family members) with ARVC associated mutations). Calkin, Circ Arrhythm Electrophysiol. 2013
ARVC Novel risk stratification for SCD Calkin, Circ Arrhythm Electrophysiol. 2013
Recommendation ARVC behandling Class VT sust or VF ICD I Primary prevention of SCD ICD IIa Extensive disease, incl. LV involvement, >1 affected family member with SCD, or undiagnosed syncope when VT / VF has not been excluded as cause of syncope, Sustained VT or VF when ICD impl. is not feasible. Amiodarone or sotalol IIa Recurrent VT, despite AA drugs Ablation as adjunctive Rx IIa Risk assessment of SCD EP testing IIb