From Vulnerable Plaque to Vulnerable Patient

Vulnerable (Arrhythmogenic) Myocardium

K.E.J. AiraksinenTurku, Finland

Sudden Death at Population LevelRole of Vulnerable Plaque

Occlusive Plaque rupture:

Sudden death, usually occurring within minutes of the onset of chest pain, is the first clinical manifestation of CAD in 20-25% of patients 40% of deaths occur within 1h after AMI

Kannel et al, Circulation 1975;51:606

Sudden Cardiac DeathGeneral Adult (”Healthy”) Population

Pathophysiology:1) Coronary plaque rupture coronary occlusion SCD2) Electrical or mechanical abnormality– WPW-syndrome– Long QT-syndrome– idiopatic VF, Brugada syndrome...– HOCM, ARVD, myocarditis...

”Why do some people die when a coronary artery suddenly occludes……and others develop only a myocardial infarction or UAP?”

Role of Autonomic Factors

Control

Single Cardiac Vagal Fiber Activity LAD Occlusion and Risk of Sudden Death (Cats)

1

2

3

4 VF-

VF+

Occlusion

Imp/s P<0.01

Cerati et al 1991

Prevention of VF after Left Stellate Ganglionectomy in Dogs

0

20

40

60

80

100 LSG

Control

20 min coronary occlusionPuddu et al 1988

P=0.001Survival

%

PTCA-model to Simulate Coronary Occlusion

2 min coronary occlusion 500 pts

Beat-to-beat RRi and BP Ventricular arrhythmias Repolarisation changes MSNA

Interventions: ß-blockade -stimulation

Continuous ECG, Heart Rate and BP Recordings

RR interval(ms)

Bloodpressure(mmHg)

RR interval(ms)

Bloodpressure(mmHg)

HRV and Sudden Cardiac Death

Malignant ventricular arrhythmias caused by abrupt coronary occlusion are a major cause of sudden death

RR interval (ms)

Bloodpressure(mmHg)

HRV increase: Vagal Activation

RR interval(ms)

Bloodpressure(mmHg)

RR interval(ms)

Bloodpressure(mmHg)

HRV decrease: Vagal Withdrawal

-10

-5

0

5

10

15C

hang

e in

RM

SD (m

s)

No VA Solitary VA Complex VA

p<0.01

p<0.05

Airaksinen et al Am J Cardiol 1999

HRV and Ventricular Arrhythmias

HRV Reactions and Ventricular Arrhythmias

No VA Solitary VA Complex VA

16%

3%26%

36%

No

RR interval(ms)

Bloodpressure(mmHg)

RR interval(ms)

Bloodpressure(mmHg)

Decrease in HRV before VT

Occlusion

Strong Vasovagal Reactions may lead to Fatal Hypotension or Asystole during coronary occlusion

BP 68/55

Arterial baroreflexes are impaired during abruptcoronary occlusion Airaksinen et al JACC 1998

Can We Predict the Risk of Sudden Death?

HRV Responses and Site of Coronary Occlusion

66%

23%

11%

26%

11%63%

26%

21%53%

LAD LCX RCA

Airaksinen et al Am J Cardiol 1993

Vagus Vagus

Gender Difference in Autonomic and Hemodynamic Reactions

Reactions in women versus men

Adjusted OR (95% CI)

Bradycardia 3.8 (1.6-8.9)RMSD 1.8 (0.8-4.1)Hypotension 2.6 (1.1-6.1)B-J Reaction 25.6 (2.6-254)VEBs 0.4 (0.2-1.3)

Airaksinen et al JACC 1998

Is a Mild Stenosis More Hazardous?? SCD is the 1st symptom of CAD in 20-25% Experimental models:

Coronary occlusion VF

Tight stenosis: Occlusion often asymptomatic Restenosis: SCD infrequent Reocclusion: 50% asymptomatic

Stenosis Severity and the Occurrence of Ventricular Ectopic Activity During Acute

Coronary Occlusion

0

10

20

30

VPB

s(%

)

*

< 75 75-89 90-99Stenosis severity (%)

Airaksinen et al Am J Cardiol 1995b

P<0.01

P<0.01

Effect of Preocclusion Stenosis Severity on Heart Rate Reactions to Coronary

Occlusion

26%42%

32%83%

17%

85% > 85%

Severity of stenosisAiraksinen et el Am J Cardiol 1994

Vagus Vagus

Adaptation Phenomena

• Psychological adaptation helpful in experimental models (Parker et al 1987)

• Missile War or earthquake: sharp rise in incidence of SCD during 1st attack, but not later (Meisel et al 1991)

• Short coronary occlusions lead to preconditioning and adaptation in experimental models

RR interval (ms)

Bloodpressure(mmHg)

RR interval (ms)

Blood pressure(mmHg)

Antiarrhythmic Effect of Repeated Coronary Occlusion

Airaksinen & Huikuri, JACC 1997;29:1035-8Similar effect on autonomicreactions

1st Occlusion

2nd Occlusion

VPCs

Genetic Factors?

• No direct evidence, but...• Clinical and angiographic factors poor

predictors• Genetic background in wide interindividual

variation in autonomic function (Singh et al Circulation 1999)

• Parental history of SCD (Jouven et al Circulation 1999)

How to Modify the Risk?

• Plaque modification

• Beta blockade• Exercise ( Billman et al

Circulation 1984,Burke et al JAMA 1999)

Conclusions Plaque rupture is the major cause of sudden death at population level

Autonomic mechanisms modify significantly clinical outcome

Clinical outcome is largely unpredictable

Plaque modification is the best way to modify the outcome

Occluded coronary artery

LAD (58%)

LCX (21%)

RCA (21%)

LAD (79%)

LCX (5%) RCA (5%)

LAD (93%)

LCX (7%)

No VA(N=219

Solitary VA(N=19)

Complex VA(N=14)

Myocardial ischemia and repolarisation

Cha

nge

in L

nHFP

Cha

nge

in L

nRM

SD

Cha

nge

iN L

nLFP

Cha

nge

in L

nHFP

Cha

nge

in L

nRM

SD

Cha

nge

in L

nLFP

Effect of Beta Blockade on Heart Rate Variability During Vessel Occlusion at theTime of Coronary Angioplasty

Airaksinen et al Am J Cardiol 1996

Can we modify HRV and is it useful ?

Pikkujämsä et al

Low HRV A marker of arrhythmic death

• Observational studies: (Farrell et al 1991, Bigger et al 1992,1993, Algra et al 1993, Hartikainen et al 1996, Copie et al 1996, Bigger et al 1996)

Problem: Definition of sudden death

• Case control studies (Huikuri et al 1995, Perkiömäki et al 1997)

Problem: Matching, HRV measurement after the end point

• HRV is altered before the onset of VF / VT in pts with a history of MI (Valkama et al 1995, Huikuri et al 1996, Shusterman et al 1998, Vybiral et al 1993)

HRV and sudden cardiac death

• Is the positive predictive accuracy enough for clinical decisions ?

- SDNN ( Nordic ICD Pilot Study): 1/33 appropriate shocks / 2 yr

• Depressed HRV identifies post-MI pts who might benefit from AMIO (EMIAT substudy, Malik et al, JACC 2000)

- new nonlinear indices better (?)

RR interval (ms)

Bloodpressure(mmHg)

Increase in HRV during coronary occlusion

LF component - measure of sympathetic (or vagal) tone ?

Increase in LF fluctuations