Ninth International Symposium

HEART FAILURE & Co.Rozzano 17-18 aprile 2009

Session IVSession IV

““Advanced Heart Failure Prognosis Guided Clinical Management:Advanced Heart Failure Prognosis Guided Clinical Management:

Definition and Clinical Impact”Definition and Clinical Impact”

Edoardo Gronda, MD, FESCEdoardo Gronda, MD, FESC

Clinical Cardiology Heart Failure UnitClinical Cardiology Heart Failure Unit

Cardiovascular DepartmentCardiovascular Department

IRCCS, Istituto Clinico HumanitasIRCCS, Istituto Clinico Humanitas

Rozzano (Milano)Rozzano (Milano)

Distribution of HF population byDistribution of HF population byACC/AHA staging ACC/AHA staging

B B 34%34%

Structural heart diseaseStructural heart diseaseLVH, MI, low LVEF, cardiac dilatation, valvular LVH, MI, low LVEF, cardiac dilatation, valvular

disease disease

C 11,8%C 11,8% Prior, current Prior, current

symptomssymptoms

DD0,2%0,2%

RefractoryRefractory

A A 22% 22%

High RiskHigh RiskHypertension, coronary disease, diabetes, renal disease, family history, etc.Hypertension, coronary disease, diabetes, renal disease, family history, etc.

Ammar et al Circulation 2007; 115: 1563Ammar et al Circulation 2007; 115: 1563

COMPANION(C) COMPANION(C) COMPANION(C) COMPANION(C)

bl 65%bl 65% bl 65%bl 65%

Class III / IVClass III / IV LVEF 23 %QRS 0,16”

HF-Hospital Adm> 1, < 12 mos

Class III / IVClass III / IV LVEF 23 %QRS 0,16”

HF-Hospital Adm> 1, < 12 mos

19%19%19%19%

T = treatment groupT = treatment groupC = control groupC = control groupT = treatment groupT = treatment groupC = control groupC = control group

% One Year Mortality% One Year Mortality% One Year Mortality% One Year Mortality

30303030

40404040

20202020

10101010

60606060

CRT-DCRT-D - 27%- 27%

1y 1y (14,5%)(14,5%)

CRT-DCRT-D - 27%- 27%

1y 1y (14,5%)(14,5%)

0000

70707070

************

COMPANION(C) COMPANION(C) COMPANION(C) COMPANION(C)

bl 52%bl 52% bl 52%bl 52%

Class IVClass IV LVEF 20,8%QRS 0,16”

HF-Hospital Adm> 1, < 12 mos

Class IVClass IV LVEF 20,8%QRS 0,16”

HF-Hospital Adm> 1, < 12 mos

44%44%44%44%

CRT-DCRT-D - 31%- 31%1y 1y (31%)(31%)

CRT-DCRT-D - 31%- 31%1y 1y (31%)(31%)

80808080

73%73%73%73%

INO 73%INO 73%INO 73%INO 73%

REMATCH ©REMATCH ©REMATCH ©REMATCH ©

Class IVClass IVend stageend stageClass IVClass IVend stageend stage

Refractory HFRefractory HF requiring requiring specialized specialized

interventions interventions (ACC/AHA Stage D)(ACC/AHA Stage D)

Refractory HFRefractory HF requiring requiring specialized specialized

interventions interventions (ACC/AHA Stage D)(ACC/AHA Stage D)

HF SEVERITYHF SEVERITYHF SEVERITYHF SEVERITY

MADIT II (C) MADIT II (C) MADIT II (C) MADIT II (C)

Class II / IVClass II / IVLVEFLVEF<<30%30% bl 70%bl 70%

Class II / IVClass II / IVLVEFLVEF<<30%30% bl 70%bl 70%

Class IVClass IV bl 100%bl 100%Class IVClass IV bl 100%bl 100%

Merit-HF(T)Merit-HF(T)CIBIS 1994 (T)CIBIS 1994 (T)CIBIS- II (T)CIBIS- II (T)

Merit-HF(T)Merit-HF(T)CIBIS 1994 (T)CIBIS 1994 (T)CIBIS- II (T)CIBIS- II (T)

11,6 - 14%11,6 - 14%11,6 - 14%11,6 - 14%

52% QRS >0,12”52% QRS >0,12”52% QRS >0,12”52% QRS >0,12”

Class IIIB / IVClass IIIB / IV

LVEF<25%LVEF<25%

Class IIIB / IVClass IIIB / IV

LVEF<25%LVEF<25%

COPERNICUS COPERNICUS Overall (T)Overall (T)

COPERNICUS COPERNICUS Overall (T)Overall (T)

RALES (T)RALES (T)RALES (T)RALES (T)

Class III / IVClass III / IVLVEF<35%LVEF<35%

Class III / IVClass III / IVLVEF<35%LVEF<35%

bl 11%bl 11% bl 11%bl 11%

18%18%18%18%

CONSENSUS (T) CONSENSUS (T) CONSENSUS (T) CONSENSUS (T)

Heart replacementHeart replacement

Advanced Heart Failure Defined Advanced Heart Failure Defined by:by:

1.1. Neurohormonal drugs failure Neurohormonal drugs failure –intolerance.–intolerance.

Ventricular Remodeling & Performance Ventricular Remodeling & Performance consequenceconsequence

Pre

ssu

re (m

m H

g)

Pre

ssu

re (m

m H

g)

Volume (ml)Volume (ml)

E.S.P.V.R

E.S.P.V.R

Kono et al. Am J Cardiol. 1991Kono et al. Am J Cardiol. 1991

Mitral Regurgitation in LV Systolic Mitral Regurgitation in LV Systolic DysfunctionDysfunction

Local LV remodeling Local LV remodeling (apical and posterior displacement of papillary muscles)(apical and posterior displacement of papillary muscles) leads to excess valvular tenting independent of global LV remodeling leads to excess valvular tenting independent of global LV remodeling

which, in turn, impacts global remodelling.which, in turn, impacts global remodelling.

posterior

apical

LV enlarges-loss of LV enlarges-loss of elliptical shape; more elliptical shape; more

sphericalspherical

Mitral annulus dilates

Papillary muscles displace

Chordae tether leaflets

Valve leaflets are not in coaptation…

Functional Functional Mitral Mitral

RegurgitationRegurgitation

Increased LV end Increased LV end diastolic pressurediastolic pressure

Functional MR begets MR in cardiomyopathy:Functional MR begets MR in cardiomyopathy:from local to global remodelling from local to global remodelling

SAVE Study: SAVE Study: Comparison of Ventriculographic Variables.Comparison of Ventriculographic Variables.

No MR (n=586)No MR (n=586)LV EF% LV EF% 3131++ 7 7

M R (n=141)M R (n=141)LV EF% LV EF% 32 32 ++ 7 7

P <P <

LV End DLV End D Vol. mlVol. ml

LV End SLV End S Vol. mlVol. ml

LV LV SphericitySphericity systolic %systolic %

Change%Change%

Lamas et al. Circulation 96:827 (97)Lamas et al. Circulation 96:827 (97)

202202 ++ 68 68

120120 ++ 47 47

3838 ++ 7 7

2828 ++ 7 7

99 ++ 6 6

239239 ++ 84 84

148148 ++ 65 65

4141 ++ 10 10

3434 ++ 11 11

77 ++ 7 7

.001.001 .001.001 .001.001 .001.001 .001.001

LV LV SphericitySphericity diastolic %diastolic %

SAVE Study: SAVE Study: Comparison of Survival on the basis of (mild) MRComparison of Survival on the basis of (mild) MR

Lamas et al., Lamas et al., CirculationCirculation 1997, 96: 827 1997, 96: 827

LVEF% 31+ 7

LVEF% 32 + 7

MR absent

MR present

Relationship between LV SIZE and VT Relationship between LV SIZE and VT

Sutton J et Al.Circulation 2003;

107:2577

Ventricular Shape and Function and Ventricular Shape and Function and Electric VulnerabilityElectric Vulnerability

Electrical Storm

NYHA f.cl. INYHA f.cl. I

Predicting the Long-Term effects of cardiac Predicting the Long-Term effects of cardiac resynchronization therapy on mortalityresynchronization therapy on mortality

Cleland J et al. J Am Coll Cardiol 2008Cleland J et al. J Am Coll Cardiol 2008

Predicting Causes of death in heart failurePredicting Causes of death in heart failureCARE HF post hoc analysisCARE HF post hoc analysis

Uretsky et al. J of Cardiac Fail 2008 Uretsky et al. J of Cardiac Fail 2008

IMR* 1,815 (1,765-2,602) .0012IMR* 1,815 (1,765-2,602) .0012

Advanced Heart Failure Defined Advanced Heart Failure Defined by:by:

1.1. Neurohormonal drugs failure Neurohormonal drugs failure –intolerance.–intolerance.

2.2. Ventricular remodelling leading Ventricular remodelling leading to mitral regurgitation and/or to mitral regurgitation and/or electric instability electric instability

dP/dT

diameter

By the La Place law : By the La Place law :

the energy the energy generationgeneration depends by ventricular depends by ventricular wall wall muscle thicknessmuscle thickness

the energy the energy transfer transfer into intracavitary blood into intracavitary blood (pressure(pressure) depends by ) depends by chamber curvature chamber curvature (zero curvature = no energy transfer).(zero curvature = no energy transfer).

Remodelling and dysfunction Remodelling and dysfunction

Heart and Kidney Heart and Kidney InteractionInteraction

Renal blood flow is maintained over a Renal blood flow is maintained over a wide range of blood pressures auto-wide range of blood pressures auto-regulating mechanisms.regulating mechanisms.

It does not fall until the mean arterial It does not fall until the mean arterial pressure falls below the critical level pressure falls below the critical level ((around 80mm Hgaround 80mm Hg).).

Sistemic Effect of CHFSistemic Effect of CHF

1. R.A.A.S.1. R.A.A.S. ActivationActivation2. Cathecolamine2. Cathecolamine secretionsecretion3. Vasopressin release3. Vasopressin release

Renal Renal UnderperfusionUnderperfusion

Renal fraction of cardiac output Renal fraction of cardiac output normally constitutes about 20% of normally constitutes about 20% of cardiac output.cardiac output.

With low cardiac output, blood is With low cardiac output, blood is shunted from the kidneys to shunted from the kidneys to heart and brain circulation: heart and brain circulation:

the renal fraction of cardiac output is the renal fraction of cardiac output is thereby lowered in a non proportional thereby lowered in a non proportional way.way.

Kidney perfusionKidney perfusionDemand Demand

Car

diac

Out

put

(L/m

in)

Left Ventricular Filling Pressure (mm Hg)

Normal

Heart Failure

Decreas

ed Renal

Function

Decreased

Congestion

0 15 30

5.0

2.5

0

Robert W. Schrier, MDCirc Heart Fail. 2008;1:2-5

Diuretic use may decrease Diuretic use may decrease cardiac outputcardiac output

and impair renal function.and impair renal function.The “Bill”The “Bill”

Lungs congestionLungs congestionusually occurs earlier thanusually occurs earlier thanSBL fall below 80 mm Hg SBL fall below 80 mm Hg

Diuretics and Mortality - PRAISE1Diuretics and Mortality - PRAISE1

0%

25%

50%

75%

100%

0 1 2 3

Years

Figure 2 -KM Survival - Daily Diuretic Dose mg/kg

4 mg/kg

3-4 mg/kg

2-3 mg/kg

1-2 mg/kg

0.5-1 mg/kg

<0.5 mg/kg

p<0.0001

Levy et al Circ 2006Levy et al Circ 2006

Advanced Heart Failure Defined Advanced Heart Failure Defined by:by:

1.1. Neurohormonal drugs failure –Neurohormonal drugs failure –intolerance.intolerance.

2.2. Progression of LV remodelling leading Progression of LV remodelling leading to mitral regurgitation to mitral regurgitation and/or electric and/or electric instability. instability.

3.3. Fluid retention indexed by diuretic Fluid retention indexed by diuretic need and declining Kidney function.need and declining Kidney function.

EchocardiographyEchocardiography

Mitral regurgitation leads leads to high LV end-diastolicto high LV end-diastolicpressure (ROA 0,22 cmpressure (ROA 0,22 cm22))

Restrictive filling patternRestrictive filling patternDrives increasing Pulmonary Artery Drives increasing Pulmonary Artery PressurePressure

Time to death, transplantation, or LVAD implantationTime to death, transplantation, or LVAD implantation in in

patients with patients with lowlow and and highhigh RV systolic pressureRV systolic pressureTedrow UB et al Am J Cardiol. 2006 Jun 15;97(12):1737-40 Tedrow UB et al Am J Cardiol. 2006 Jun 15;97(12):1737-40

Color Doppler:Color Doppler:

• Tricuspid RegurgitationTricuspid Regurgitation

• TAPSE 8TAPSE 8

• Right ventricular Right ventricular

impairment leads toimpairment leads to

progressiveprogressive

Venous congestionVenous congestion

EchocardiographyEchocardiography

Increased MyocardialIncreased MyocardialWall Stress and Wall Stress and EdomyocardialEdomyocardial

IschemiaIschemia

Increased MyocardialIncreased MyocardialWall Stress and Wall Stress and EdomyocardialEdomyocardial

IschemiaIschemia

Right Ventricular Right Ventricular Dilatation andDilatation andRemodelingRemodeling

Right Ventricular Right Ventricular Dilatation andDilatation andRemodelingRemodeling

Increased CardiacIncreased CardiacFillingFilling

PressurePressure

Increased CardiacIncreased CardiacFillingFilling

PressurePressure

Extracellular FluidExtracellular FluidVolume ExpansionVolume Expansion

Extracellular FluidExtracellular FluidVolume ExpansionVolume Expansion

Pulmonary Arterial Pulmonary Arterial Hypertension and Hypertension and Right Ventricular Right Ventricular

FailureFailure

Pulmonary Arterial Pulmonary Arterial Hypertension and Hypertension and Right Ventricular Right Ventricular

FailureFailure

TricuspidTricuspidRegurgitationRegurgitation

TricuspidTricuspidRegurgitationRegurgitation

Septal Shift andSeptal Shift andDecreased LeftDecreased LeftVentricular OutputVentricular Output

Septal Shift andSeptal Shift andDecreased LeftDecreased LeftVentricular OutputVentricular Output

1. R.A.A.S.1. R.A.A.S. ActivationActivation2. Cathecolamine2. Cathecolamine secretionsecretion3. Vasopressin release3. Vasopressin release

1. R.A.A.S.1. R.A.A.S. ActivationActivation2. Cathecolamine2. Cathecolamine secretionsecretion3. Vasopressin release3. Vasopressin release

Renal sodiumWater Retention

Renal sodiumWater Retention

Schrier RW. Clin J Am Soc Nephrol 2008;3:1223-37

Severe MR – moderate RV Severe MR – moderate RV dilat.dilat.

(MRI)(MRI)

Congestion and outcome Congestion and outcome

Damman K et al. J Am Coll Cardiol 2009;53:582–8

Damman K et al. ESC 2008

CIBIS II post hoc analysisCIBIS II post hoc analysisPatients # 2,557

Advanced Heart Failure Defined Advanced Heart Failure Defined by:by:

1.1. Neurohormonal drugs failure –intolerance.Neurohormonal drugs failure –intolerance.

2.2. Progression of LV remodelling leading to Progression of LV remodelling leading to mitral regurgitation mitral regurgitation and/or electric instability. and/or electric instability.

3.3. Fluid retention indexed by diuretic need and Fluid retention indexed by diuretic need and declining kidney function.declining kidney function.

4.4. Pulmonary hypertension leading to Pulmonary hypertension leading to progressive right ventricular dysfunction and progressive right ventricular dysfunction and venous congestionvenous congestion

p < .05

p < .05Raised Venous Pressure:

A direct cause of renal sodium retention

Effect of Increasing Central Venous Pressure on GFR in Dogs Effect of Increasing Central Venous Pressure on GFR in Dogs with Constant BPwith Constant BP

0.5

0.8

1.1

1.4

0 2 4 6 8 0 6.25 12 18.75 25 0 (Central Venous Pressure)

GF

R (

ml/m

in)

GF

R (

ml/m

in)

mm Hg

High CVP significantlyimpairs GFR

Firth et al Lancet 5/7/88

Impact of Venous Congestion on Impact of Venous Congestion on Glomerular Net Filtration PressureGlomerular Net Filtration Pressure

Jessup and Costanzo JACC 2009 Vol. 53, No. 7, 597–9

The net effect is a further decrease in urine flow rate!The net effect is a further decrease in urine flow rate!

14 mm Hg 14 mm Hg 4 mm Hg4 mm Hg

Tubular urea reabsorption and flow dependence of urea clearance.

The decreased distal fluid delivery will slow tubular flow in the collecting duct and enhance the flow-dependent urea reabsorption.

1401401201201001008080

6060

4040

2020

00

Cle

arn

ce m

l/m

in

Urine flow rate ( ml/min)121210108866442200

Inuline

Creatinine

urea

Change in BUN mg /dLChange in BUN mg /dL

UREA not EGFR predicts 60 days UREA not EGFR predicts 60 days mortality in AHF ptsmortality in AHF pts

OPTIME-CHF InvestigatorsCirc Heart Fail. 2008; 1: 25–33

II

IIII

IIIIII

IVIV

JVP>6 cm

67 %

67 %

69 %

78 %78 %P=0,02 P=0,02

significant rise in jugular significant rise in jugular venous pressure asvenous pressure asquartile BUN values rosequartile BUN values rose

significant rise in jugular significant rise in jugular venous pressure asvenous pressure asquartile BUN values rosequartile BUN values rose

Advanced Heart Failure Defined Advanced Heart Failure Defined by:by:

1.1. Neurohormonal drugs failure –intolerance.Neurohormonal drugs failure –intolerance.

2.2. Progression of LV remodelling leading to mitral Progression of LV remodelling leading to mitral regurgitation and/or electric instability. regurgitation and/or electric instability.

3.3. Fuid retention indexed by diuretic need and Fuid retention indexed by diuretic need and declining Kidney function.declining Kidney function.

4.4. Pulmonary hypertension leading to progressive right Pulmonary hypertension leading to progressive right ventricular dysfunction and venous congestionventricular dysfunction and venous congestion

5.5. Increasing venous congestion further impacting Increasing venous congestion further impacting renal failurerenal failure

LVDysfLVDysf

Hemodynamic Derangement and HF Mortality: Hemodynamic Derangement and HF Mortality: a Matter of Multi-Systems Failurea Matter of Multi-Systems Failure% %

deaths / ydeaths / y

ACC/ACC/AHAStagAHAStag

e Be B

ACC/ACC/AHAStagAHAStag

e Be B

HF SeverityHF SeverityHF SeverityHF Severity

ACC/AHAACC/AHAStage CStage C

ACC/AHAACC/AHAStage CStage C

SevereSevereAsymptomaticAsymptomaticAsymptomaticAsymptomatic MildMildMildMild ModerateModerateModerateModerate

LVDysfLVDysf

2020

00

4040

6060

8080

100100

LVDysfLVDysf

ACC/AHAACC/AHAStage DStage D

ACC/AHAACC/AHAStage DStage D

NE RELEASENE RELEASE

RAAS RAAS activationactivation

Liver function in End-stage HF

Centrilobular Necrosis Centrilobular Necrosis

Dual blood supply: 80% portal vein 20% hepatic arteryHaemodynamic failure: flow redistibution

Hypoperfusion small intestine Hypoxic damageHypoxic damage

= MOF – starter

Gut related Gram-movement:sepsi

(Systemic inflammatory response syndrome)

Intrahepatic cholestasis

(Pierro:seminar 2004)(Pierro:seminar 2004)

(Moore:J trauma 1994)(Moore:J trauma 1994)

(Crawford:Hepatology1998)

Centrilobular Necrosis (Wadia JHLT 2005)

LVDysfLVDysf

LVDysfLVDysf

Hemodynamic Derangement and HF Mortality: Hemodynamic Derangement and HF Mortality: a Matter of Multi-Systems Failurea Matter of Multi-Systems Failure% %

deaths / ydeaths / y

ACC/ACC/AHAStagAHAStag

e Be B

ACC/ACC/AHAStagAHAStag

e Be B

HF SeverityHF SeverityHF SeverityHF Severity

ACC/AHAACC/AHAStage CStage C

ACC/AHAACC/AHAStage CStage C

SevereSevereAsymptomaticAsymptomaticAsymptomaticAsymptomatic MildMildMildMild ModerateModerateModerateModerate

LVDysfLVDysf

Periphery

HypoxicHypoxicdamagedamage

2020

00

4040

6060

8080

100100

LVDysfLVDysf

Inflammatory Inflammatory response:response:

IL2,6IL2,6TNF TNF Cytochines = Cytochines = Tissue Tissue NecrosisNecrosis

End Stage End Stage

ACC/AHAACC/AHAStage DStage D

ACC/AHAACC/AHAStage DStage D

NE RELEASENE RELEASE

RAAS RAAS activationactivation