Advanced Heart FailureAdvanced Heart Failure

Concepts and OptionsConcepts and Options

Vinay Thohan, MDVinay Thohan, MDWake Forest UniversityWake Forest University

Baptist Medical CenterBaptist Medical Center

Director of Advanced Cardiac CareDirector of Advanced Cardiac Care

and Heart Transplantationand Heart Transplantation

I have no financial relationships pertaining to this presentation to disclose

GoalsGoals

• Define advanced heart failure– Pathophysiology– Epidemiology

• Current therapeutic options– Therapeutic strategies (case presentation)

• The Future– Application of cutting edge technologies

PathophysiologyPathophysiology (Downhill Cascade)(Downhill Cascade)

Myocardial Myocardial InsultInsult

Myocardial Myocardial DysfunctionDysfunction

Hemodynamic Defense SystemsHemodynamic Defense SystemsInflammationInflammation

Reduced System Reduced System PerfusionPerfusion

Altered Gene Altered Gene Expression Apoptosis Expression Apoptosis

RemodelingRemodeling

CardiomyopathyCardiomyopathyIschemicValvularHypertensionTachycardiacFamilial/GeneticIdiopathicToxinsMetabolicInfectiousSystemic diseasesAllergicPeri-partumNeuromuscular

ACC/AHA StagingACC/AHA StagingNYHA ClassificationNYHA Classification

Severe HFMild and Moderate HF

Asymptomatic

IVII–IIII

Refractory symptoms requiring

specialized interventions

Structural heart disease with symptoms,

either prior or current

Structural heart disease

without symptoms

High risk of developing HF

DCBA

ACC/AHAHF Stage

NYHAFunctionalClass

Hunt SA et al. Circulation 2005;112:1825

250,000

5,000,000

10,000,000

72,600,000

ACC / AHA staging of CHF syndromeACC / AHA staging of CHF syndrome

50,000,000

12,000,000

10,600,000

Stage AStage A

Stage BStage BStageStage D D

StageStage C C

HTNHTN

DMDMCADCAD

Symptomatic CHFSymptomatic CHF•(70%) Antecedent HTN(70%) Antecedent HTN•(65%) Documented CAD(65%) Documented CAD

•1.5 million MI per year1.5 million MI per year•30-40% LV dysfunction30-40% LV dysfunction•30% disabled < 6years30% disabled < 6years

•DM 2 fold increaseDM 2 fold increase

Class II1.68 M(35%)

Class IV240 K(5%)

Class III1.20 M(25%)

Class I1.68 M(35%)

AHA Heart and Stroke Statistical Update 2009

Systolic Heart Failure by NYHA ClassSystolic Heart Failure by NYHA Class

Symptomatic CHFSymptomatic CHF15-18 million office visits15-18 million office visits3.2 million admits as either 13.2 million admits as either 1erer

or 2or 2nd nd diagnosisdiagnosis$37 billion in & out-patient $37 billion in & out-patient costcost$700 million direct drug cost$700 million direct drug cost

100

75

50

25

0I II III IV

1

10

NYHA CLASS

An

nu

al S

urv

ival

Rat

e

Ho

spit

aliz

atio

ns

/ ye

ar

.1

Deceased

Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 6th edition, ed. Braunwald et al.

Survival RateHospitalizations

ununNatural History of Heart FailureNatural History of Heart Failure

Advanced Heart FailureAdvanced Heart Failure

N=200,000N=200,000age 65 (50%)age 65 (50%)# of meds (9)# of meds (9)# hosp (5)# hosp (5)$$$ (12 billion)$$$ (12 billion)Mortality (50%/yr)Mortality (50%/yr)Rx???Rx???

Little W Heart Fail Rev 2000

Normal PhysiologyNormal Physiology

Little W Heart Fail Rev 2000

CHF PhysiologyCHF Physiology

Measures of systolic Measures of systolic function correlate function correlate poorly with functional poorly with functional capacitycapacity

Classic ObservationsClassic Observations (systolic dysfunction)(systolic dysfunction)

Lapu-Bula AJC 1999

•47 pts DCM (EF 28%)•Echo and gated ventriculogram•Exercise MVO2

Pressure(mmHg)

40

80

120

0

90

75

60

45

30

15

ATRIUM

Volume(ml)

LAPLAP EDPEDP

2828 3636

1616 2020

88 1212

Important Concepts•Delay relaxation•Higher Filling Pressure•Diastole ~ Systole•Sinus rhythm

Hemodynamic Implications of Heart Hemodynamic Implications of Heart FailureFailure

VENTRICLE

HigherLA pressure

High LVpressure

Left Atrial PressureLeft Atrial Pressure

DeathDeath

Pulmonary CongestionPulmonary Congestion

Shortness of breath with activityShortness of breath with activity

Disability and HospitalizationsDisability and Hospitalizations

Impact of abnormal fillingImpact of abnormal filling

Molecular mechanisms of heart failureMolecular mechanisms of heart failure

General Concepts

RegulatedVoltage gated channelsNeurohormone (SNS, RAS,

ET-1, Aldo, etc.)Receptor mediated ReduntantNeurons, Cardiomyocytes,

blood vessels, fibroblasts

Relentless

Molecular Mechanism of Heart Molecular Mechanism of Heart Failure (SERCA 2A)Failure (SERCA 2A)

SERCA 2A• Animals with deficient or

defective SERCA 2A develop heart failure/ die

• Humans with heart failure have defective or inadequate amounts SERCA 2A

• Treatment with heart failure therapy improves SERCA 2A levels

Markers for Advanced CHF (EF<35%)Markers for Advanced CHF (EF<35%)

Rapidly Assessable

Clinical ScenarioInotrop/pressor dependance (~50% 1-3 mos)Acute myocardial Infarction (~50%1-3 week)

DemographicEtiology (infiltrative>ischemic>non-

ischemic>paripartum)Age (>68)

SymptomsNYHA (PND)Syncope

SignsChronic S3JVP

Easily Available

12 lead ECGA-Fib QRS (>120ms)

Cardiopulmonary TestingVO2 max < 14 ml/kg/min

Blood WorkNa (<130)BUN/Cr (>40 / >2.3)Hgb (<11 men, <10 women)Cholesterol (<150) BNP or nt-BNP

2 D Echo with DopplerLVEF (<25%)Depressed RV functionLVEDD (>6cm)Restrictive Mitral Inflow Pattern (Doppler)Pulmonary Hypertension (Doppler)

Assigning prognosis does not have to Assigning prognosis does not have to be be painfulpainful……

Heart Failure ModelsHeart Failure Models1. ADHERE cart model

– Inpatient (Bun>43, SBP<115, Cr>2.7)

– Fonarow JAMA 2005

2. HF Risk Scoring System– Inpatient (Multivariable)– 30 day and 1 year outcome– Lee JAMA 2003

3. Seattle Heart Failure Model– Outpatient (Multivariable)– SeattleHeartFailaureModel.org

4. Heart failure Survival Score– Outpatient (multivariable)– Lund AJC 2005

New Therapies for Heart FailureNew Therapies for Heart Failure

Direct Renin Direct Renin InhibitorsInhibitors

Vasopeptidase Vasopeptidase InhibitorsInhibitors

Sympathetic Sympathetic Blockade Blockade

Endothelin Endothelin receptor receptor blockersblockers

Cytokine Cytokine InhibitionInhibition

Statin therapyStatin therapy

Vasopressin Vasopressin (V(V22) receptor ) receptor

antagonistantagonistLeft Left Ventricular Ventricular Assist DeviceAssist Device

Case 1. Dying in front of you!Case 1. Dying in front of you!

• 57 yo man presents 48 hours after PCI and stent implant with crushing substernal chest pain and severe SOB

• ER: Hypotensive, cool, clammy with ST elevation anterior leads.

• CATH: Acute stent closure and a PCI was performed with an open artery.

• VT/VF requiring multiple cardioversions, intubation and initiation of high doses of dopamine and dobutamine

• WFB: Accepted the patient in transfer after placement of IABP

HR=130 ABP=88/60 Pox=92%Dopamine 20 Dobutamine 15

HEENT: cyanosis lipsNECK: elevated neck veinsHEART: regular tachycardiac with

prominent S3 and soft holosystolic murmur

LUNG: ralesABD: enlarged liverEXT: cool with trace lower extremity edema

BUN/Cr=70/2.7 Hgb=12.2Troponin I=65 CK=2200 MB=260Lactic Acid= 6 LFT=1000’s

CXR: Pulmonary Edema

74%74%LV dysfunctionLV dysfunction

3%3%RV InfarctionRV Infarction

2%2%Free WallFree Wall RuptureRupture

1%1%VSDVSD

9%9%Mitral Mitral

RegurgitationRegurgitation

11%11% Others OthersPEPE

HCMHCMTakotsuboTakotsubo

SepsisSepsis

Differential Diagnosis of ShockDifferential Diagnosis of Shock with Myocardial Infarction with Myocardial Infarction

Cardiogenic Shock Acute MI

• Timing– 10% at presentation

– 59% within the first 48 hrs

– 30% 5 days or more

– STEMI earlier than NSTEMI

• Location– Higher incidence with LAD

(proximal)

– 50% myocardial dysfunctional

•NO mechanical complication of MINO mechanical complication of MI•NO occult valvular heart diseaseNO occult valvular heart disease•NO intracardiac thrombusNO intracardiac thrombus

Regional wall motion c/w the anterior MIRegional wall motion c/w the anterior MI

47%52% 53%56%

64% 66%

0

10

20

30

40

50

60

70

80

30-Day 6-Month 1-Year

Mo

rtal

ity

(%)

ERV

IMS

P = .11 P = .04

SHOCK Trial MortalitySHOCK Trial Mortality

Hochman et al NEJM 1999;341:625-Hochman et al NEJM 1999;341:625-3535

P < 0 .03

LONG-TERM SURVIVAL

YEARS FROM RANDOMIZATION

PR

OP

OR

TIO

N A

LIV

E

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

IMSIMS

ERVERV

30 days

Logrank p = .024

~ SHOCK~ SHOCK Trial ~ Trial ~

Congestive Heart FailureCongestive Heart FailurePharmacologicPharmacologic

RevascularizationRevascularization

DeviceDevice

DiagnosticDiagnostic

Novel TreatmentNovel TreatmentEducationEducation

FinancialFinancial

Psycho SocialPsycho Social

SurgicalSurgical

PalliativePalliative

InvasiveInvasiveNoninvasive ImagingNoninvasive Imaging

SerologicSerologicExercise MetabolicExercise Metabolic

Coronary BypassCoronary BypassValvular HeartValvular Heart

Artificial Cardiac SupportArtificial Cardiac SupportVentricular ReconstructionVentricular Reconstruction

Coronary InterventionCoronary InterventionPercutaneous ValvePercutaneous Valve

Internal Cardiac DefibrillatorInternal Cardiac DefibrillatorCardiac ResynchronizationCardiac Resynchronization

Heart TransplantHeart Transplant

SymptomsSymptomsMedicationsMedications

DietDietExerciseExercise

Vasopressin antagonistVasopressin antagonistImmune modulatory therapyImmune modulatory therapy22ndnd and 3 and 3rdrd generation VAD generation VAD

Pump

Blood outlet

Blood inlet

ImpellaImpella (Cardiac Recovery System)(Cardiac Recovery System)

Acute LV decompressionAcute LV decompressionIncrease in MAPIncrease in MAPReduction in PAP Reduction in PAP

Clinical F/UClinical F/U

• CCU: – (6 hours) Improvement of central hemodynamics– (12 hours) Normalization of metabolic and laboratory parameters– (48 hours) Ween pressors and inotropes– Reduce ventilator support FiO2=35%– Removed IMPELLA at bedside

• Telemetry– Ambulation and titration of heart failure therapy– Comprehensive evaluation for cardiac transplantation– D/C home on day 10

HEART TRANSPLANTATION Kaplan-Meier Survival (1/1982-6/2005)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Years

Su

rviv

al

(%)

Half-life = 10.0 yearsConditional Half-life = 13.0 years

N=74,267

ISHLT 2008

N at risk at 22 years: 70

HEART TRANSPLANTATION Kaplan-Meier Survival (1/1982-6/2006)

J Heart Lung Transplant 2008;27: 937-983

ADULT HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: 1995 - June 2006)

0%

20%

40%

60%

80%

100%

1 Year (N = 15,388) 3 Years (N = 13,600) 5 Years (N = 11,698) 7 Years (N = 9,306)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

ISHLT 2008 Last updated based on data as of December 2006 J Heart Lung Transplant 2008;27: 937-983

Transplant FactsTransplant Facts

Medically EligibleMedically Eligible

~50-75 k~50-75 k~125 k~125 k age > 65 age > 65

EvaluatedEvaluated(15-10 k)(15-10 k)MedicalMedicalΨ / SocialΨ / SocialFinancialFinancial

ListedListed(3-5 k)(3-5 k)

AttritionAttrition(0.5-1 k)(0.5-1 k)DeathDeathCancerCancer

TransplantTransplant(2 k)(2 k)

2200 donors2200 donors

NUMBER OF HEART TRANSPLANTS REPORTED BY YEAR

189 318665

1182

2159

2713

31363363

40034171 4203

4364 4429 4396 4263 41993864

3581 3433 3390 3283 3226 3065 3185 3205

0

500

1000

1500

2000

2500

3000

3500

4000

4500

Nu

mb

er

of

Tra

ns

pla

nts

ISHLT 2008

NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of hearts transplanted worldwide has declined in recent years.

J Heart Lung Transplant 2008;27: 937-983

Cardiac Assist Applications 21st Cardiac Assist Applications 21st CenturyCentury

INVASIVE

HE

MO

DY

NA

MIC

General Indications for VAD Support•Cardiogenic Shock

Hypotension (ABP<80 or pressors)Hypoperfusion (UO<30cc /FiO2>40 /AMS) Hemodynamics (CI<2.2 /PWCP>20)

•Refractory Heart FailureNYHA IV (>30d)Inotrope dependance (30d)

•Pulmonary Hypertension (2nd to CHF)•TPG > 14 or PVR > 5

NEJM Aug 2007

SERCA2a in Heart Failure

35

Restoration of SERCA 2ARestoration of SERCA 2A

AdenovirusAffinity for the heartCan replicate

Adeno-associated virus(AAV)Particles of the viral shellAffinity for heart

CANNOT replicate

SERCA 2A

AAV

AAV vector

•Splice Human SERCA 2A gene into AAV genome•Harvest AAV-vector and deliver to the heart

37

CUPID Trial CUPID Trial (first in humans)(first in humans)

• Age 18-75 years old• NYHA class III/IV• Ischemic (vessel patency) or

non-ischemic cardiomyopathy • Maximal oxygen consumption

(VO2max) of ≤16 mL/kg/min • Left ventricular ejection

fraction ≤ 30% • ICD implanted • If indicated, resynchronization

pacemaker implanted for >6 months

• Stable, optimized HF regimen for 30 days, except for diuretics

Baseline Patient CharacteristicsBaseline Patient Characteristics

Characteristic MYDICAR Low N=8

MYDICAR Mid N=8

MYDICAR High

N=9

PlaceboN=14

Age, yrs, (SD) 60 (10) 64 (9) 57 (14) 61 (12)

Sex, male, n, (%) 7 (88) 8 (100) 6 (67) 13 (93)

CAD/Non-CAD, % 75/25 50/50 22/78 50/50

6MWT (m) (mean ± SD) 359 ±134 334 ±117 347 ±120 336 ±138

Peak VO2, (mL/kg/min) 14.8 ± 4.2 14.4 ± 3.7 15.1 ± 3.2 12.4 ± 4.2

LVEF (% ) 25 ±7 26 ±9 28 ±5 23 ±7

LVESV (mL) 206 ±97 238 ±149 169 ±48 198 ±65

NYHA III (n, %) 8 (100) 8 (100) 9 (100) 14 (100)

MLWHFQ 58 ±16 35 ±29 41±26 49 ±16

NT-proBNP (pg/mL) 1353 ±386 3310 ±3112 2141 ±1997 4072 ±3906 38

6 Minute Walk Test6 Minute Walk TestFunctional DomainFunctional Domain

39

Low Mid High Placebo

Mea

n (

SE

) C

han

ge

Fro

m B

asel

ine

(m)

-250

-200

-150

-100

-50

0

50

100

3 3 33

66

6

69 9

9

912

12

12

12

Imp

rove

me

nt

Quality of Life: MLWHFQ Quality of Life: MLWHFQ Symptomatic DomainSymptomatic Domain

40

Low Mid High Placebo

Me

an (

SE

) C

han

ge

Fro

m B

as

eli

ne

-20

-10

0

10

20

30

40

11 1 1

33

3

36

6

66

99

9

9 12

12

1212

Imp

rove

me

nt

Peak VOPeak VO22 Functional DomainFunctional Domain

41

Low Mid High Placebo

Mea

n (

SE

) C

han

ge

Fro

m B

asel

ine

(mL

/kg

/min

)

-7

-6

-5

-4

-3

-2

-1

0

66

6

6

12

12

12

12 Imp

rove

me

nt

Left Ventricular Ejection FractionLeft Ventricular Ejection FractionRemodeling DomainRemodeling Domain

42

Low Mid High Placebo

Me

an (

SE

) C

ha

ng

e F

rom

Ba

sel

ine

(%

)

-10

-8

-6

-4

-2

0

2

4

6

1212

12

12

9 9

9

9

6 6

6

6

3

3

3311

1

1

Imp

rove

me

nt

Cumulative Clinical Event RateCumulative Clinical Event RateAdjusted for Competing Risk of Terminal Event (CV Death,

Transplant, LVAD)

Biometrics 2000;56(2):554-62.Circulation 2009; 119(7): 969-977.

**

P (N=14)L (N=8) HR(CI)=0.40 (0.13, 1.21), p = 0.11M (N=8) HR(CI)=0.44 (0.16, 1.24), p = 0.12H (N=9) HR(CI)=0.12 (0.03, 0.49), p = 0.003**

ACT program is a ACT program is a Group EffortGroup Effort

04’-05’04’-05’

4 transplant4 transplant

9/069/06

ACT-programACT-program

2/112/11

33 transplant 33 transplant (2 peds, 1 re-transplant)(2 peds, 1 re-transplant)

11 transplants 2009, 10 in 201011 transplants 2009, 10 in 2010

95% survival 95% survival (better than national avg.)(better than national avg.)

12 LVAD 12 LVAD (1 removed, 3 transplant, 6 ongoing)(1 removed, 3 transplant, 6 ongoing)

17 patients actively listed17 patients actively listed

12/0612/06

CMS closure?CMS closure?

4/074/07

CMS POCCMS POC

ACT programACT programCompassionate, individualized Compassionate, individualized cutting edge cardiovascular carecutting edge cardiovascular care

Local resource for advanced cardiacLocal resource for advanced cardiac disease disease (transplants, pumps, research)(transplants, pumps, research)

Innovation and educationInnovation and education

4/094/09

CMS approvedCMS approved