Out-of-Hospital cardiac arrest survivors

EF < 30% heart failure

Any prior coronary event

High coronary risk sub-group

Overall incidence in adult

population

Convalescent phase

VT/VF after MI Sudden

Non-Sudden

Sudden Non-

Sudden

50 25 5 0 5 25 50

Percent/year 0 250.000 250.000

Events/year

CARDIAC DEATHS – INCIDENCE AND TOTAL EVENTS

Modified from Myerburg

ANAMNESI PATOLOGICA REMOTA

Precedente ischemia coronarica o IMA o ICTUS, claudicatio intermittens, ipercolesterolemia, ipertrigliceridemia, ipertensione arteriosa; valvulopatia aortica; malattie della coagulazione. Disordini endocrini, Cushing, feocromocitoma, ipo o ipertiroidismo, diabete e gotta; Fenomeno di Raynaud.

From Netter’s Cardiology, Icon Learning Systems (mod)

ANAMNESI FISIOLOGICA

Età, sesso, stress , obesità, sedentarietà, alimentazione ricca di grassi animali. Abitudini: fumo di sigaretta, abuso di cocaina, uso di contraccettivi orali.

From Netter’s Cardiology, Icon Learning Systems (mod)

• LVEF is far to be an ideal risk-stratification test on

which to base prophylactic ICD therapy

• Multiple factors interact with EF to influence mortality

of patients with similar degrees of left ventricular

dysfunction. Thus, we need combinations of tests

based on individual characteristics if we are to use

ICD therapy most efficiently for primary prevention of

sudden death

AE Buxton Circulation 2005; 111: 2537

Ejection Fraction for risk

stratification

The evidence is accumulating that the occurrence of

an abrupt ventricular arrhythmia is a multifactorial

process …..

We are most likely dealing with a probabilistic event in

which each of the currently measured risk factors

identifies only a small fraction of the multifactorial risk

process…

At present is probably better to predict coronary

patients for both sudden and non sudden cardiac

death and simply assume that SCD accounts for

approximately 50% of all cardiac deaths

AJ Moss JACC 2003, 42: 659

Is it still valuable to look for “specific”

sudden death predictors?

Functional contractile

surrogates

Measures of myocardial conduction disorders

- Signal averaged ECG

- Electrophysiologic Study

Measures of dispersion of repolarization

- QT dispersion

- T-wave alternans

Measures of autonomic imbalance

- Resting Heart Rate

- Heart Rate Variability

- Baroreflex Sensitivity

Measures of electrical instability

- VPCs

- NSVT

Electrophysiologic

surrogates

NYHA CLASS

Left Ventricular Ejection Fraction

Left Ventricular Volume

Peak Oxygen Consumption

Brain Natriuretic Peptide

Conventional Risk Stratifiers for SD

Dispensed ACE Inhibitors or ARB Prescriptions Dispensed -Adrenoreceptor Antagonists

Low-Risk

Average-Risk

High-Risk

Risk-Treatment Mismatch in the

Heart Failure

Lee DS et al JAMA. 2005;294:1240-1247

24 31 37 44

54 63

84

105

132

154

180

208

250

280

2,5 4 6 8 10 14 18 27 31 38 44

56 60

22

0

50

100

150

200

250 Annual ICD implants

per million inhabitants

Europe

USA

Updated from S. Nisam

The Gap in ICDs

Acute Exacerbations May Contribute to the Progression

of the Disease

Time

Ventr

icula

r fu

nctio

n

Acute event

With each event,

hemodynamic alterations

and myocardial damage

contribute to progressive

ventricular dysfunction

From Gheorghiade . Am J Cardiol 2005 (modified)

Acute Exacerbations may Contribute to

the Progression of the Disease

Time

Ventr

icula

r fu

nction

Acute event

With each event,

hemodynamic alterations

and myocardial damage

contribute to progressive

ventricular dysfunction

From Gheorghiade . Am J Cardiol 2005 (modified)

• In the first years after MI the benefit

of ICD is dominating and with

progression of HF-disease the benefit

of CRT-D becomes more dominant.

•After > 15 years, HF progression

shows an increasing event rate for

ICD and CRT-D population which can

be less and less impacted by device

therapy.

< 3 years 3-8 years 8-15 years >15 years

MADIT TRIALS – Long Term Follow up data HF duration and device benefit

Barsheshet A et al,Eur Heart J. 2011 Jul;32(13):1614-21.

Magnitude of sympathoexcitation predicts mortality in heart failure.

Cohn et al., NEJM 1984;311:819.

Pro

bab

ilit

y o

f su

rviv

al

Elapsed time in months 0 10 20 30 40 50 60

0

0.2

0.4

0.6

0.8

1.0

Plasma

norepinephrine

200 pg/ml

400 pg/ml

700 pg/ml 1000 pg/ml 1200 pg/ml

Distribution of QTc values among patients and

controls

Schwartz PJ, Wolf S. Circulation 1978;57:1074

Endocardial

Repolarization

Mapping

Swann et al. JCE 2003

21 in-hospital CA in 216 pts admitted

for evaluation for Txt

% Mortality

Severe Bradycardia

III AVB, AV dissociation

VT/VF

M Luu et al Circulation 1989

VT/VF

Bradyarrhythmia

% Mortality

P Faggiano et al, Am J Cardiol 2001

48 in-hospital CA

Sudden is always Arrhythmic?

N° at Risk BRS >3, LVEF >35 879 851 761 598 373

BRS <3, LVEF >35 124 116 104 81 47

BRS >3, LVEF <35 120 110 94 71 52

BRS <3, LVEF <35 59 53 46 35 19

Years

0,8

0,82

0,84

0,86

0,88

0,9

0,92

0,94

0,96

0,98

1

1,02

0 0,5 1 1,5 2

Pro

po

rtio

n S

urv

ivin

g

Log Rank = 47.97

(p<0.0001) BRS <3, LVEF <35 ( 59)

BRS >3, LVEF <35 (120)

Autonomic Tone and Reflexes After

Myocardial Infarction

1 2 3 4 5 6

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Cu

mul

ativ

e

sur

viv

al

BRS < 3 ms/mmHg

BRS > 3 ms/mmHg

Follow-up (years)

p = 0.0007

Freedom from All-cause Mortality

103 stable HF pts in sinus rhythm, endpoint cardiac death + urgent TXT

Prognostic Value of BRS in the

ß-Blocking Era

MT La Rovere et al,

11/92 6/93 12/93 7/94 2/95 8/95 1/96 10/96

2

4

6

8

10

12

14

16

18 B

RS

(m

s/m

mH

g)

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Card

iac Index (

l/m

in/m

2)

r = .92

Time

Cardiac Index

BRS

Reduce Compliance

UNIVARIATE MULTIVARIATE RR (95% C.I.) RR (95% C.I.)

LVEF (%)

35-50 2.5 (1.13-5.62) 2.0 (0.87-4.48)

< 35 7.3 (3.34-15.8) 3.8 (1.57-9.28)

SDNN (ms)

70-105 2.1 (1.00-4.19) 1.6 (0.76-3.53)

< 70 4.5 (2.17-9.24) 2.3 (1.01-5.38)

24-h RR Interval (msec)

740-855 1.01 (0.48-2.21) 0.87 (0.39-1.91)

< 740 4.0 (2.01-7.95) 1.81 (0.82-4.01)

VPC per h

> 10 2.4 (1.27-4.53) 1. 67 (0.86-3.23)

HRV and HR: ATRAMI Study

MT La Rovere et al.

Relative Contribution of HR and

HRV to Prognosis in HF

SDNN < 15 ms (n = 65)

SDNN > 15 ms (n = 198)

Log-rank 8.6 P = 0.003

Time (months)

Sur

viva

l

MT La Rovere et al, G Ital Cardiol 2008

Short-Term HRV Strongly Predicts Sudden Cardiac Death in

Chronic Heart Failure Patients

MT La Rovere et al, Circulation 2003; 107: 565-70

202 consecutive CHF patiens (age 52±9 yrs, NYHA 2.3±0.7, LVEF 24±7%)

Multivariate Prognostic Model for SCD

RR (95%CI) p

LFP (< 13ms2) 3.7 (1.5-9.3) 0.005

LVEDD (>77mm) 2.6 (1.0-6.3) 0.042

Survival Curves by HRV 3717 post-MI pts with EF < 35% - > 15%

ALIVE Study

HRV > 20 U

HRV < 20 U

Perc

ent

Surv

ivin

g

Time Since Randomization in Days

70

80

100

90

0 30 60 90 180 270 360

PJ Schwartz et al, 2004

Age (>60 yrs) 1.25 - 0.8 -

Aetiology (CAD) 2.5 2.2 4.4 4.1

NYHA cl (III-IV) 2.0 - 1.4 -

LVEF (<30%) 2.2 -

Cardiot ratio (60%) 2.5 2.5 2.5 -

VT on Holter (yes) 1.7 - 1.6 -

mean RR 1.3 - 1.2 - SDNN (<67 ms) 2.7 2.5 2.1 -

Day LF p (<3.3 ln) 2.2 - 3.0 2.8 Night LF p (<3.6 ln) 2.3 - 2.2 - Day HF p (< 2.7 ln) 1.6 - 1.6 -

Univariate analysis

Multivariate analysis

Univariate analysis

Multivariate analysis

Sudden Death All-cause Mortality

Depressed Low Frequency Power of HRV as

an Independent Predictor of Sudden Death in

CHF

M Galinier et al, Eur Heart J 2000; 21:475

HR and HRV Profile

in Patients with HF

C Fantoni et al, JACC 2005; 46: 1875-82

LFP >11 ms2 , PVCs < 83/h (n=150)

Log Rank = 18.6

p=0.001

LFP 11 ms2 , PVCs < 83/h (n=38)

LFP >11 ms2 , PVCs 83/h (n=41)

LFP 11 ms2 , PVCs 83/h (n=13)

MT La Rovere et al, Circulation 2003; 107: 565-70

The combination of LFP > 11 ms2

and PVCs < 83/h identifyes a

population with a 3-year mortality

risk of arrhythmic death = < 3%

For all the other combinations

the cumulative 3-year

arrhythmic mortality risk is =

23%

HRV and Arrhythmic Death in HF

17 28 30 Total

0 4 7 Deceased

17 24 23 Alive

>105 ms 70-105 ms < 70ms

HRV (SDNN)

17 28 30 Total

0 2 9 Deceased

17 26 21 Alive

>6 ms/mmHg 3-6 ms/mmHg < 3 ms/mmHg

BRS

ANS

Medical

Therapy

Decisional process LVEF < 30

MT La Rovere et al, Heart Rhythm 2005

Clinical Value of a Preserved Autonomic

Balance in Pts with MADIT-II characteristics

HR

V m

se

c

Nig

ht

HR

P

atie

nt A

ctiv

ity

(min

ute

s/day

)

Days Relative to Hospital Admission

-80 -60 -40 -20 0 20 60

70

80

-80 -60 -40 -20 0 20 140 160 180 200 220

-80 -60 -40 -20 0 20 72 74 76 78

80

Continuous HRV Before Hospitalization

Adamson PB et al Circulation 2004;110:2389-

2394

Falcone et al Circulation 2005

Falcone et al Circulation 2005

RL Baker et al, J Electrocardiol 2005; 38:64

355 consecutive patients with LVEF < 40% enrolled between 1988 and 1999 Pateints with history of syncope, sustained VT or VF not included

PVCs/h 90 ± 215 NSVT 31%

Age 56 ± 17 years LVEF 31 ± 9%

Prognostic Value of Ambulatory ECG Monitoring in Patients

with Dilated Cardiomyopathy

NO TVNS

TVNS

R Berger et al Circulation 2002; 105:2392

337 patients

LVEF < 35%

3-yr SD = 9.7%

Brain Natriuretic Peptide and Sudden Death

MADIT II Patients

QRS Duration < 120 ms (63%) QRS Duration > 120 ms (37%)

SAECG – (31%) SAECG + (32%)

MADIT II: Relation between QRS Duration, SAECG

and Mortality

Mortality = 33%

Mortality = 20% Mortality = 7%

SH Hohnloser et al, Lancet 2003

Primary end-point

sudden cardiac death/

cardiac arrest

Secondary end-point

sudden cardiac death/

cardiac arrest

sustained VT

Negative

Not Negative

Negative

Not

Negative

P=0.010

P=0.023

TWA in MADIT-II like Patients

Bigger JT, et al. Heart Rhythm 2005

66 %

34 %

Paired Results No Endpoint (%)

TWA normal, EF 31% to 40% 55 .0

TWA normal, EF 30% 134 3.5

TWA abnormal, EF 31% to 40%

89 11.8

TWA abnormal, EF 30% 271 16.1 TWA normal

TWA abnormal

TWA and LVEF: Death and Sustained Ventricular

Arrhythmias in Patients with LV Dysfunction

549 pts with LVEF < 40%

(74% < 30%)

NYHA I-III, sinus rhythm

End-point: death + nonfatal SVT

Parameter RR (95% C.I.)

TO + TS 6.87 (3.06 –

15.45)

BRS + SDNN 7.68 (3.61 –

16.32) Ghuran et al., 2001

HRT in ATRAMI

Ghuran et al., 2001

TS > 2.5 ms/RRI

TS £ 2.5 ms/RRI

HRT in ATRAMI

Conclusion

TS is a significant predictor of cardiac mortality post myocardial infarction; TO was of borderline significance.

The combination of TO and TS

significantly predicted cardiac mortality post myocardial infarction.

Like BRS and 24-hour HRV, HRT is

dependent on the prevailing autonomic tone.

The combination of heart rate turbulence and

deceleration capacity identifies a high risk

group among post-MI patients with LVEF >

30% equivalent in size and mortality risk to

patients with LVEF ≤ 30%.

I Cygankiewicz et al, Am J Cardiol 2006; 98: 1635-40

Heart Rate Turbulence and

Severity of Heart Failure

MT La Rovere et al, AHA 2005

200 consecutive CHF patiens (age 54± 9 yrs, NYHA cl II-III, LVEF 24± 6%)

HRT computable in 173 patients (83%)

5-year follow-up: 73 events (cardiac death including urgent heart Txt)

TO TS

P=.0002 P=.0003

Cox Proportional Hazard Analysis

TS significantly related to cardiac death

after adjustment for NYHA cl, CI, SAP,

pVO2 (p.007)

Prognostic Value of HRT in

Heart Failure

46

47

48

49

Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1101-8

Multiple autonomic and repolarization investigation of

sudden cardiac death in dilated cardiomyopathy and controls.

Pezawas T et al

Noninvasive testing and left ventricular ejection fraction

could not reliably identify patients with dilated

cardiomyopathy at risk of fatal ventricular tachyarrhythmias.

Therefore, the strategy to confine prophylactic implantable

cardioverter-defibrillator implantation to patients with dilated

cardiomyopathy and severely reduced LV function should be

reconsidered. .

Onishi T, et al. Circ J 2010;74:709-714

Kaplan-Meier curves for all-cause

mortality and major cardiovascular

events in the cardiac rehabilitation

group and control group.

Major adsverse cardiovascular events combined

with cardiovascular death, acute coronary

syndrome, refractory ischemia requiring

percutaneous coronary intervention or coronary

artery bypass grafiting, congestive heart failure,

and stroke.

Rehabilitation and risk after MI

Giannuzzi P, et al. Arch Intern Med. 2008;168:2194-2204

Kaplan-Meier curves of all event free survival

Trained patients (broken line); untrained controls (solid line) during follow-up.

+ indicates censored cases. Belardinelli R, et al. Circulation 1999;99:1173-1182

Kaplan-Meier survival curves of cardiac death

Belardinelli R, et al. Circulation 1999;99:1173-1182

Trained group (broken line); untrained control group (solid line) during follow-up.

+ indicates censored cases.

Exercise training (n=24) Controls (n=27)

Patients with LVEF 40%

100

80

60

40

20

0 15 30 45 60

months

RR 8.63 p = 0.04 % s

urv

ival

Exercise Training and Survival Post-MI

Specchia et al, Circulation 1996

Ranpuria R, et al. Nephrol Dial Transplant 2008;23:444-

449

Probability of Cardiac Arrest in the CKD Population

as Compared to the non-CKD Population

Cumulative Probability of Cardiac Arrest

Amongst the Different Populations

Ranpuria R, et al. Nephrol Dial Transplant 2008;23:444-

449

HF Patients Outcome in SOLVD trials based on

LVEF (a) and Serum Creatinine Level (b)

Kirkwood FA, Zannad F. Am Heart J 1998;135:S204-S205

100

80

60

40

20

0 1 2 3 4 5

(b) Serum cr >1,5 mg/dl

(a) LVEF <20%

% Survival

Years of follow up

0

Renal Function and Survival in HF Patients

Relationship Between LVEF- NYHA f.Cl. and GFRc

Hillege HL et Al. Circulation 2000; 102 (2) 203

CHARM PRESERVED – LVEF >40%

0.7

0,5

0.6

0,2

0,4

0,3

0,4

0,1

1 2 3 4 5

Years

<45

45 -50

>50

cum

ula

tive incid

ence o

f CV

death

or

unpla

nned H

F a

dm

issio

n

0.5

0,4

0,2

0,1

1 2 3 3,5

Years

cum

ula

tive incid

ence o

f CV

death

or

unpla

nned H

F a

dm

issio

n

0

0,3

Candesartan

Placebo

Lancet 2003; 362: 777–81.

Circulation. 2006;113:671-678

GFR ml/min

60

ADMIRE-HF

60 Jacobson et al JACC 2010

A Cardio-renal reflex

Single-unit recordings of afferent renal nerve

activity

Ulla C. Kopp. Neural Control of Renal Function. Copyright © 2011 by Morgan & Claypool Life

Sciences DOI: 10.4199/C00034ED1V01Y201106ISP022

Norepinephrine

spillover to plasma in CHF

patients: evidence of

increased overall and

cardiorenal sympathetic

nervous activity.

Hasking GJ, et al. Circulation 1986; 73:615– 621.

64 Adapted from Petersson et al. Eur H J 2005

65

ADMIRE-HF

Jacobson et al JACC 2010

66

ADMIRE-HF

Jacobson et al JACC 2010

Heart rate is a predictor of CV death

and/or hospitalizations for HF

Böhm M, et al. Lancet. 2010;376:886-894.

50

40

30

20

10

0 0 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.0001

Patients with primary composite end point in the placebo group (%)

Risk increases by 3% per 1 bpm increase, and by 16% per 5 bpm increase

% s

urv

ivin

g

0 2.5 5 7.5 10

70

80

90

100

years

(n=7)

(n=60)

Training, BRS and Mortality

Not trained + trained, BRS < 3 ms/mmHg after 1 month training

Trained, BRS 3 ms/mmHg after 1 month training

Survival Curves for Freedom from

Cardiovascular Death

1 2 3 4 5 6

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mul

ativ

e

sur

viv

al

Follow-up (years)

BRS < 3 ms/mmHg

BRS > 3 ms/mmHg

p < 0.0001

0

Transthoracic ECG and arterial pressure from dog

after cage rest (top panels) and after 6 weeks of

exercise training

Hull SS Jr., et al. Circulation 1995;89:548-552

Percent change observed after exercise training in baroreflex

sensitivity (BRS), heart rate variability (HRV, standard deviation of the

mean RR intervals), repetitive extrasystole threshold (RET), and

incidence of ventricular fibrillation (VF) during the exercise and

ischemia test in the seven dogs

Hull SS Jr., et al. Circulation 1995;89:548-552

BR

S

HRV RET INCIDENC

E of VF

EXERCISE TRAINING AUTONOMIC

MARKERS AND CARDIAC ELECTRICAL

STABILITY

-

120

-80

-40

0

40

80

120

% C

HA

NG

E F

RO

M C

ON

TR

OL