A History of Dropsy: From Edema to Transplant Timothy A. Denton, M.D. Attending Cardiologist High Desert Heart Institute Victorville, CA

Outline History Physiopathology Evaluation Medical therapy Other therapies

Independent program at UCLA associated with a significant increase in drug utilization in patients with CAD at the time of hospital discharge and during long term follow-up. Increase in the number of these patients reaching the NCEP target of LDL-C < 100 during follow-up. Demonstrates that a protocol for initiation of comprehensive risk factor management prior to hospital discharge can be considerably more effective than usual care for modification of coronary risk in AMI patients.

Independent program at UCLA associated with a significant increase in drug utilization in patients with CAD at the time of hospital discharge and during long term follow-up. Increase in the number of these patients reaching the NCEP target of LDL-C < 100 during follow-up. Demonstrates that a protocol for initiation of comprehensive risk factor management prior to hospital discharge can be considerably more effective than usual care for modification of coronary risk in AMI patients.

The Time Line BC AD 500 500 1000 1500 2000 dropsy Socrates 500 1000 1500 2000 dropsy Socrates (470-399 BC) Hippocrates (460-377 BC) Galen (180) Harvey (1616) Independent program at UCLA associated with a significant increase in drug utilization in patients with CAD at the time of hospital discharge and during long term follow-up. Increase in the number of these patients reaching the NCEP target of LDL-C < 100 during follow-up. Demonstrates that a protocol for initiation of comprehensive risk factor management prior to hospital discharge can be considerably more effective than usual care for modification of coronary risk in AMI patients. Laënnec (1700)

Heart Failure ~400 B.C. – SOB, edema, rales First described by Hippocrates Ear directly on chest How to drain effusions caused by excess of “phlegm” (cold humor) Moving from brain to chest

Dropsy A morbid condition characterized by the accumulation of watery fluid in the serous cavities or the connective tissue of the body. Hydrops, Idropsie First use in 1290 – “Some fullen in-to be dropesie” OED

“A Treatise on the Diseases of the Chest” Dropsy A woman, 50 years of age, had been affected for twelve years with all the symptoms of disease of the heart, in a very high degree, viz. strong and frequent palpitations, habitual dyspnoea, breathlessness on using the least exercise, sudden startings from sleep, almost constant edema of the lower extremities, and lividity of the cheeks, nose and lips. Laennec “A Treatise on the Diseases of the Chest” 1821

Dropsy Treatment of the Weak and probably Dilated Heart… During this treatment, and especially when free diuresis is established, it is necessary that wine or some other diffusible stimulus should be carefully administered, and the system supported by a proper aliment… Stokes “Diseases of the Heart and the Aorta” 1853

William Harvey 1578-1657 1639: De Motu Cordis

Groucho on the Circulation “We then come to the bloodstream. The blood rushes from the head, down to the feet… gets a look at those feet, and rushes back to the head again.” from “Horse Feathers” 1932 (Julius Henry Marx)

William Withering Born: 1741 - 1799 1775: Obtained first “tea” from gypsy From German: Fingerhut (finger hat or thimble) Mid-1500’s: Latinized to “digitalis” – finger (digitus) Digitalis purpurea – a common variety 1775 – William Withering

Heart Failure - Etiology Treat the underlying cause “Pure” LV Heart failure _________________ Systolic dysfuntion Diastolic dysfunction Ischemic LV Heart failure _________________ Prior MI Ongoing ischemia Large vessel disease Small vessel disease Mechanical Heart failure _________________ AS MR Pericardium Endocardium Myocardium Treat the underlying cause

Definition of Heart Failure Clinical syndrome resulting from a structural or functional disorder that impairs the heart from filling or ejecting blood Clinical syndrome includes Symptoms (dyspnea, fatigue) and Signs (fluid retention) Heart failure ≠ congestive heart failure 2005 ACC/AHA HF Guidelines

AHA CHF Guidelines Stage A – Risk for CHF Stage B – Heart disease, no symptoms Stage C – Heart disease, symptoms Stage D – Heart disease, refractory symptoms ACC/AHA CHF Guidelines – 2005 www.americanheart.org

Heart Failure Diagnosis Clinical SOB, DOE Orthopnea Edema CxR BNP Echo (or equivalent) Is there another cause of symptoms?

New York Heart Association Classes I – symptoms similar to normal patients II – symptoms with ordinary exertion III – symptoms at less-than-ordinary exertion IV – symptoms at rest 2005 ACC/AHA HF Guidelines

Heart Failure Diagnosis What is the EF? Echo MUGA Low Normal High

Heart Failure Diagnosis Is there ischemia? Yes No PTCA CABG EECP

Heart Failure Normal Heart Enlarged Heart

Heart Failure Dilated Normal Hypertrophic

Heart Failure Systole = contraction (inotropy) Diastole = relaxation (lusitropy)

What is diastolic dysfunction? Heart Failure What is diastolic dysfunction?

Heart Failure Dilated Normal Hypertrophic

Systolic vs Diastolic Failure Heart Failure Systolic vs Diastolic Failure Systolic Diastolic *No valvular or mechanical causes Kitzman,et al., Am J Cardiol, 2001;87:413-419

LV Systolic Heart Failure It’s a hemodynamic disease Preload Contractility Afterload It’s a neurohormonal disease Other factors affecting therapy

It’s a hemodynamic disease ! Heart Failure It’s a hemodynamic disease ! Afterload Preload Contractility

Preload Inpatient and Outpatient Therapy IV diuretics Lasix (20,40,80,160,320) Lasix drip Combination (Lasix / zaroxolyn) Naturetic peptic (nesiritide) Dialysis / Ultrafiltration Nitrates

Control of Volume Status Patient Responsibilities Weight yourself every day Write it down 2,000 mg of Sodium per day 2,000 cc of fluids per day If your weight goes up by “X”, change your diuretics

0.5 – 1.0 qd BID 20 – 40 qd BID 10 – 20 qd 25-50 qd BID Diuretics Drug Dosing Max Duration Loop Bumetanide Furosemide Torsemide Ethacrynic acid 0.5 – 1.0 qd BID 20 – 40 qd BID 10 – 20 qd 25-50 qd BID 10 mg 600 mg 200 mg 200 mg 4-6 h 6-8 h 12-16 h 6-7 h Thiazide Chlorothiazide Chlorthalidone HCTZ Indapamide Metolazone 250 500 qd BID 12.5 – 25 qd 25 qd BID 1.5 qd 2.5 qd 1000 mg 100 mg 200 mg 5 mg 20 mg 6 – 12 h 24-72 h 6-12 h 36 h 12-24 h Potassium sparing Amiloride Spironolactone Triamterene 5 qd 12.5 – 25 qd 50 – 75 qd BID 20 mg 50 mg 200 mg 24 h 2-3 days 7-9 h

Preload Southey’s Tubes Used into the late 1950’s

Ultrafiltration CHF Solutions, Inc.

Dialysis / Ultrafiltration

It’s a hemodynamic disease ! Heart Failure It’s a hemodynamic disease ! Afterload Preload Contractility

Contractility Digoxin Dobutamine Milrinone Epinephrine Dopamine LVAD Heart transplantation

Ambulatory Infusion Pumps Dobutamine Milrinone

LV Assist Devices Bridge to Transplant Destination therapy

Heart Transplantation Ejection fraction Cardiopulmonary exercise testing – VO2 < 14 (???) Other risk factors “Risk Score” Referral to transplant team Local “work-up” ISHLT Guidelines – 2006 Heart and Lung Transplantation 2006;25:1024

HEART TRANSPLANTATION Kaplan-Meier Survival (1/1982-6/2004) 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 21 22 Years Survival (%) . Half-life = 9.9 years Conditional Half-life = 13 years N=69,536 N followed at longest time point: 28,463 Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients. Therefore, 95% confidence limits are provided about the survival rate estimate; the survival rate shown is the best estimate but the true rate will most likely fall within these limits. The half-life is the estimated time point at which 50% of all of the recipients have died. The conditional half-life is the estimated time point at which 50% of the recipients who survive to at least 1 year have died. Because the decline in survival is greatest during the first year following transplantation, the conditional survival provides a more realistic expectation of survival time for recipients who survive the early post-transplant period. ISHLT 2006 J Heart Lung Transplant 2006;25:869-79

It’s a hemodynamic disease ! Heart Failure It’s a hemodynamic disease ! Afterload Preload Contractility

Afterload Lowered afterload improves hemodynamics in MR (Ann Int Med 1975;83:312) Vasodilator therapy in heart failure (Ann Int Med 1975;83:421) Hydralazine / Minoxidil in refractory CHF (Ann Int Med 1976;85:467) Lowered afterload improves hemodynamics in AI (Circulation 1976;53:879) Lowered afterload improves hemodynamics in CHF (Ann Rev Physiology 1977;39:277 1987 - CONSENSUS I

Afterload Nitroprusside ACE inhibitors ARB’s Hydralazine / nitrates

Heart Failure SOLVD NEJM 1991;325:293-302

ACE / ARB Drug Dosing Max ACE Captopril Enalapril Fosinopril Lisinopril Perindopril Quinapril Ramipril Trandolapril 6.25 tid 2.5 bid 5-10 qd 2.5-5 qd 2 qd 5 bid 1.25-2.5 qd 1 qd 50 tid 10-20 bid 40 qd 20-40 qd 8-16 qd 20 bid 10 qd 4 qd ARB Candesartan Losartan Valsartan 4-8 qd 25-50 qd 20-40 bid 32 qd 50-100 qd 160 bid

It’s a neurohormonal disease ! Heart Failure It’s a neurohormonal disease ! 1963 – Plasma norepinephrine elevated in CHF (NEJM 1963;269:653) 1970’s digoxin reduces plasma renin and norepinephrine levels

Neurohormonal Beta blocker Spironolactone / eplerenone ACE inhibitors ARB’s

Randomised Aldactone Evaluation Study (RALES) Davies, M K et al. BMJ 2000;320:428-431

Is there a BEST Beta Blocker? Carvedilol Bisoprolol Metroprolol succinate

Is there a BEST Beta Blocker? 17% Reduction Carvedilol or Metoprolol European Trial (COMET) Lancet 2003; 362:7

Beta Blockers Drug Dosing Max Bisoprolol Carvedilol Metoprolol succinate (CR/XL) 1.25 qd 3.125 bid 12.5 – 25 qd 10 qd 25 bid 200 qd

CHF with or without Dysrhythmia ICD Antiarrhythmics Beta blockers

ICD’s and Survival MADIT II Survival N Engl J Med. 2002;346:877-883

Dysynchrony Bi-V pacing

Heart Failure Clinic Central location with ICU nurses Drug infusion diuretics dobutamine nesiritide (Fusion II) Education “CAREFUL” follow-up

Medical Therapy Preload + Lasix + Ultrafiltration + Nitrates Contractility Digoxin Transplant evaluation / LVAD Afterload ACE / ARB Hydralazine Neurohormonal Beta blocker Spironolactone / eplerinone Dysrhythmia ICD + Antiarrhythmics Dysynchrony BiV Pacing

Therapy of Heart Failure Systolic Dysfunction Diastolic Dysfunction Normal Range 0 10 20 30 40 50 60 70 80 90 100 Ejection Fraction

Therapy of Heart Failure ICD Heart transplant BiV pacer Aggressive MedRx Systolic Dysfunction Diastolic Dysfunction Normal Range 0 10 20 30 40 50 60 70 80 90 100 Ejection Fraction

Therapy of Heart Failure Medical therapy N Y H A C L S II BiV ICD III ICD and Transplant evaluation IV 0 10 20 30 40 50 60 70 80 90 100 Ejection Fraction

The END