2007 rieti, convegno regionale, quale terapia nelle channelopatie

Quale terapia nelle Quale terapia nelle Channelopatie ?Channelopatie ?

quando e come approfondire la diagnosiquando e come approfondire la diagnosiStefano Nardi MD, PhD

AZIENDA OSPEDALIERA SANTA MARIA TERNIAZIENDA OSPEDALIERA SANTA MARIA TERNIDIPARTIMENTO CARDIOTORACOVASCOLAREDIPARTIMENTO CARDIOTORACOVASCOLARE STRUTTURA COMPLESSA DI CARDIOLOGIA STRUTTURA COMPLESSA DI CARDIOLOGIA

UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE

PERCEZIONE del Problema

T waves flattened, inverted (esp in V1-V3)

Precordial QRS prolongation

ε waves (small amplitude pot. at start of ST – “intrav. myocardial defect”)

SAECG


sopralsivell punto J ≥ 2 mm con onda T negativa.


•QTC 470 ms.


DIMENSIONE del PROBLEMA

• Until 20% survival

• Between 30 - 80% of survivals suffer of Anoxic Encephalopaty

Magnitude (annual mortality)

•U. S. U. S. 450.000 450.000

•Europe Europe 600.000 600.000

•Germany Germany 80.000 80.000

•ItalyItaly 65.00065.000

Incidence in Italy Incidence in Italy

1 case each 9 minutes 1 case each 9 minutes

Total DeathTotal Death 557.584 (100%) 557.584 (100%)

Death for CV diseaseDeath for CV disease 242.248 (43%) 242.248 (43%)

Sudden DeathSudden Death 57.000 (10.2%)57.000 (10.2%)

ISTAT source ‘00ISTAT source ‘00

0

50000

100000

150000

200000

250000 Cancro dellaMammellaCancro ColonRettoCancroBronchi/PolmoniIctus

Morte Improvvisa

MalattieCardiovascolari

Mort

i p

er

an

no

Mortality Distribution

Magnitude and Etiology of SCD

• ion-channel abnormalities, valvular or congenital HD, other causes

80% CAD15% CM

5% Other*

SCA4

450,000

#1 Killer in the U.S.

4 Zheng Z. Circulation. ‘01

• 2 peak age-related in which SCD is more prevalent

• Between born and 6 mo (sudden infant death syndrome)

• Between 45 and 75 years old

Sudden Cardiac Death Sudden Cardiac Death

Relationship with Age

• 1 case each 1 case each 10 10 hours hours (UMBRIA)(UMBRIA)

• 912/850.000 each years912/850.000 each years

•10 %10 % of all total mortality of all total mortality

•40 %40 % of all deaths for CARDIAC DISEASE of all deaths for CARDIAC DISEASE

Cardiopatia Non cardiopatia

- I-DCM- H(O)CM- Valvular CM- Congenital HD- Altre forme (ARVD)

- Tachicardia monomorfa dal tratto d’efflusso del VDx (RVOT)

-Tachicardia ventricolare sinistra idiopatica (ILVT)

- Tachicardia Ventricolare monomorfa catecolaminergica - Sindrome del QT lungo

- Sindrome del QT breve - Sindrome di Brugada - Altre forme

SUBSTRATO SOTTOSTANTE

Stratificazione del Rischio • AMPIO spettro di

substrati sottostanti

• Diverse combinazioni fra TIPO di ARITMIA e SUBSTRATO configura differenti quadri clinici con diversi profili di rischio

SUBSTRATOSUBSTRATO• I-DCM

- riduzione LVEF - NSVT - Sincope

• H(O)CM• ARVD• Brugada syndrome• QTLS• FV Idiopatica• VT Idiopatica

Condizioni cliniche

• Cardiopatia Coronarica• Cardiomiopatia Ipertrofica • Cardiomiopatia Dilatativa• Cardiopatia Valvolare• Sindromi Aritmogene Ereditarie

(ARVD, QTLS, BS, VT Polimorfa Catecolam)• Altre (Cuore d’atleta, Cuore normale, ecc.)

Stratificazione del RischioStratificazione del Rischio

Primary Based on Studies and Clinical Research in a large cohort of

ptsBased on Statistical Analisys but strickly

linked with Personal Experiences and common good practise

What is Evidence Based Medicine (EBM)?

Magnitude of Sudden Cardiac Arrest

Esiste un modo per stratificare i pazienti?

La maggior parete dei soggetti che SPERIMENTA un Arresto

Cardiaco non sopravvive per poterlo

raccontare

Morte Improvvisa PATOGENESI

BradiaritmiaBradiaritmia15-20%15-20%

VT/VF 75-80%VT/VF 75-80%

EMD 5%EMD 5%

Ritmo registrato nei pz Ritmo registrato nei pz risuscitati ad arresto risuscitati ad arresto cardiaco extraospedaliero cardiaco extraospedaliero o nei pazienti deceduti o nei pazienti deceduti improvvisamente durante improvvisamente durante registrazione Holter registrazione Holter

Cummins RO, Annals Emerg Med. ‘89

Albert CM. Circulation ‘03

Bayés de Luna A. Am Heart J. ‘89

Ma quali sono le categorie a rischio ?

• Dati raccolti sottoposti a revisione sintetica da parte della Task Force della ESC

• Da tale revisione sono emerse

raccomandazioni (NON LINEE GUIDA !!!) in base alla EBM che coinvolgono la fase diagnostica e terapeutica dell’approccio alla MI

Priori S - Eur Heart J ‘01

Premessa Metodologica

• Considerazioni ESTRAPOLATE dai dati a nostra disposizione NON risultano essere SEMPRE TRASFERIBILI DIRETTAMENTE nei pazienti con condizioni di base DIVERSE, malgrado segni/sintomi di uguale espressione


orienta l’investigatore circa la strategia da utilizzare nei singoli casi!

STRATIFICAZIONE del RISCHIO

AltoRischio

MedioRischio

Popolazione Basso Rischio

In quale popolazione esiste un REALE BENEFICIO ????

Sindrome del QT - Lungo

TdP = Torsades de Pointes; VF = Fibrillazione Ventricolare; AC = Arresto Cardiaco; JLN = Jervell and Lange

Nielsen; Sin = Sindattilia; BAV = Blocco AtrioVentricolare; SCD = Morte Improvvisa;

I IIa IIbClasse•QTc > 600ms•Evento Cardiaco nei neonati•Post-partum•Sind + BAV •Alternanza onda T•Sesso Femminile

• TdP / VF / AC• Sincope• JLN• LQT3

• Familiarità di SCD Dispersione del QTStratificazio

ne del Rischio

5 Priori et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 2001; 22:1374-1450. [Full text]

Sindrome di Brugada

VF = Fibrillazione Ventricolare; VT = Tachicardia Ventricolare; SCD = Morte Improvvisa; VT Sost.= Tachicardia Ventricolare

Sostenuta

I IIa IIb

•Sincope•Familiarità di SCD• VF - VT

• Inducibilita VT Sost. - VF

Classe

Stratificazione

del Rischio


VT Polimorfa Catecolaminergica

VF = Fibrillazione Ventricolare; SCD = Morte Improvvisa; VT Non Sost. = Tachicardia Ventricolare Non Sostenuta

I IIa IIb

•Familiarità di SCD•VT Non Sost. / sincope nell’età pediatrica

• VF• Sincope

Classe

Stratificazione

del Rischio


Stratificazione del rischio

Letalità patologia

Vantaggio dell’ICD

Costo

Beneficio

Per la serie: le ultime parole famose... Maggiore è il rischio di

MORTE ARITMICA

Maggiore il beneficio dell’ICD

Profilassi della Morte Improvvisa

Vantaggi Svantaggi

Defibrillatore impiantabile

• Riconoscimento e trattamento di

un’aritmia ventricolare (1-2% MI per anno di FU)

• • Costi• Terapia inappropriata• Impatto su QoL sconosciuto• Complicanze precoci e tardive• Consumo batterie ed elettrodi

• ICD molto efficaci ed affidabili nell’interruzione della VT/VF

• FV causa principale della morte improvvisa

ICD indispensabile nella lotta contro la morte improvvisa!


POSSIBILE IMPLICAZIONE

Mortalità totale

Frazione di eiezione

Morte per causa aritmicaDiss. E-M

ElettricaInfettiva

NeoplasticaNeurologica

Ecc.

Considerazioni

• L’ impatto di una determinata strategie si basa sulla riduzione di probabilità dell’evento “END POINT”

– Per dimostrare l’applicabilità clinica dell’ICD è necessaria una PROVA

INCONFUTABILE della sua efficacia

- Tale prova è spesso vincolata dai filtri a maglie strette della metodologia applicata alla pratica clinica (EBM).

Implicazioni

Indicazioni Indicazioni CONSOLIDATECONSOLIDATE

• Sopravvissuti a MI

• TV sostenute spontanee

• Sincope + TV inducibile

ICD

Costo

Beneficio

Class I Class I

Cardiac arrest due to VF or VT not due to a transient or reversible cause(Level of Evidence: A)

Spontaneous sustained VT in association with structural heart disease (Level of Evidence: B)

Syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at EP study when drug therapy is ineffective, not tolerated, or not preferred (Level of Evidence: B)

AVIDCASHCIDS

CIDSAVID Registry

AVID Substudy Gregoratos G. ACC/AHA/NASPE Circulation ‘02

L’evidence based è dominata dalla frazione di eiezione (LVEF)

(vincolo PREVALENTE)


SCD RISK

ICD efficacy

Cost

Benefit

I-DCM – RISK stratification

• Prior CA or S-VT (I)Prior CA or S-VT (I)• Syncope (II a)Syncope (II a)• Ridotta LVEF (II b)Ridotta LVEF (II b)• NSVT (II b)NSVT (II b)

HIGH RISK

Priori et al. Eur Heart J ‘01Priori et al. Eur Heart J ‘01

– Quale rapporto COSTO/BENEFICIO ?

Considerazioni aggiuntive

ICD in soggetti senza aritmie sostenute

CAT, DEFINITE, SCD-HeFT CAT, DEFINITE, SCD-HeFT

QoL • Impatto psicologico• Terapia inappropriata• Terapia appropriata in stato di coscienzaAssenza di dati prospettici!

END POINT mortalità: è corretto?END POINT mortalità: è corretto?

Arresto cardiaco

Completo recupero

Intervento

Invalidità Invalidità permanentepermanente

MORTE

Basic

Life

Support

T

E

M

P

O

Indicazioni Indicazioni CONSOLIDATECONSOLIDATE

• Sopravvissuti a MI

• TV sostenute spontanee

• Sincope + TV inducibile

• I-DCM - Riduzione LVEF - NSVT - Sincope

EMERGENTIEMERGENTI

• HCM• ARVD• Brugada syndrome• QTLS• FV Idiopatica• VT Idiopatica

ICD

Esiste oggi una terapia che può essere considerata il GOLD STANDARD nelle

CARDIOPATIE ARITMOGENE ?

Qual è la percezione del PROBLEMA ?

Quali sono le INDICAZIONI univocamente ACCETTATE ?

RISK stratification

AltoRischio

MedioRischio


In quale popolazione esiste un REALE BENEFICIO ?

Patologie EMERGENTIPatologie EMERGENTI

• HCM• Brugada syndrome• ARVD• QTLS

CLINICAL GOVERNANCE

• National Operative Organized System by which is possible to CTR the Standard references of QUALITY and the Continuous Educational System • Merge between Clinical Practice and Health Management

• Efficacy and Effectivness of Local Source

Big Brother

CLINICAL GOVERNANCE

PerformancePerformance Disease Disease Management Management

Evento Evento Sentinella Sentinella

AUDIT AUDIT EBM EBM

Clinical Governance is a cyclical process

GUIDELINES GUIDELINES

In both aviation and

medicine, people

depend on technology

as the solution…

SCD RISK

ICD efficacy

Cost

Benefit

HCM – RISK stratification

• Prior CA or S-VTPrior CA or S-VT• Family history of 1Family history of 1stst degree degree

SCD SCD • LVH wall thickness >3,0cmLVH wall thickness >3,0cm• Syncope Syncope

(exercional/repetitive)(exercional/repetitive)• Repetitive/prolonged NSVT Repetitive/prolonged NSVT • BP flat response during STBP flat response during ST

HIGH RISK

HCM – RISK stratification

AltoRischio

MedioRischio


• Prior CAPrior CA• Sust. VTSust. VT• VFVF

• Family history of SCDFamily history of SCD• SyncopeSyncope• Extreme LVH (>3cm)Extreme LVH (>3cm)• BP flat during STBP flat during ST• NSVT (Holter)NSVT (Holter)

• High risk mutationHigh risk mutation

• VT/VF at PESVT/VF at PES• LV outflow gradientLV outflow gradient• MRMR• Chest-pain/dispneaChest-pain/dispnea• Paroxismal AFib Paroxismal AFib

Class I Class IIClass III

Priori et al. EHJ ‘01Priori et al. EHJ ‘01

The ‘Swiss cheese’ model of organizational accidents

Some holes dueTo active failures

Other holes due tolatent conditions

Successive layers of defences

Hazards

Losses

It takes an average of 4.5 errors in the system for a medical accident to result Modified from James

Reason, 1991.

1. FAILURE to use a systematic approach to the

assessment of critically ill pts

2. POOR communication

3. LACK of teamwork

4. INSUFFICIENT use of treatment limitation plans.

Addictional factors

Deficiencies in Acute Care

PrevenzionePrimaria

PrevenzioneSecondaria

I IIa IIbClasse

•ICD

•ICD

•Amiodarone

HCMHCM


HCMHCMManagement of high risk ptsManagement of high risk pts

• InIn “PREVENZIONE PRIMARIA” nei pts con ≥2 fattori di rischio (f. annua SCD 3-6%)

• InIn “PREVENZIONE PRIMARIA” nei pts con ≥2 fattori di rischio (f. annua SCD 3-6%)

• Frequenza annua di SCD variabile da un minimo di 1% (community-based population) ad un max di 2-4% (referral centre cohorts)

• Frequenza annua di SCD variabile da un minimo di 1% (community-based population) ad un max di 2-4% (referral centre cohorts)

• In questo specifico “sub-set” pts, dati retrospettivi recenti riportano un 5% annuo di DC shock appropriati, con no SCDs

• In questo specifico “sub-set” pts, dati retrospettivi recenti riportano un 5% annuo di DC shock appropriati, con no SCDs

ARVDARVDStefano Nardi MD



• “ARVC” proposed in 1977 by Fontaine

• Occurs in teenagers and young adults (>80% diagnosed by age 40)

– Rarely in early childhood

• INCIDENCE: unknown (6/10000 ???)

• PREVALENCE: unknown

• Italian study - 20% of postmortem SD in pts < 35 ys old

• Incidence 1:~5,000

Background

1:5000

Epidemiology

- Typical ECG, VTs from RV and structural and functional RV abnormalities represent only one extreme of the disease spectrum.

- Clinically silent cases are not recognized because asymptomatic

- The first presentation could be SD

- Diagnosys could be difficult by conventional non-invasive tools.

Task Force of the World Health Organization/International Society and Federation of Cardiology

• Degeneration– Myocyte death due to inherited metabolic or

ultrastructural defect– “Myocardial dystrophy”

• Inflammatory/infectious/myocarditis– Coxsackie-like RNA found in some cases

• Apoptosis

• Trans-differentiation– From myocardial cells to adipose tissue

Etiology

• ~50% Autosomica Dominante• Espressione Variabile• Penetranza incompleta (30%)• Chromosomi 14, 1, 10• Patologia della Plakoglobina

Genetica

•Atrofia muscolare cardiaca•Sostituzione fibro-adiposa•Aritmie ventricolari (RV)•Morte Cardiaca Improvvisa

DefinizioneDESMOPLAKINAPLAKOGLOBINA (Naxos)

RIANODINA (MAVD2)

STRESS MECCANICO INTERCELLULARE

APOPTOSI

SOSTITUZIONE FIBROSA ED

ADIPOSA

PRESENTAZIONE CLINICA • PALPITAZIONI (67%)

• Sincope (32%)• Cardiac Arrest (7-23%)• Dolore toracico atipico (27%)• Dispnea (11%) • ASINTOMATICI

• “Concealed” phase - subtle RV changes - minor VTs - rarely SD ( competitive athletics)

• “Overt electrical disorder” – overt RV - structural/functional changes - symptomatic RV tachyarrhythmias

•“RV failure” – global RV dysfunction with - preserved LV function

•”Biv CHF” – signif LV dysfunction

Task Force of the World Health Organization/International Society and Federation of Cardiology

Dynamic and evolutive substrate




SAECG

CLINICAL PRESENTATION

TV1- APEX

TV2- Subtricuspidal

TV3- Infundibular

• The assessment of SD risk is still not well established, • No precise guidelines are available to determine which are the pts who need to be treated• Which is the best management approach?• Therapeutic options include beta blockers, AADs, CA and ICD. • In pts in whom ARVD/C has progressed to severe RV or BIV systolic dysfunction, treatment consists of current therapy for HF including diuretics, ACE-I, and digitalis, as well as ACT. • These pts may become candidates for heart transplantation.

THERAPY

43

66

47

22

81

45 48

69

11 12 15

JRACataracts

Syncope

1311

AdoptedLung CASudden deathEtiology?

VSDAsthma

Hypothyroid

FibromyalgiasBell’s palsy

Hypothyroid

45 51

1468

ARVCHypothyroid

OK OK OK OK

OK

Palps OK

OK

* *

*

ARVD: family tree

ARVD – RISK stratification

AltoRischio

MedioRischio


• Family history of Family history of ARVD/SCDARVD/SCD

• SyncopeSyncope• Late potential + Late potential +

RV dysfRV dysf• VTVT• RVSTIM + RVSTIM +

• QTc disp and TWAQTc disp and TWA• PVCs PVCs

Class IIa Class IIbClass III

Priori et al. EHJ ‘01Priori et al. EHJ ‘01

• VT sostenuteVT sostenute• Diffuse RV dilDiffuse RV dil• LV LV

involvementinvolvement• RV dysf/dilat RV dysf/dilat

+ + RVSTIM +RVSTIM +

• Previous Previous CA/VF CA/VF

LEVEL of EVIDENCE CLEVEL of EVIDENCE C

ARVD/RVCARVD/RVC

• Il valore PREDITTIVO dei MARKERS non è stato definito in studi prospettici su larga scala

• Il valore PREDITTIVO dei MARKERS non è stato definito in studi prospettici su larga scala

• I dati riportati sono basati su PICCOLI STUDI (prevalentemente derivanti da centri terziari nei quali il paziente era giunto per l’aritmia

• I dati riportati sono basati su PICCOLI STUDI (prevalentemente derivanti da centri terziari nei quali il paziente era giunto per l’aritmia

• Il PROFILO di RISCHIO dei pts asimptomatici (albero genialogico) NON E’ STATO sistematicamente VALUTATO

• Il PROFILO di RISCHIO dei pts asimptomatici (albero genialogico) NON E’ STATO sistematicamente VALUTATO

•VT Sost./ VF•Dilatazione RV•Disfunzione RV +inducibilita’ SATE

I IIa IIbClasse

•Familiarity SCD•PT+ RV dysfunction•VT•Inducibilita’ SATE

Stratificazione

del Rischio

Priori, Eur Heart J ‘01

• ICD

I IIa IIb

• ICD

•AADs (Sotalol)

PrevenzionePrimaria


Classe

ARVARVDD

• ICD

I IIa IIb

• ICD

•AADs (Sotalol)

PrevenzionePrimaria


Classe





SAECG

RegistroInternazionale

•www. arvd.org

•www.arvd.net

Onda Epsilon (ε)

Incisura onda S ascendente >55 ms

• Right ventricular angiography– Dilated, poorly contractile RV free wall

and RV outflow tract

• RV endomyocardial biopsy– Excessive fatty infiltration

– Sporadic, typically involves epicardium first (ie. False negative sampling)

ARVD: Cardiac Catheterization

ANGIOGRAFIA

PATRON DE ORO - VD

1.- Aumento trabeculatura a “pila di piatti”

2.- Dilatazione ed Ipocinesia

3.- Alterazione segmentaria della Contrattilita`

4.- Discinesia

5.- Abultamiento e aneurisma localizzato

??????

????

Ouyang et al, 2002

ArrhythmogenicRight Ventricular Dysplasia

??????

????

Ouyang et al, 2002

??????

????

Marchlinski et al, 2000

• The definitive test?

• Requires experienced cardiac imaging specialist

• Can distinguish fat from muscle

• Cine MRI helps qualitate free wall function

ARVD: MRI

• Restricted activities

• Medic Alert bracelet/necklace

• Medications– Amiodarone, sotalol, beta-blockers

• RF Catheter ablation

• ICD

ARVD: treatment

One of the major causes of SCD in pts in pre-CAD age, accounting for approximately 25% of SD in young athletes

One of the major causes of SCD in pts in pre-CAD age, accounting for approximately 25% of SD in young athletes

ARVD/RVCARVD/RVC

AADs is often used as primary Rx, however this approach is often “INEFFECTIVE” AADs is often used as primary Rx, however this approach is often “INEFFECTIVE”

PREVALENCEPREVALENCE is not well defined (post-mortem features of RVC may be subtle/confined to region of RV wich may not have been routinely examined at autoptic evaluation

PREVALENCEPREVALENCE is not well defined (post-mortem features of RVC may be subtle/confined to region of RV wich may not have been routinely examined at autoptic evaluation

Disease that involve Plakoglobin, an intracellular adhesion molecule involved in the apoptosis process Disease that involve Plakoglobin, an intracellular adhesion molecule involved in the apoptosis process

ARVD/RVCARVD/RVC

ARVD/RVC manifests with VTs, however the initial presenting symptom may be SINCOPE (29%) or CA (7-23%)

ARVD/RVC manifests with VTs, however the initial presenting symptom may be SINCOPE (29%) or CA (7-23%)

Familiar disease with autosomal dominant and incomplete penetrance Familiar disease with autosomal dominant and incomplete penetrance

LIMITED INFORMATIONS LIMITED INFORMATIONS are available on risk assessment of SCD LIMITED INFORMATIONS LIMITED INFORMATIONS are available on risk assessment of SCD

Predictive marker have not yet been defined in prospective studies focus on SURVIVAL, therefore data reported here are based on small studies in pts who presented with arrhythmia

Predictive marker have not yet been defined in prospective studies focus on SURVIVAL, therefore data reported here are based on small studies in pts who presented with arrhythmia

The RISK PROFILE of asymt. Pts hase not been systematically evaluated The RISK PROFILE of asymt. Pts hase not been systematically evaluated

ARVD/RVCARVD/RVC

ARVD/RVCARVD/RVCManagement of high risk ptsManagement of high risk pts

Data regarding efficacy of various AADs for prevention VTs or SCD relies on retrospective and prospective “non-randomized” studies

Data regarding efficacy of various AADs for prevention VTs or SCD relies on retrospective and prospective “non-randomized” studies

Sotalol showed higher efficacy, then is recommended as a first choice drug to prevent recurrence of VTs, however in pts with aborted SCD ICD Rx is likely to reduce mortality

Sotalol showed higher efficacy, then is recommended as a first choice drug to prevent recurrence of VTs, however in pts with aborted SCD ICD Rx is likely to reduce mortality

ARVARVDD

• ICD

I IIa IIb

• ICD

•AADs (Sotalol)

PrevenzionePrimaria


Classe


BRUGADA Syndrome BRUGADA Syndrome

Stefano Nardi MD



•AUTOSOMAL DOMINANT trait and incomplete penetrance with variable expression.


•Genetic defects in the α-subunit of cardiac Na+ channel, (reduction the Na+ channel current) that accentuates the epicardial action potential notch leading to ST-segment elevation.

•Abnormal EP activity in the RV epicardium that leads to the development of coupled PVCs that precipitates VT/VF.

•Mutations in the cardiac Na+ channel gene SCN5A

• RBBB and ST-segment elevation in the right precordial leads (V1 to V3), w/o evidence of structural HD.

• Exclusion of mimic diseases (hypothermia, pericarditis, myocarditis, or ischemic events).

• ECG pattern could be intermittent (variable and dynamic) and influenced by many factors (°C, ANS, Drugs) that can affect ion channel function.


ST segment elevation in Brugada syndrome

•Autonomic tests– Isoproterenol, propranolol, norepinephrine, phentolamine

•Antiarrhythmic drugs– Ia (procainamide) Ib (lidocaine) Ca channel blocker (verapamil)

•Early repolarization hypothesis

•PREVALENCE: 0.1% in Europe

•DIAGNOSIS: ~ 40 years (2 to 77 years)

•MALE/FEMALE: 3:1

•TACHYARRHYTHMIAS at rest or during the night.

•RECURRENCE of arrhythmic events is as high as 40%.

•Sudden Infant Death Syndrome (SIDS) in the first mo. of life where it may be misdiagnosed as


•Provocative test with Na+ channel blockers proposed to unmask the diagnostic ECG pattern. – Ajmaline (1mg/kg IV) or

– Flecainide (2mg/kg IV) or

– Procainamide (10mg/kg IV) as a bolus over 10 m’.

– ST-segment further elevation > 2 mm


•The inducibility during the EPS was used to identify the risk of cardiac event, although its accuracy was limited


BRUGADA Syndrome BRUGADA Syndrome •α-agonist, neostigmine/edrophonium and Class IA

AADs should be avoided because they consistently augmented ST segment elevation in pts with BS

•Although the number of pts was small in this study.

•Indication for ICD– symptomatic Brugada syndrome patients including syncope, cardiac arrest or documented VT

– Asymptomatic individuals with a positive ECG and a family history of sudden death and/or inducible during electrophisiological study


A sudden syncope in a 35-year old man, with no prior cardiac history. The physical examination was unremarkable, the echo parameters were normal and an head-up test does not reproduced the symptoms.

The ECG shown is obtained.

At this point you would advise:

A.No specific therapy

B.Empiric B-blocker

C.EP Study with ICD implantation if positive

D.ICD implantation

A clinical and electrocardiographic syndrome

- no demonstrable structural HD

• - suffering from cardiac arrhythmias

• - a very specific ECG

• apparent RBBB

• ST elevation in leads V1-V3

Description of the syndrome

• The disease is associated with a mutation in sodium channel (SCN5A).

• The early theory was that the syndrome reflected an increase in the Ito channel (governing the potassium current in phase 1 of the ECG).

• In fact, the Ito current is only increased relative to the sodium current, because the sodium channel

closes prematurely.

Ionic basis of disease

• ECG definition has become more and more strict.

• ST elevation of a coved type of at least 2 mm or ST elevation of saddleback type if it becomes

coved type under stress with anti-arrhythmics.

• Elevation is always present in V2, and either V1 or V3 (usually both).

Diagnosing the syndrome

• Flecainide used now that ajmaline is no longer available.

• Given in an IV in Europe, but maybe 200mg orally but patient must be monitored for 8 hours

because of the long half-life.

• Procainamide is effective in unmasking the syndrome, but the ECGs are much less

spectacular. May have less specificity and sensitivity than ajmaline.

Drugs for diagnosis

• In all pts where we had genetic confirmation of the disease, we did not have a single false negative or false positive with ajmaline.

• The ajmaline test was consistently reproducible in over 100 pts.

• Pts’ hearts are different and the positioning of the leads can play an important role in

diagnosis since the syndrome is localized in a specific region of the heart.

Sensitivity and specificity

EP testing

• Every single patient that has a classic Brugada ECG gets an EP test.

• Asymptomatic patients who have a normal basal ECG have 0% events in follow-up so far.

• So we don’t do EP tests in these patients.

• Wait and watch because there is no evidence they are at risk.

Asymptomatics • If the base ECG is abnormal, then we follow with EP testing.

• In these pts, 2/3 are non-inducible.

• If non-inducible, we do nothing, because the event rate is extremely low.

• Events in asymptomatic pts with abnormal basal ECG occurred in pts who were inducible by EP

testing.

• Pt with a father who died of SD – no ECG available.

• The pt has abnormal ECG, which becomes classic Brugada after stressing with flecainide.

• This pt should get EP study due to family history.

• If the study is positive, give them a defibrillator. If negative, do nothing.

Clinical decision making

• Only 60% of SD in families with known Brugada syndrome can be attributed to the syndrome.

• ECGs can normalize over time. A completely normal ECG in one moment doesn’t mean it

will always be normal.

• If the ECG ever becomes abnormal, you then follow up with drug tests and then EP testing.


• A 28 year old uncle who died suddenly, no ECG available. My father died suddenly at 46. No autopsy.

• The kid has a classic Brugada ECG but is non-inducible to EP testing.

• I would suggest a defibrillator due to the strong family history, but there is no evidence that the risk is extremely high.

• But with the strong family history and the baseline Brugada ECG, I would be nervous.


Definition of Brugada ECG

• RBBB in V1-V3 (V2 most important)

• Coved ST-segment elevation of > 2mm

• If not present at baseline, ECG can be induced by flecainide or procainamide.

• ICD is treatment of choice for pts with documented cases of serious arrhythmias

• In general if the EP study shows no inducible VT, watch and wait.

Review

Brugada syndrome: RISK stratifiaction

Sindrome ereditaria caratt. da un tipico pattern ECG, spesso in presenza di mutazione genetica.

1 Brugada, Circulation ‘98

COVED TYPE: sopralsivellamento punto J ≥ 2 mm con onda T negativa. Tipo 2 e 3

CLINICA Sincope Morte improvvisa

Brugada - Circulation ‘05

547 “coved type”

124 Sinco

pe170

Routine

253 Familiarit

à

391 Spointanei

156 dopo ajmalina

28±42 mesi Follow Up

45 (8%) eventi

Età media 40 aa

Brugada - Circulation ‘05

ECG spontaneo coved type, % (95% IC)

ECG dopo test

ajmalina, % (95% IC)Sincope

•Inducibilità

•Non inducibilità

Asintomatici•Inducibilità

•Non inducibilità

27.2 (17.3-40.0)

4.1 (1.4-11.7)

4.5 (1.0-17.1)

0.5 (0.1-2.7)

14.0 (8.1-23.0)

1.8 (0.6-5.1)

9.7 (2.3-33.1)

1.2 (0.2-6.6)

• FU 28±42 mo

• 45 FV (8%)

• Inducibilità durante PES/ storia di sincope

Analisi di

REGRESSIONE LOGISTICA: Sincope sufficiente rischio da giustificare un ICD (1.2 % -27.2 %)

COVED TYPE: sopralsivell punto J ≥ 2 mm con onda T negativa.

BS

Sindrome di Brugada

•Storia di sincope

•Un episodio di arresto cardiacoICD

Ma qual è il RISCHIO degli altri pazienti?

•NON ESISTE una terapia medica di sicura e documentata efficacia.

•ICD funziona in pazienti che SVILUPPANO o SVILUPPERANNO una VF

•Altrimenti ……….. tutti i rischi dell’impianto e nessun beneficio

Sindrome di Brugada

CONSIDERAZIONI

Possibile strategia “insertable LR + ICD esterno”

BRUGADA syndrome: stratificazione

Alto rischioRapporto di rischio:

6.4Rischio intermedio

Rapporto di rischio: 2.1

Basso rischio

Priori et al - Circulation ‘02

RischioSincope e pattern

ECG positivo

Pattern ECG positivo

Pattern ECG negativo con o senza sincope

Percentuale popolazione

10 %

41 %

49 %ICD

Terapie

Ulteriori controlli in caso di sintomi

Sindrome di Brugada

I IIa IIb

•Sincope•Familiarità per SCD

• VF - VT• Inducibilita VT-S/ VF

Classe


STRATIFICAZSTRATIFICAZdel RISCHIOdel RISCHIO

I IIa IIb

• ICD in Pz. con Sincope/ TV

•ICD

•ICD in pz asintomatici EPS inducibili

PrevenzionePrimaria


Classi


Sindrome di Sindrome di BrugadaBrugada

QTc long syndrome QTc long syndrome

Stefano Nardi MD



Anestimated prevalence below 5 in 10 000 (0,5% each 1000 inhabitants).

Which aspects should be considered before developing recommendations for risk stratification and management of patients?

Most of the data available for these conditions derive from large registries

No randomized studies are available

LEVEL of EVIDENCE B for data collected by the registries on LQTS (large nr of pts with a long FU

Data on the natural history of these diseases are potentially biased by the fact that it is more likely that a highly symptomatic case is referred to a registry

Some concepts applied for risk stratification are common to the different inherited arrhythmogenic diseases

the severity of the ECG phenotype is generally a marker of increased risk of SCD

(1) In LQTS, the “severe” phenotype is represented by the presence of a QTc exceeding 500 ms

(2) In the Brugada syndrome by the spontaneous presence of ST-segment elevation in the right precordial leads

(3) In CPVT by VT induced by exercise stress testing

Because these diseases are characterized by electrical abnormalities occurring in the structurally intact heart, the use of the ICD is always indicated with a class I indication in the secondary prevention of cardiac arrest (CA). Its use in primary prevention is more debated, considering the young age of patients at diagnosis

In LQTS and in CPVT, pharmacological therapy with beta blockers is effective in reducing the risk of cardiac events

In the Brugada syndrome, no effective pharmacological treatment is known

Physical activity is not considered to be the trigger for arrhythmic episodes, such as in patients with Brugada syndrome and LQT3

• Mutations in 8 genes have been identified: • 7 of them encode cardiac ion channel subunits• 1 encodes an anchoring protein that has been implicated in controlling ion channel targeting specific membrane sites

identification of the genetic subtypes

A QTc exceeding 500 ms

Long QTc syndromeLong QTc syndrome

• the interplay between (1) genetic defect, (2) QT duration, and (3) gender may provide an algorithm for risk stratification (103)

(A) the highest risk of becoming symptomatic are LQT1 and LQT2 patients with a QTc greater than 500 ms and males with LQT3 irrespective of QT interval duration

GENETIC ARRHYTHMIA SYNDROMES

Arrhythmogenic Hereditary Syndromes (LQTcS, BS and CPVT) are inherited arrhythmogenic diseases

Share genetically determined susceptibility to VT and SCD in the absence of recognizable structural abnormalities of the heart.

General Concepts for Risk Stratification

• Primary electrical disorder with BROAD SPECTRUM• NO macroscopic EVIDENCE of structural HD

• PROLONGED QTc interval

• DEFORMATION of T wave/presence of U wave

• STRESS MEDIATED life-threatening VTs

• One variant AUTOSOMAL RECESSIVE (J-LN)

• One prevalent AUTOSOMAL DOMINANT (RW)

Long QTc syndromeLong QTc syndrome

CARDIACMYOCITErepolarization

•IK responsible for repolarization of cell during action potential

– IKs helps keep action potential

duration at normal levels

– Problems with channel longer APD (lengthened because of abnormal repolarization)

Quantitative Data

Age and Sex

Prolonged QTc (sec)

Reference Range (sec)

Children (< 15

y)

> .46 < .44

Adult Males

> .45 < .43

Adult Females

> .46 < .45

-Deformation of T wave-Presence of U wave

LQTS Type

Chromosomal Locus

Mutated Gene

Ion Current Affected

LQT1 11p 15.5 KVLQT1 IKs

LQT2 7q 35-36 HERG IKr

LQT3 3p 21-24 SCN5A INa

LQT4 4q 25-27 ? ?LQT5 21q 22.1-22.2 KCNE1

(heterozygotes)

IKs

LQT6 21q 22.1-22.2 MiRP1 IKr

GENETICsubtypes

DISEASE statistics

•Affects 1 in about 3000-5000 individuals

•LQTcS type 1 and LQTcS type 2: Potassium channel mutations (KvLQT1 and HERG) estimated to cause 87% of all Long QTc Syndromes

•LQT3 (SCN5A): approximately 8%

•LQT5 (KCNE1/minK), LQT6 (MiRP1): 5%

• LQT1 (IKs) is more susceptible to cardiac events occurring during exercise (particularly

swimming)

• LQT2 (IKr) is more susceptible to cardiac events occurring during rest or emotion (characteristically acoustic stimuli)

• LQT3 carrying mutations in the SCN5A (cardiac Na channel) is susceptible to cardiac events occurring at rest and during sleep

• LQT2 patients, those with a mutation resulting in a change in the pore region of the protein appear to be at higher risk of cardiac events than are those with mutations in other regions of the gene.

• Beta blockers are highly effective in LQT1, whereas they offer incomplete protection in LQT2 and LQT3

Romano-Ward and JLN

• Romano-Ward: autosomal dominant

– Characterized by gradual hearing loss

• Jervell-Lange-Nielsen (JLN): autosomal recessive

– Characterized by congenital deafness

Chromosome 11

11p15.5

Potassium Channel and Current

• affects KvLQT1 gene

• Encodes K channel α subunit

• Mutation leads to loss of function of K+ channel

• Delayed potassium rectifying current (IKs)

Cardiac related symptoms

Abnormal heartbeat (aka Cardiac arrhythmia)

- Tachyarrhythmias – fast heart rate (>100 bpm) - Torsades de Pointes

•Syncope (Fainting)

•Cardiac arrest (heart failure)

•Sudden death

Risk stratification

Causa più frequente:mutazioni dei geni relativi al canale del potassio (sito LQT1 o LQT2) o del sodio (sito LQT3)

Stratificazione proposta:a seconda del genotipo e di altre variabili quali sesso e lunghezza del QT

Probabilità di evento cardiaco prima dei 40 anni e prima della terapia? (sincope, CA, SCD)

Alto rischio

( 50 %)

Rischio intermedio (30-49%)

Basso rischio

(< 29%)

S. Priori et al. - NEJM ‘03

Probabilità di evento cardiaco prima dei 40 anni e prima della tx (sincope, CA, SCD)QTc M = sesso maschileF = sesso femminile

QTc 500 msLQT1LQT2

M, LQT3

QTc < 500 msF, LQT2F, LQT3M, LQT3

QTc 500 msF, LQT3

QTc < 500 msM, LQT2

LQT1

QTLS: Risk stratification

Caution!

Arrhythmia can be induced by:– Stress/ Exercise

• Accelerated heart rate

• Superposition of action potentials

• β-blockers (suppresses sympathetic nervous system)

• Pacemakers (control heart rhythm)

• Gene therapy

A quantification of the actual prevention of SCD A quantification of the actual prevention of SCD with with β-blocker is missing, because we have to rely on retrospective data

A quantification of the actual prevention of SCD A quantification of the actual prevention of SCD with with β-blocker is missing, because we have to rely on retrospective data

Clinical Implications

•IKs gating can be changed with drug therapy or gene therapy

– This will alter channels so that values change

– Decrease in time constant

•Change in gating variables will be suggestive of a change in the voltage-gating properties

– Drug will target fourth domain of KvLQT1

• 41- The ECG shows a prolonged QT interval (QTC 470 ms). The repolarisation abnormality in the chest leads attached in the figure is suggestive for which subtype of the long QT syndrome?

• a.- Long QT 1

• b.- Long QT 2

• c.- Long QT 3

• d.- Long QT 4

• e.- Long QT 5

QTLS

TdP = Torsades de Pointes; VF = Fibrillazione Ventricolare; AC = Arresto Cardiaco; JLN = Jervell and Lange

Nielsen; Sin = Sindattilia; BAV = Blocco AtrioVentricolare; SCD = Morte Improvvisa;

I IIa IIbClasse•QTc > 600ms•Evento Cardiaco nei neonati•Post-partum•Sind + BAV •Alternanza onda T•Sesso Femminile


• Familiarità di SCD Dispersione del QTStratificazio

ne del Rischio


QTLSQTLS

I IIa IIb

•Stellectomia sx•Pacemaker

•Evitare i farmaci che allungano il QT•Evitare Sport•Beta-bloccanti

•ICD + betabloccanti + evitare i farmaci che allungano il QT•Evitare Sport

PrevenzionePrimaria


Classi


QTLS

I IIa IIbClasse

•QTc > 600ms•Evento Cardiaco nei neonati•Post-partum•Sind + BAV •Alternanza onda T•Sesso Femminile


• Familiarità di SCD Dispersione del QT


STRATIF RISCHIO

QTLSQTLS

I IIa IIb




PrevenzionePrimaria


Classi


• Primary electrical disorder with BROAD spectrum• No macroscopic evidence of structural HD• Prolonged QTc interval• Stress-mediated life-threatening VTs• One variant autosomal recessive (J-LN)• One prevalent variant autosomal dominant (RW)

QTc long syndromeQTc long syndrome

QTLS

I IIa IIbClasse

•QTc > 600ms•Evento Cardiaco nei neonati•Post-partum•Sind + BAV •Alternanza onda T•Sesso Femminile


• Familiarità di SCD Dispersione del QT


STRATIF RISCHIO

Alto rischio( 50 %)

Rischio intermedio (30-49%)

Basso rischio(< 29%)

S. Priori et al. - NEJM ‘03

Probabilità di evento cardiaco prima dei 40 anni e prima della tx (sincope, CA, SCD)

QTc M = sesso maschileF = sesso femminile

QTc 500 msLQT1LQT2

M, LQT3

QTc < 500 msF, LQT2F, LQT3M, LQT3

QTc 500 msF, LQT3

QTc < 500 msM, LQT2

LQT1

QTLS: Risk stratification

QTLSQTLS

I IIa IIb




PrevenzionePrimaria


Classi


• Any QTc-interval > 440 msec is considered prolonged• Borderline QT shows a prolongation of QTc, but not prolonged enough to clearly make the diagnosis.• 450 to 470 msec is considered borderline. • The average QTc for someone who has L-QTS is 490 msec• A QTc ≥ 480 msec in females or 470 msec in males, is probably a sign for L-QT S, in the absence of drugs, electrolyte disturbance, or other conditions that might independently lengthen the QT-interval.

What is borderline QT ?What is borderline QT ?

• Frequency is unknown but it appears to be a common cause of SD unexplained in children and young adults. • It is certainly much more common than previously thought.• It may be as frequent as 1 in 5000 to 7000. • This means, one of 5000 to 7000 newborns have the

disease. • In USA the presence of L-QT S is estimated to affect

about 50.000 people and to cause as many as 3000 deaths each year.

How common is inherent L-QT How common is inherent L-QT S ?S ?

• SYNCOPE or SD, typically occurring during physical activity or emotional upset. • Most commonly in preteen to teenage yrs, but may present from a few days of age to middle age. • Syncopal episodes are often misdiagnosed as the common faint (vasovagal event) or a seizure. Actual seizures are uncommon in L- QT S, but epilepsy is one of the common errors in diagnosis. • Sudden loss of consciousness during physical exertion or during emotional excitement should strongly raise the possibility of the L-QT S.• Family history of unexplained syncope or SD in young people should also raise suspicion. Importantly, about 1/3 of individuals who have the L- QT S never exhibit symptoms, and therefore, the lack of symptoms does not exclude a person or family from having L- QT S.• Any young person that has an unexplained CA should be considered for L-QT S, as well as those with unexplained syncope.

What are the Symptoms ?What are the Symptoms ?

• Swimming, running

• An alarm clock, a loud horn, a ringing phone

• Emotions: anger, crying, test taking or other stressful situations

• Sudden death may also occur during sleep

What are known triggers in L-What are known triggers in L-QTS ?QTS ?

• Beta blocker medications are the mainstay of Rx for most pts with the L- QT S

• These AADs are effective in about 90 % of affected subjects. • However, a new study (JAMA ‘04) shows that among treated patients with LQT2 and LQT3 genotypes, there still is a high rate of cardiac events.• New information regarding the genetics of the syndrome suggests that a subset of patients might be treated with other drugs, either instead of or in addition to the beta blocker medications. This can be discussed with your physician and it depends upon the gene type which you have.

What is the THERAPY ?What is the THERAPY ?

• In pts who do not respond to medication, the insertion of a PM or the ICD can be utilized. • Another procedure, mainly used in Europe, is the surgical cutting of certain nerves in the neck, called left cardiac sympathetic denervation. • All patients with symptoms should be treated, and because it is not possible to predict which patients are vulnerable to the syncope and sudden death, and sudden death often occurs with the first episode, asymptomatic patients, especially children, should also be treated.

What is the THERAPY ?What is the THERAPY ?

9. CAN AN AUTOPSY REVEAL LONG QT SYNDROME?There are two ways to make a diagnosis for QT syndrome. The first is to check if the QT-interval on the ECG of a suspected patient is prolonged. Because the heart stopps beating when death occurs, this possbility is out of question - except an ECG of the dead person already exists, of course.The only possibility would be to check body fluids of the dead person - in this case blood - for the known gene mutations that cause QT syndrome.

• SYMPTOMATIC pts should receive treatment. • It is RECOMMENDED to screen the family members• The BEST TREATMENT should be aimed at the specific gene types of L- QT S. • However, it has not yet been proven that such therapy is effective.

Beta -adrenergic blocking agents. Effective in preventing cardiac events in approximately 70% of patients, while cardiac events continue to occur despite beta-blocker therapy in the remaining 30% of pts.

ICD: Pts who have experienced CA, particularly if already on drug treatment, or who continue to have syncope in spite of medications, might best be treated with ICD.

Management of L-QT S ?Management of L-QT S ?

Left thoracic sympathectomy. This procedure has mainly been used in Europe, for patients who were not responding to Beta blockers. It now has been largely replaced with permanent pacemaker and cardioverter-defibrillator implantation.Asymptomatic patients. In asymptomatic patients, preventive therapy is required. The reason is that it cannot be predicted with any accuracy which patient will subsequently have symptoms and which one will not. It is important to point out that 30% to 40% of sudden deaths occur at the first event. The treatment option is the long-term use of Beta blockers agent. It is generally recommended to treat all asymptomatic patients younger than 40 years old at the time of. However, on the other hand, some investigators have recommended treating asymptomatic patients only if they have high-risk characteristics

Management of L-QT S ?Management of L-QT S ?

• Non esistono evidenze circa l’efficacia, nella prevenzione della mortalità totale e MI, per nessuno degli AADs in nessuna delle residue forme di CP

• Storicamente, impiego clinico diffuso non validato per alcune categorie in alcune CP (ß-bloccanti in LQTS, Amiodarone in HCM)

Sintesi nelle forme non CAD, non SC

Rx Medica della Morte Improvvisa

ICD in non-ischaemic CM ICD in non-ischaemic CM


Blocchi atrioventricolari

acquisiti

Blocchi atrioventricolari

congeniti III°

Blocchi cronicibifascicolari

o trifascicolari

I IIa IIbClasse

•BAV III° •BAV II° di tipo II•Sincope •Coesistente Cardiopatia / HF

• Sincope• HV100 ms o blocco infraissiano• Inducibilita’ alla NIPS

• Sincope• Intervallo QT lungo• Cardiopatia congenita

• Coesistente Cardiopatia / HF

HF = Scompenso Cardiaco; BAV = Blocco Atrioventricolare;

NIPS = Stimolazione Programmata Non Invasiva

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VF = Fibrillazione Ventricolare; SCD = Morte Improvvisa; VT Non Sost. = Tachicardia Ventricolare Non Sostenuta

I IIa IIb

•Familiarità di SCD•VT Non Sost. / sincope nell’età pediatrica

• VF• Sincope

Classe

Stratificazione

del Rischio


Described in ’99 by Swan AUTOSOMAL DOMINANT arrhythmic syndrome characterized by exercise induced polymorphic VTs in the absence of detectable structural HD. A similar disorder was clinically described by Coumel in ‘83 and more extensively (21 cases reported) by Lenhardt et al. in ’95. Usually occurs in young, healthy children and young adults and is characterized by stress- or emotion-induced syncope due to the onset of polymorphic VTs. Peculiar ECG pattern of bi-directional VTs and are reproducibly elicited either during exercise or by beta adrenergic stimulation with IPN infusion. At rest no significant ECG abnormalities are present. QT interval is within the normal limits and no ST segment elevation or intraventricular conduction abnormalities suggesting Brugada syndrome are evident. A familial history of syncope or sudden death is reported in approximately one third of the cases. Beta blocker therapy has been suggested as an effective approach in preventing the recurrences of syncope. In the paper by Swan et al, this disease was linked to chromosomal locus 1q42-q43 in two families. Interestingly, ARVD2 also maps at the same locus, possibly suggesting that CPVT and ARVD2 may represent allelic variants with the same underlying molecular background. Mutational analysis of possible candidate genes in this region failed to detect abnormalities in of the TWIK-1 gene encoding a two transmembrane segment potassium channel. (Swan and et al.1999). The human Cardiac Ryanodine Receptor (hRyR2) is another gene mappted to the CPVT critical region (Otsu et al. 1990). RyR2 is a protein functionally involved in the Ca2+ release from the sarcoplasmic reticulum (Tunwell et al. 1996) in response to the activation of the ICa2+ current through the dihydropyridine receptor during the plateau phase of the action potential. Since the CPVT arrhythmias and the clear adrenergic-mediated onset of arrhythmias closely resembles the arrhythmias developing during intracellular calcium overload and delayed afterdepolarization (Rosen et al. 1980, Priori et al. 1990), hRyR2 was considered a strong candidate gene for CPVT. In December 2000 Priori and co-workers identified RyR2 mutations in four families with the typical pattern of CPVT and history of sudden cardiac death, thus demonstrating that hRyR2 is the gene for Catecholaminergic Ventricular Tachycardia. The fact that only 4 out of 12 probands affected with CPVT have been genotyped on hRyR2 gene might suggest that, in analogy with other arrhythmogenic disorders, genetic heterogeneity is present in Catecholaminergic Ventricular Tachycardia. These data have been shortly after confirmed by Laitinen PJ et al., who identifed hRyR2 mutations co-segregating with adrenergic-mediated ventricular tachycardia in three families. A recessively inherited CPVT phenotype as been described by Lahat et al. who analyzed 7 kindreds from a Bedouin tribe from north Israel. By means of genome-wide linkage analysis they mapped the disease locus to a 16-megabase interval on chromosome 1p13-21 (between D1S2868 to D1S2764). A maximal lod score of 8.24 was obtained with D1S189 at theta=0.00. Sequencing of KCND3, a gene that encodes an I(to) potassium channel transporter, did not reveal any significant sequence alterations. In December 2001 the same group showed a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form. The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor. This mutation was identified in seven Bedouin families affected by the disorder, and, based on the amino acid charge variation and on the position of the mutation, it has been hpothesized that this defect is likely to exert its deleterious effect by disrupting Ca(2+) binding. In February 2001 Tiso et al. reported the identification of RYR2 mutations in four independent families, Thus suggesting that CPVT and ARVD2 are allelic diseases. PathophysiologyDespite the different models used for expression (lipid bilayer, HEK293 cells, HL1-cardiomyoacytes) there is agreement in indicating that that the RYR2 mutations cause a Ca2+ "leakage" from the SR in condition of sympathetic (catecholamines) activation (Wehrens et al 2003; George et al 2003) while the basal channel activity appears normal. Only one experimental study investigated the mechanisms by which CASQ2 abnormalities may induce the CPVT phenotype is available (Viatchenko-Karpinski ey al.). The CASQ2 mutation previously identified by Lahat et al. (D307H) expressed in rat cardiac myocytes, impairs the SR Ca2+ storing and release functions and destabilizes the Ca2+-induced Ca2+ release mechanism via reduced Ca2+ buffering inside the SR and/or altered responsiveness of the Ca2+ release channel complex to luminal Ca2+.Taken together the experimental data demonstrated that both genes involved in CPVT pathogenesis affect the amount of Ca2+ released from the SR during adrenergic stimulation. Such effect may create an electrically unstable substrate probably through triggered activity-mediated arrhythmogenesis.


Implicazioni CLINICHE

• Non esistono Non esistono TRIALS TRIALS RANDOMIZZATI RANDOMIZZATI a supporto delle a supporto delle attuali indicazioniattuali indicazioni

• Le indicazioni proposte son Le indicazioni proposte son prevalentemente basate su prevalentemente basate su STUDI STUDI RETROSPETTIVI RETROSPETTIVI o piccoli o piccoli STUDI STUDI PROSPETTICI PROSPETTICI (level B) o sull’opinione (level B) o sull’opinione degli degli ESPERTIESPERTI (level C) (level C)

• I criteri di stratificazione non sono ben I criteri di stratificazione non sono ben definitidefiniti

Se è difficile la corretta stratificazione di patologie ad alta prevalenza nella

popolazione generale

... che richiede TEMPO e COLLABORAZIONE

Stratificare il rischio in patologie (relativamente ) rare diventa un

obiettivo ...

• La revisione sintetica dei dati raccolti dalla Task Force della

ESC ci ha fornito delle raccomandazioni (NON LINEE GUIDA !!!) in base alla EBM che coinvolgono la fase diagnostica e terapeutica dell’approccio alla morte improvvisa

… … il PRESENTE …il PRESENTE …

orienta l’investigatore circa la strategia da utilizzare nei singoli casi!

– Vincoli metodologici legati ai filtri a maglie strette della EBM, determinano il fatto che strategie terapeutiche che prevedono l’impiego dell’ICD sono confinate a

popolazioni limitate (costo) e selezionate (rischio elevato MI), con conseguente generazione di ipotesi di lavoro forzate

… … il PRESENTE …il PRESENTE …

CONSEGUENZA: possibile mancanza di verifica legata ai vincoli!

… … il PRESENTE …il PRESENTE …• Tale condizione rende di DIFFICILE

realizzazione una indagine SISTEMATICA circa gli effetti delle strategie profilattiche e terapeutiche nelle specifiche condizioni.

• La maggioranza delle considerazioni estrapolate dai dati a nostra disposizione NON sono SEMPRE TRASFERIBILI direttamente a pazienti che malgrado segni e sintomi di uguale espressione, presentano condizioni di base profondamente DIVERSE.

Necessario il giusto “link” tra RICERCA e PRATICA CLINICA

… … ed il FUTURO …ed il FUTURO …

Perfezionare ulteriormente le conoscenze sui meccanismi fisiopatologici delle aritmie

Migliorare ulteriormente la fase DIAGNOSTICA

Sudden Death with Normal Left Ventricular Function

•Brugada Syndrome– Incompete RBB ST elevation V1V2

– exacerbated by Procainamide and Flecainide

– ICD implantation

•Right ventricular Dysplasia– Delayed Right Ventricular activation

– Epsilon wave , deep precordial Twave inversion

– fatty infiltration RV, MRI, RV gram

Sudden Death with Normal Left Ventricular Function

•Hypertrophic Cardiomyopathy– Majority of sudden death in U.S. in young patients

without coronary artery disease

– Risk factors extreme hypertrophy(>3.0 cm)exertional hypotension, nonsustained VT,syncope, family history sudden death

– ICD effective but appropriate selection for primary prevention problematic

2007 rieti, convegno regionale, quale terapia nelle channelopatie

Health & Medicine

Transcript of 2007 rieti, convegno regionale, quale terapia nelle channelopatie