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Icke ischemisk VT ‐ senaste nytt
Carina Blomström Lundqvist,Jonas Schwieler
Etiologi till VT• Genomgången hjärtinfarkt
– vanligaste orsaken• DCMP• 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
Varje år, i Sverige, dör ca 30 individer < 30 års ålder av hjärtsjk
associerade med plötslig död.
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 diagnosCriteria – 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, multi‐modality 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 onlyNormal 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 HCMFamily 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
Icke predikterbara VA, vanligen unga asymptomatiska pat < 35 år
Kan ske progress till slutsstadie med extensiv myokard ärrbildning
FF; PAF el persist. FFVarierande grad av hjärtsvikt –ökad stroke risk
3 prognos profiler
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
Elliott, EHJ 2014
Bakomliggande etiologi vid HCM
HCM utredning – komplex utredningSigns 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.
Ackerman, Heart Rhythm, 2011
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%
Elliott, EHJ 2014
HCMP ‐ risk stratifiering för plötslig död
Risk factors Recom. Evidence1. Family history of SCD ‐ HCM Class IIa B2. Syncope (exertion, in young) Class IIa B3. 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 B6. 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
Major clinical features associated with increased risk of SCD in adults
Risk Factor Comment
Age Higher risk for SCD if nsVT, LVH, unexplained syncope
Non‐sustained VT 20–30 % of pats during Holter, independent predictor of SCD.
Maximum LV wall thickness Greatest risk of SCD in pats with max wall thickness of ≥30 mm
Family history of SCD at young age
1‐2 first degree relative SCD < age 40 yrs or if SCD any relative with HCM
Syncope Syncope is common in pats with HCM but is challenging to assess as it has multiple causes
Left atrial diameter Positive association between LA size and SCD
LV OT obstruction Association with SCD
Exercise BP response 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 pressureHigher risk of SCD in pats aged ≤40 years
Elliott, EHJ 2014
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
Elliott, EHJ 2014
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 CMPARVC
Arytmier• VES• VT• VF• Plötslig död
Structur/ funktion• RV dilatation• Abnorm väggrörelse• Vägg förtunning
– Sacculationer• RVEF sänkt
– starkare prediktor för plötslig död än LP.
• LV påverkan
Progressiv förlust av myocyterFibros + fett omvandling RV myokard
LV
RV
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
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).
* 25 - 40%15 - 20% av ARVC fall.
ARVC2 -juvenil SCD, ansträngn utlöst polymorp VT. Liknar typ 1 CPVT –sannolikt en CPVT phenotyp kopia o inte ARVC.
PKP2 genen vanligast Hos 50% med strikta ARVC-kriterier Hos 70% med familjär ARVC Saknas vid icke familjär ARVC
GentestClass 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
Tonet, AJC -91; Leclercq, EHJ -89Berder, AJC -94; B-Lundqvist, -87
VT från höger kammare
• LBBB morfologi: 96 %• Ansträngningsutlöst:
43-75 %• Multipla QRS
morfologier (>2): 41%
ARVC ‐ Kliniska fynd
• Fysikaliskt status– Oftast normalt
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
EKG fynd %• T vågs neg. V1-V3 70-92• Inkompl./kompl. RBBB 10-33• RV hypertrofi 5-15• ”Low voltage” 0-19
• Small amplitude potentials after the QRS complex
• Right precordial leads
Epsilon waves
Signal medelvärdes-bildat EKG
*Turrini, AJC-99; Hermida, AJC-97; Mehta JACC-96; Kinoshita, Circul -95; Leclercq, EHJ-93; B-Lundqvist, EHJ -88;
Imaging: RV + LV
Echocardiography (RV projections)• Dimensions• Wall thickness• Wall motion abnormalities
– Sacculations• RVEF
• MR• CT• RV angiography
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
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/conductionabnormalities• 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
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 sample3. Repolarization abnormalities
• T‐inversions V1‐V34. 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
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
O'Donnella, European Heart Journal (2003) 24, 801–810
Freedom from VT recurrence post ablation in pats with ARVC vs RVOT ‐VT
Idiopathic RV arrhythmias
• responsive to medical and ablative treatment
• benign prognosis
IRVOT
ARVC
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
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
VF/VFl-free survival
Actual survival
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
ARVC ‐ behandlingRecommendation 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
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