Advanced Heart Failure Concepts and Options

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Advanced Heart FailureConcepts and Options

• Vinay Thohan, MD
• Wake Forest University
• Baptist Medical Center
• Director of Advanced Cardiac Care
• and Heart Transplantation

• I have no financial relationships pertaining to
  this presentation to disclose

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Goals

• Define advanced heart failure
• Pathophysiology
• Epidemiology
• Current therapeutic options
• Therapeutic strategies (case presentation)
• The Future
• Application of cutting edge technologies

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Pathophysiology (Downhill Cascade)
Cardiomyopathy Ischemic Valvular Hypertension Tach
ycardiac Familial/Genetic Idiopathic Toxins Metabo
lic Infectious Systemic diseases Allergic Peri-par
tum Neuromuscular
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ACC/AHA StagingNYHA Classification
ACC/AHAHF Stage
NYHAFunctionalClass
Hunt SA et al. Circulation 20051121825
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ACC / AHA staging of CHF syndrome
CAD
DM
Stage C
Stage D
Stage B
HTN

• Symptomatic CHF
• (70) Antecedent HTN
• (65) Documented CAD
• 1.5 million MI per year
• 30-40 LV dysfunction
• 30 disabled lt 6years
• DM 2 fold increase

Stage A
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Systolic Heart Failure by NYHA Class
Class IV 240 K (5)
Class I 1.68 M (35)
Class III 1.20 M (25)

• Symptomatic CHF
• 15-18 million office visits
• 3.2 million admits as either 1er or 2nd
  diagnosis
• 37 billion in out-patient cost
• 700 million direct drug cost

Class II 1.68 M (35)
AHA Heart and Stroke Statistical Update 2009
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unNatural History of Heart Failure

• Advanced Heart Failure
• N200,000
• age 65 (50)
• of meds (9)
• hosp (5)
• (12 billion)
• Mortality (50/yr)
• Rx???

Adapted from Bristow, MR Management of Heart
Failure, Heart Disease A Textbook of
Cardiovascular Medicine, 6th edition, ed.
Braunwald et al.
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Normal Physiology
Little W Heart Fail Rev 2000
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CHF Physiology
Little W Heart Fail Rev 2000
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Classic Observations (systolic dysfunction)

• Measures of systolic function correlate poorly
  with functional capacity

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

Lapu-Bula AJC 1999
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Hemodynamic Implications of Heart Failure
90
75
Pressure (mmHg)
60
VENTRICLE
LAP EDP
ATRIUM
45
28 36
30
16 20
15
8 12
0
120

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

Volume (ml)
80
40
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Impact of abnormal filling
?Left Atrial Pressure
Higher LA pressure
?Pulmonary Congestion
?Shortness of breath with activity
High LV pressure
?Disability and Hospitalizations
? Death
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Molecular mechanisms of heart failure

• General Concepts
• Regulated
• Voltage gated channels
• Neurohormone (SNS, RAS, ET-1, Aldo, etc.)
• Receptor mediated
• Reduntant
• Neurons, Cardiomyocytes, blood vessels,
  fibroblasts
• Relentless

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Molecular Mechanism of Heart 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

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Markers for Advanced CHF (EFlt35)

• Rapidly Assessable
• Clinical Scenario
• Inotrop/pressor dependance (50 1-3 mos)
• Acute myocardial Infarction (501-3 week)
• Demographic
• Etiology (infiltrativegtischemicgtnon-ischemicgtparip
  artum)
• Age (gt68)
• Symptoms
• NYHA (PND)
• Syncope
• Signs
• Chronic S3
• JVP

• Easily Available
• 12 lead ECG
• A-Fib QRS (gt120ms)
• Cardiopulmonary Testing
• VO2 max lt 14 ml/kg/min
• Blood Work
• Na (lt130)
• BUN/Cr (gt40 / gt2.3)
• Hgb (lt11 men, lt10 women)
• Cholesterol (lt150)
• BNP or nt-BNP
• 2 D Echo with Doppler
• LVEF (lt25) Depressed RV function
• LVEDD (gt6cm)
• Restrictive Mitral Inflow Pattern (Doppler)

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Assigning prognosis does not have to be painful

• Heart Failure Models
• ADHERE cart model
• Inpatient (Bungt43, SBPlt115, Crgt2.7)
• Fonarow JAMA 2005
• HF Risk Scoring System
• Inpatient (Multivariable)
• 30 day and 1 year outcome
• Lee JAMA 2003
• Seattle Heart Failure Model
• Outpatient (Multivariable)
• SeattleHeartFailaureModel.org
• Heart failure Survival Score
• Outpatient (multivariable)
• Lund AJC 2005

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New Therapies for Heart Failure
Vasopeptidase Inhibitors
Direct Renin Inhibitors
Endothelin receptor blockers
Sympathetic Blockade
Cytokine Inhibition
Vasopressin (V2) receptor antagonist
Left Ventricular Assist Device
Statin therapy
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Case 1. Dying in front of you!
Acute MI and Cardiogenic Shock

• 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

• HR130 ABP88/60 Pox92
• Dopamine 20 Dobutamine 15
• HEENT cyanosis lips
• NECK elevated neck veins
• HEART regular tachycardiac with prominent S3 and
  soft holosystolic murmur
• LUNG rales
• ABD enlarged liver
• EXT cool with trace lower extremity edema
• BUN/Cr70/2.7 Hgb12.2
• Troponin I65 CK2200 MB260
• Lactic Acid 6 LFT1000s
• CXR Pulmonary Edema

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Differential Diagnosis of Shock 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

74 LV dysfunction
3 RV Infarction
2 Free Wall Rupture
1 VSD
11 Others PE HCM Takotsubo Sepsis
9 Mitral Regurgitation
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• NO mechanical complication of MI
• NO occult valvular heart disease
• NO intracardiac thrombus
• Regional wall motion c/w the anterior MI

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SHOCK Trial Mortality
P .11
P .04
P lt 0 .03
Hochman et al NEJM 1999341625-35
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SHOCK Trial
LONG-TERM SURVIVAL
1.0
Logrank p .024
0.8
0.6
ERV
PROPORTION ALIVE
0.4
0.2
IMS
0.0
30 days
0
1
2
3
4
5
6
YEARS FROM RANDOMIZATION
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Vasopressin antagonist Immune modulatory
therapy 2nd and 3rd generation VAD
Symptoms Medications Diet Exercise
Invasive Noninvasive Imaging Serologic Exercise
Metabolic
Novel Treatment
Education
Diagnostic
Financial
Congestive Heart Failure
Pharmacologic
Psycho Social
Device
Palliative
Revascularization
Surgical
Coronary Intervention Percutaneous Valve Internal
Cardiac Defibrillator Cardiac Resynchronization
Coronary Bypass Valvular Heart Artificial Cardiac
Support Ventricular Reconstruction
Heart Transplant
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Impella (Cardiac Recovery System)
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(No Transcript)
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• Acute LV decompression
• Increase in MAP
• Reduction in PAP

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Clinical 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 FiO235
• Removed IMPELLA at bedside
• Telemetry
• Ambulation and titration of heart failure therapy
• Comprehensive evaluation for cardiac
  transplantation
• D/C home on day 10

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HEART TRANSPLANTATION Kaplan-Meier Survival
(1/1982-6/2005)
HEART TRANSPLANTATION Kaplan-Meier Survival
(1/1982-6/2006)
N at risk at 22 years 70
ISHLT
2008


J Heart Lung Transplant 200827 937-983
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ADULT HEART RECIPIENTS Functional Status of
Surviving Recipients (Follow-ups 1995 - June
2006)
ISHLT
2008


Last updated based on data as of December 2006
J Heart Lung Transplant 200827 937-983
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Transplant Facts
2200 donors
Medically Eligible 50-75 k 125 k age gt 65
Transplant (2 k)
Attrition (0.5-1 k) Death Cancer
Listed (3-5 k)
Evaluated (15-10 k) Medical ? / Social Financial
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NUMBER OF HEART TRANSPLANTS REPORTED BY YEAR
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.
ISHLT
2008


J Heart Lung Transplant 200827 937-983
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Cardiac Assist Applications 21st Century

• General Indications for VAD Support
• Cardiogenic Shock
• Hypotension (ABPlt80 or pressors)
• Hypoperfusion (UOlt30cc /FiO2gt40 /AMS)
• Hemodynamics (CIlt2.2 /PWCPgt20)
• Refractory Heart Failure
• NYHA IV (gt30d)
• Inotrope dependance (30d)
• Pulmonary Hypertension (2nd to CHF)
• TPG gt 14 or PVR gt 5

HEMODYNAMIC ? ? ?
INVASIVE ? ? ?
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NEJM Aug 2007
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(No Transcript)
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SERCA2a in Heart Failure
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Restoration of SERCA 2A
Adenovirus Affinity for the heart Can replicate
Adeno-associated virus(AAV) Particles of the
viral shell Affinity for heart CANNOT replicate

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

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CUPID Trial (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 gt6 months
• Stable, optimized HF regimen for 30 days, except
  for diuretics

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Baseline Patient Characteristics
Characteristic MYDICAR Low N8 MYDICAR Mid N8 MYDICAR High N9 Placebo N14
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 4126 49 16
NT-proBNP (pg/mL) 1353 386 3310 3112 2141 1997 4072 3906
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6 Minute Walk TestFunctional Domain
9
3
3
6
12
3
6
3
6
9
9
6
9
12
12
12
39
40
Quality of Life MLWHFQ Symptomatic Domain
12
12
12
9
9
9
6
3
6
12
9
1
1
3
1
6
3
3
6
1
40
41
Peak VO2 Functional Domain
6
6
6
12
6
12
12
12
41
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Left Ventricular Ejection FractionRemodeling
Domain
1
9
6
3
3
12
1
1
6
3
6
3
6
1
12
9
9
9
12
12
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Cumulative Clinical Event RateAdjusted for
Competing Risk of Terminal Event (CV Death,
Transplant, LVAD)

P (N14)
L (N8) HR(CI)0.40 (0.13, 1.21), p 0.11
M (N8) HR(CI)0.44 (0.16, 1.24), p 0.12

H (N9) HR(CI)0.12 (0.03, 0.49), p 0.003
Biometrics 200056(2)554-62. Circulation 2009
119(7) 969-977.
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ACT program is a Group Effort

• ACT program
• Compassionate, individualized cutting edge
  cardiovascular care
• Local resource for advanced cardiac
• disease (transplants, pumps, research)
• Innovation and education

CMS approved?
12/06
9/06
2/11
4/07
04-05 4 transplant
4/09
CMS POC?
ACT-program
33 transplant (2 peds, 1 re-transplant) 11
transplants 2009, 10 in 2010 95 survival
(better than national avg.) 12 LVAD (1 removed, 3
transplant, 6 ongoing) 17 patients actively listed
CMS closure?