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Advanced Heart Failure Concepts and Options

Advanced Heart Failure Concepts 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. Goals. Define advanced heart failure

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Advanced Heart Failure Concepts and Options

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  1. 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

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

  3. Myocardial Insult Myocardial Dysfunction Reduced System Perfusion Hemodynamic Defense Systems Inflammation Altered Gene Expression Apoptosis Remodeling Pathophysiology(Downhill Cascade) Cardiomyopathy Ischemic Valvular Hypertension Tachycardiac Familial/Genetic Idiopathic Toxins Metabolic Infectious Systemic diseases Allergic Peri-partum Neuromuscular

  4. A B C D High risk of developing HF Structural heart disease without symptoms Structural heart disease with symptoms, either prior or current Refractory symptoms requiring specialized interventions I II–III IV Asymptomatic Mild and Moderate HF Severe HF ACC/AHA StagingNYHA Classification ACC/AHAHF Stage NYHAFunctionalClass Hunt SA et al. Circulation 2005;112:1825

  5. 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 < 6years • DM 2 fold increase Stage A

  6. 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

  7. 100 10 Survival Rate Hospitalizations 75 Annual Survival Rate 50 1 Hospitalizations / year 25 .1 0 II III IV I Deceased NYHA CLASS unNatural History of Heart Failure Advanced Heart Failure N=200,000 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.

  8. Normal Physiology Little W Heart Fail Rev 2000

  9. CHF Physiology Little W Heart Fail Rev 2000

  10. 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

  11. Hemodynamic Implications of Heart Failure 90 75 Pressure (mmHg) 60 VENTRICLE LAP EDP ATRIUM 45 28 36 30 1620 15 8 12 0 120 • Important Concepts • Delay relaxation • Higher Filling Pressure • Diastole ~ Systole • Sinus rhythm Volume (ml) 80 40

  12. Impact of abnormal filling Left Atrial Pressure Higher LA pressure Pulmonary Congestion Shortness of breath with activity High LV pressure Disability and Hospitalizations Death

  13. 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

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

  15. Rapidly Assessable Clinical Scenario Inotrop/pressor dependance (~50% 1-3 mos) Acute myocardial Infarction (~50%1-3 week) Demographic Etiology (infiltrative>ischemic>non-ischemic>paripartum) Age (>68) Symptoms NYHA (PND) Syncope Signs Chronic S3 JVP Easily Available 12 lead ECG A-Fib QRS (>120ms) Cardiopulmonary Testing VO2 max < 14 ml/kg/min Blood Work Na (<130) BUN/Cr (>40 / >2.3) Hgb (<11 men, <10 women) Cholesterol (<150) BNP or nt-BNP 2 D Echo with Doppler LVEF (<25%) Depressed RV function LVEDD (>6cm) Restrictive Mitral Inflow Pattern (Doppler) Pulmonary Hypertension (Doppler) Markers for Advanced CHF (EF<35%)

  16. Assigning prognosis does not have to be painful… Heart Failure Models • ADHERE cart model • Inpatient (Bun>43, SBP<115, Cr>2.7) • 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

  17. 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

  18. 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 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/Cr=70/2.7 Hgb=12.2 Troponin I=65 CK=2200 MB=260 Lactic Acid= 6 LFT=1000’s CXR: Pulmonary Edema Case 1. Dying in front of you! Acute MI and Cardiogenic Shock

  19. 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

  20. NO mechanical complication of MI • NO occult valvular heart disease • NO intracardiac thrombus • Regional wall motion c/w the anterior MI

  21. SHOCK Trial Mortality P = .11 P = .04 P < 0 .03 Hochman et al NEJM 1999;341:625-35

  22. ~ 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

  23. 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 Coronary Intervention Percutaneous Valve Internal Cardiac Defibrillator Cardiac Resynchronization Surgical Coronary Bypass Valvular Heart Artificial Cardiac Support Ventricular Reconstruction Heart Transplant

  24. Pump Blood outlet Blood inlet Impella(Cardiac Recovery System)

  25. Acute LV decompression • Increase in MAP • Reduction in PAP

  26. 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 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

  27. HEART TRANSPLANTATIONKaplan-Meier Survival(1/1982-6/2005) HEART TRANSPLANTATIONKaplan-Meier Survival(1/1982-6/2006) N at risk at 22 years: 70 ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983

  28. ADULT HEART RECIPIENTSFunctional Status of Surviving Recipients(Follow-ups: 1995 - June 2006) ISHLT 2008 J Heart Lung Transplant 2008;27: 937-983 Last updated based on data as of December 2006

  29. Transplant Facts 2200 donors Medically Eligible ~50-75 k ~125 k age > 65 Transplant (2 k) Attrition (0.5-1 k) Death Cancer Listed (3-5 k) Evaluated (15-10 k) Medical Ψ / Social Financial

  30. 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 2008;27: 937-983

  31. Cardiac Assist Applications 21st Century • 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 Failure • NYHA IV (>30d) • Inotrope dependance (30d) • Pulmonary Hypertension (2nd to CHF) • TPG > 14 or PVR > 5 HEMODYNAMIC    INVASIVE   

  32. NEJM Aug 2007

  33. SERCA2a in Heart Failure 35

  34. Restoration of SERCA 2A AAV vector SERCA 2A AAV 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

  35. 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 CUPID Trial (first in humans) 37

  36. Baseline Patient Characteristics 38

  37. 6 Minute Walk TestFunctional Domain Improvement 9 12 3 6 3 3 6 3 6 9 9 6 9 12 12 12 39

  38. Quality of Life: MLWHFQ Symptomatic Domain Improvement 12 12 12 9 9 9 6 3 6 12 9 1 1 3 6 1 3 6 3 1 40

  39. Peak VO2Functional Domain 6 6 Improvement 6 12 6 12 12 12 41

  40. Left Ventricular Ejection FractionRemodeling Domain Improvement 1 9 6 3 3 1 1 12 6 3 6 3 6 1 12 9 9 9 12 12 42

  41. Cumulative Clinical Event RateAdjusted for Competing Risk of Terminal Event (CV Death, Transplant, LVAD) * P (N=14) L (N=8) HR(CI)=0.40 (0.13, 1.21), p = 0.11 M (N=8) HR(CI)=0.44 (0.16, 1.24), p = 0.12 * H (N=9) HR(CI)=0.12 (0.03, 0.49), p = 0.003 Biometrics 2000;56(2):554-62. Circulation 2009; 119(7): 969-977.

  42. 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?

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