Cardiovascular response to exercise and Rehabilitation in the

Heart Failure patientAlain COHEN SOLAL

Hôpital Lariboisière, Paris

Bruxelles, 14.10.06

• Rest is the first treatment of chronic heart failure …..

E Braunwald, Textbook of Internal Medicine, WB Saunders Ed, 1986

Peripheral abnormalities

Cardiac dysfunction

Fatigue

Physical deconditioning

Vicious circle of CHF

No relationship between LVEF and exercise capacity

0

10

20

30P

eak

VO

2 (m

l/m

in/k

g)

0% 10% 20% 30% 40% 50%

LV EJECTION FRACTIONCohen Solal A et al. Heart 1996

VO2max(ml/min/kg)

The O2/CO2 transport chain in CHF

LungsHeart

Peripheralcirculation

Musclemetabolism

O2 transport

CO2 elimination

Training

Vascular abnormalities :Major endothelial

dysfunction in CHF

B Hornig et al, Circulation, 1995;1996:210B Hornig et al, Circulation, 1995;1996:210

p<0.05

* *

0

5

10

15

20

Normals CHF

% change in arterial diameter before L-NMMA

after L-NMMA

- 50%

Morphologic abnormalities of peripheral muscles in CHF

H Drexler et al

CHF Normals

Mitochondrial density and exercise capacity in CHF

H Drexler et al, Circulation 1992 ; 85 : 1751H Drexler et al, Circulation 1992 ; 85 : 1751

Peak VO2

ml/kg/mn

CHFControls

0 2 4 6 8

Mitochondrial density

p< 0.0001r = 0. 57n = 60

05

101520253035404550

Comparison ACE-I/physical training in CHF

T Meyer et alInt J Cardiol

Physical rehabilitation

Princeps study in London

• 20 patients

• LVEF < 35%

• NYHA III

• 3 months of home training (cycle) vs 3 months of inactivity (cross over)

Effets de 6 semaines d'entrainement physiqueà domicile chez l'insuffisant cardiaque

Duré

e d

'eff

ort

(m

in)

10

20

Avant Réadaptation Inactivité

² = +20% p<0.05

d'après AJS Coats et al, Lancet 1989

Overall effects of rehabilitation on peak VO2

(10 controlled studies)

0

10

20

30

40

50

Control Trained

Gain in peak VO2 (%)

Exercise training and peak VO2

Circulation 2003; 107: 1210-25

Peak VO2: OKbut what about Quality of Life ?

from R Belardinelli et al

Is it dangerous to train CHF patients ?

• No,– If contra-indications related to the cause of HF

are respected– (major hypotension, invalidating angina,

uncontrolled ventricular arrhythmias, PHT? cardiac thrombus ?)

– Far from an episode of decompensation– On optimal treatment(at least ACE-I/diu + BB

++ ..)

Mechanisms of action of cardiac rehabilitations ?

• Heart

• Vessels

• Muscle

• Autonomic nervous system

• Lung

Effects on the heart

• Improvement in myocardia perfusion (1)

• Decrease in myocardial ischemia (2)

• Improvement in ED vasodilatation (5)

• Increase in exercise CO (3)

• No deleterious effect on cardiac remodeling (4)

(1) V. Froelicher et al, JAMA 1984; 10: 1291(2) AA. Ehsani et al, Am J Cardiol 1982; 50: 246

(3) AJS. Coats et al,Circulation 1992; 85: 2119P. Dubach et al, JACC 1997; 29: 1591

(4) P. Giannuzzi et al (Etude EAMI), JACC 1993; 22: 1821(5) R. Hambrecht et al, JACC 1993; 22: 468

The PET Study100 CAD pts, PTCA-stent based therapy vs exercise training6 months follow up

Hambrecht R et al. Circulation 2004

Exercise

PTCA/Stent

Benefits of training in HF

Sullivan MJ - Circulation 1988; 78: 506-15 * e 1989; 79: 324-9 **

Anaerobic treshold **Exercise *

4 - 6 months

EDV ml/mEDV ml/m22

EVS ml/mEVS ml/m22

EF %EF %

LV Function and RemodelingLV Function and RemodelingELVD - CHFELVD - CHF

BaselineBaseline

147 147 41 41

110 110 34 34

25 25 4 4

6 Months6 Months

156 156 42*† 42*†

118 118 34‡ 34‡

25 25 5‡ 5‡

BaselineBaseline

142 142 26 26

107 107 24 24

25 25 4 4

6 Months6 Months

135 135 2* 2*

97 97 24* 24*

29 29 4* 4*

Exercise Training GroupExercise Training Group(n=45)(n=45)

Control GroupControl Group(n=44)(n=44)

* p<0.01 time effect within group; † p<0.001 interaction; ‡ p<0.01 interaction* p<0.01 time effect within group; † p<0.001 interaction; ‡ p<0.01 interaction

LV remodeling & exercise training

Afzal A - Progress Cardiov Dis 1998: 41: 175-90

JACC, 1997

Circulation, 1997

JACC, 1993

Am Heart J, 1996

Effects on the vessels

• Rest and exercise vasodilatation improved (1)

• Improvement in endothelium-dependent vasodilatation (2)

(1) AJS. Coats et al, Circulation 1996; 85: 2119(1) AJS. Coats et al, Circulation 1996; 85: 2119

(2) B. Hornig et al, Circulation 1996; 93: 210(2) B. Hornig et al, Circulation 1996; 93: 210

R. Hambrecht et al, Circulation 1998;98: 2709R. Hambrecht et al, Circulation 1998;98: 2709

Effects of training on endothelial function in CHF pts

B Hornig et al, Circulation, 1995;1996:210B Hornig et al, Circulation, 1995;1996:210

p<0.05 p<0.05

0

5

10

15

20

Controls CHF Trained CHF

Change in diameter (%)

Mechanisms of the effects of training on peripheral

vasodilatation

• Increased eNOS ?

• Increased VEGF ?

• Decrease in oxydative stress ?

Effects on the muscle

R Hambrecht et al

CHF CHF trained

Effects on the autonomic nervous system

• Decrease in sympathetic tone and increase in parasympathetic tone (1)

• Decrease in plasma norepinephrine, improvement in MIBG uptake (2)

• Increases HR variability (3)

(1) AJS. Coats et al, Circulation 1992; 85: 2119(1) AJS. Coats et al, Circulation 1992; 85: 2119(2) R. Hambrecht et, JACC 1995; 25: 1239, Agostini D, 2000(2) R. Hambrecht et, JACC 1995; 25: 1239, Agostini D, 2000

(3) AJS. Coats et al, Circulation 1992; 85: 2119(3) AJS. Coats et al, Circulation 1992; 85: 2119

Effects on HRV

AJS. Coats et al, Circulation 1992; 85: 2119AJS. Coats et al, Circulation 1992; 85: 2119

Electric myocardial stability and exercise training

Groups VFT (mV)

ERP (msec)

HW/BW

LVP (mm Hg)

dP/dT max

Control (n=10)

3.1±1.6** 48±8 4.9±0.8* 112±32 4,075±

1,128

Exercise (n=5)

9.6±0.8** 50±10 3.7±0.3 119±18 5,462

±1,528

(*p<0.05, ** p<0.01)Male rats, treadmill, 8 weeks H Dor-Haim, Israel Heart Society 06

Exercise ventilation and training

0

10

20

30

40

50

Repos 25 W 50 W Max

Ventilation (l/min)

BeforeTrained

AJS Coats et al, Circulation 1992; 85: 2119AJS Coats et al, Circulation 1992; 85: 2119

*

*

* p < 0.05

17 patients -Lactate-PWP?+ diaphragm- ergoreflex

Training and BNP in CHF

Passino et al. JACC 06

Other possibles mechanisms of action potentially beneficial

• Increase in cardiac NO synthase

• Reduction in oxidative stress

• Anti-inflammatory action (TNF alpha, interleukins)

• ……

Which patients ?

• Patients in NYHA class II-III

• Class IV ?

• Patients on a transplant list ?

• Class I patients ?

• Women ?

• Which peak VO2?

Which protocol ?

• High (usually, 60-70% peak VO2) vs low (40% peak VO2) level exercise training – Low level : periphery +++, autonomic tone– High level : heart

• Anaerobic threshold based • Interval training vs usual training • Segmental training vs dynamic training • Home-based or hospital-based training • 3 or 5 days per weeks ? 2, 3 or 6 months

Compliance and training response

AJS. Coats et al, Circulation 1990;85:2119-31AJS. Coats et al, Circulation 1990;85:2119-31

-10

-20

-30

-400 20 40 60 80 100 120

Observance (%)

0

10

20

30

40

50

60

70 % increase in exercise tolerance

r = 0.74, p< 0.01

Duration of the effect

• Most of the studies have used 3-6 month periods of training

• Improvement seems to level off after the 1st-3rd month

• Acceptability of a long-term training program ? Phase III remains a major problem

Other questions

• Do betablockers limit benefit ?

• Should we systematically propose a rehab programme to a patient on a transplant list?

• Can we remove from the transplant list a patient significantly improved by training?

• Effects on outcome ?

Van Bortel L.M.A.B. 1992 Cardiovascular Drugs and Therapy 6:239-247

Du

rée

(min

.)

p<0.01 vs placebo

20

30

40

50

60

70

Placebo Atenolol 50mg Nebivolol 5mg

Effects of betablockers on exercise toleranceEffects of betablockers on exercise tolerance

nTA 70% VO2 max

Effects of traing in CRT patientsEffects of traing in CRT patients

VO

2max

(m

l/kg

/min

) P = 0.003

10

12

14

16

18

20

baseline 1 mth 3 mths 5 mths

l CRT +

n CRT -

VO

2pea

k (m

l/kg/

min

)

Conraads V et al. WCC 06

Am J Cardiol 2005;95:734–741

Conclusions

3. Patients who improved to low risk for peak VO2 had a 1-year survival, but patients who improved to low risk and were treated with blockers had a 1-year survival rate (83%) comparable to that after transplant (84%).

• 227 advanced HF adults referred for initial HxT evaluation• 52 ± 10 years old• 2nd evaluation: > 60 days after initial evaluation (352±238 days)

Effects on outcome

EXTRAMATCH

RRR 95% CI p

Deaths 35% 0.46-0.92 0.015

Deaths+

Hospitalisations

28% 0.56-0.93 0.011

NNT during 2 years to save 1 life: 17

ExtraMATCH : mortality

HR 95% CI p

Ischemic 0.54 0.35-0.83 0.01

Male 0.60 0.41-0.87 0.01 

NYHA III-IV 0.63 0.40-0.99 0.05 

EF<25% 0.59 0.38-0.92 0.02 

VO2m<15 0.63 0.42-0.96 0.03

Duration > 28weeks

0.64 0.41-0.99 0.04 

ExTraMATCH coll BMJ 16.01.2004

Unsustained effects of Exercise on mortality (EXERT Study, Montreal)

McKelvie RS et al. Am Heart J. 2002;144:23-30McKelvie RS et al. Am Heart J. 2002;144:23-30

N=181N=181

Heart Failure - A Controlled Trial Investigating Outcomes of exercise

TraiNing

Randomized trial, 3 000 pts NYHA class II–IV,

EF<35%

ET + usual care vs usual care - 2 years

intervention

52 centres in US (44 centres), Canada (8

centres), 5 in France Expecting to find a 20 % reduction in death and

hospitalization rates

HF – Action NHLBI initiative and funding

Subject Demographics

Age Median (25th, 75th) 59 (51, 68)

Sex Female Male

507 (29%) 1235 (71%)

Ethnicity Hispanic or Latino Not Hispanic or Latino

58 (3%) 1673 (97%)

Race Asian Black or African American White Other2

28 (2%) 595 (34%)

1085 (62%) 63 (4%)

BMI Median (25th, 75th) 30 (26, 35)

Prior Cardiac Procedures

CABG 450 (26%)

PCI 399 (23%)

CABG or PCI 669 (38%)

Valve surgery 99 (6%)

Pacemaker 319 (18%)

AICD 635 (36%)

CRT 287 (17%)

AICD or CRT 703 (40%)

AICD and CRT 219 (13%)

Cost-effectiveness

• Data lacking in CHF

Circulation 2003; 107: 1210-25

Recommendation ESC : IC

CONCLUSION• Importance of the peripheral abnormalities in

CHF• Physical activity beneficial in stable patients• Mechanism of action mainly peripheral and

neurohormonal with current protocols• Unequaled effect on symptoms, mood and QOL • Long term effects on morbimortality unknown • Could (should) be proposed to all CHF patients

with systolic dysfunction