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Artwork by Aaron Jameson Cast of Characters Plan of Attack Importance Evaluate a Case Explain the Pathophysiology Develop the Armamentarium – Why they work – How to monitor Cover the important evidence for each group CHF and Super Heroes The Role of Rx Man Surgeon General’s Warning This lecture will require you to write some things down You could develop carpal tunnel syndrome You could develop an irreversible hand cramp You could retain something longer than 5 minutes A Fatal Choice You can have a cancer that: kills 40% of people in 5 years OR You can have your first episode of symptomatic CHF Did You Choose CHF? OOPS !! Epidemiology CHF Kills A LOT of People CHF Makes A LOT of People’s lives miserable CHF costs a WHOLE LOT of $ New York Heart Association Class Class Class Class I II III IV New Approach to the Classification of Heart Failure A B C D Stage High risk for developing heart failure (HF) Asymptomatic HF Patient Description Symptomatic HF Refractory end-stage HF Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113. Hypertension CAD Diabetes mellitus Family history of cardiomyopathy Previous MI LV systolic dysfunction Asymptomatic valvular disease Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional Class ACC/AHA HF Stage A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery 2113. disease) B Structural heart disease but without symptoms of heart failure C Structural heart disease with prior or current symptoms of heart failure D Refractory heart failure requiring specialized interventions Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113. NYHA Functional Class None I Asymptomatic II Symptomatic with moderate exertion III Symptomatic with minimal IV Symptomatic at rest exertion Penelope A 74 year old white female 5 feet tall 160 pounds S/P CVA Hx mild CHF , HTN and DM 2 Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles 1/2 way up on both sides CXR shows mild interstitial infiltrates BP: 150/80 2+ pitting edema Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles 1/2 way up on both sides CXR shows mild interstitial infiltrates BP: 150/80 2+ pitting edema NYHA class? Penelope Drugs: Insulin Dyazide daily Zestril 5 mg daily Penelope is tied to the railroad tracks You can save her from floods You can give her a pillow and make her more comfortable You can even delay the train But you can’t take her off the tracks. Circulation Review Preload Afterload High pressure Low pressure Famous Last Words Everything that can be invented has been invented.” --Charles H. Duell, Commissioner, U. S. Office of Patents, 1899. Systolic vs. Diastolic Dysfunction Normal Heart 120 ml Normal Heart EF EF70/120 70/120 58 58 % % 120 ml 70ml CO = 70ml /beat * 72/min=5040 ml/min Systolic Dysfunction 160 ml Systolic Dysfunction 160 ml EF EF40/160 70/120 25 58 % % 40ml CO = 40ml /beat * 72/min=2880 ml/min Diastolic Dysfunction 57 ml Diastolic Dysfunction EF EF 40/57 70/120 70% 58 % 57 ml 40ml CO 40ml / beat * 72/min =2880 ml/min Diastolic Heart Failure and Intravascular Congestion Describe Diastolic Dysfunction Other Neuroendocrine mediators Arginine Vasopressin (ADH) Stimulated by extreme low kidney perfusion, just like Aldosterone. Causes free water retention and hyponatremia Endothelin One of the absolute most potent vasoconstrictors. Endothelin antagonists in the works Atrial and B-type Natriuretic peptide Stimulated by stretch of the atria and the ventricles and cause sodium and water excretion. Sort like a counterregulatory hormone to aldosterone CHF: Compensation Cardiac Output Cardiac Output (Compensated) SNS Kidney Perfusion Preload Na+ & H2O retention Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output CHF: Compensation Cardiac Output Kidney Perfusion CHF: Compensation Cardiac Output Kidney Perfusion Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output Kidney Perfusion Na+ and H2O retention Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output Kidney Perfusion Preload Na+ and H2O retention Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output Cardiac Output (Compensated) Kidney Perfusion Preload Na+ and H2O retention Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output Cardiac Output (Compensated) Kidney Perfusion Preload Na+ and H2O retention Renin Angiotensin Aldosterone CHF: Compensation Cardiac Output Cardiac Output (Compensated) Preload Na+ and H2O retention SNS Kidney Perfusion Renin Angiotensin Aldosterone CHF: Warning: New Slide! Cardiac Output WHY? CHF: Warning: New Slide! Cardiac Output WHY? Systolic Dilated Cardiomyopathy CAD HTN CHF: Warning: New Slide! Cardiac Output WHY? Diastolic Hypertension CAD Hypertrophic Cardiomyopathy Systolic Dilated Cardiomyopathy CAD HTN God is Dead Another famous last quote Nieztsche 1885 Nieztsche is Dead God 2007 CHF: The Viscious Cycle Cardiac Output Kidney Perfusion Renin Angiotensin Aldosterone CHF: The Viscious Cycle Cardiac Output Vasoconstriction SNS Kidney Perfusion Renin Angiotensin Aldosterone CHF: The Viscious Cycle Cardiac Output Afterload Vasoconstriction SNS Kidney Perfusion Renin Angiotensin Aldosterone High Pressure Left Ventricle Arteries High Pressure: Vasoconstriction Left Ventricle Arteries CHF: The Viscious Cycle Cardiac Output Kidney Perfusion Renin Angiotensin Aldosterone CHF: The Vicious Cycle Cardiac Output Kidney Perfusion Na+ and H2O retention Renin Angiotensin Aldosterone CHF: Vicious Cycle Cardiac Output Preload and Pulmonary Edema Na+ and H2O retention Kidney Perfusion Renin Angiotensin Aldosterone CHF: Vicious Cycle Strain Cardiac Output Preload and Pulmonary Edema Na+ and H2O retention Kidney Perfusion Renin Angiotensin Aldosterone CHF: Symptoms Strain Cardiac Output Fluid Overload Preload and Pulmonary Edema Na+ and H2O retention Low Perfusion Kidney Perfusion Renin Angiotensin Aldosterone CHF Pharmacotherapy New Drugs Mechanism(s) Monitoring for Efficacy Monitoring for Adverse Effects Back to Penelope: Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles 1/2 way up on both sides CXR shows mild interstitial infiltrates BP: 150/80 2+ pitting edema This is a Job for... Water Boy Diuretics: Mechanism Sodium and Water Excretion Preload Necessary Poison Fluid Overload Pulmonary Edema Low perfusion Loss of Renal Function Fluid Overload Pulmonary Edema Low perfusion Loss of Renal Function Low perfusion Loss of Renal Function Fluid Overload Pulmonary Edema Diuretics: Efficacy ~1 Kg / day (short term) ~1000 mls net loss / day 700 mls insensible loss (output) Lung Sounds / CXR Decreased Edema Diuretics: Efficacy Example: Input: IV at 100ml/hour Output: 2700 ml in 24 hours Net: Don’t forget 700ml insensible + 300ml = 1000ml lost Diuretic Dosing Short Term: The Nike Rule Long Term: Be a Sissy. Diuretics: Loops Thiazides vs Loops torsemide vs furosemide Absorption, duration and Cost Other loops Potency vs efficacy Diuretics: Side Effects BUN / Cr Ratio Potassium Do Orthostatics !! Clinical Hydration Status Glucose Uric Acid Ca++ Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles 1/2 way up on both sides CXR shows mild interstitial infiltrates BP: BP 150/80 150/80 2+ pitting edema Which rule should we use? Nike or Sissy? Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles 1/2 way up on both sides CXR shows mild interstitial infiltrates BP: BP 150/80 150/80 2+ pitting edema What about the Zestril dose? ACE of Hearts Angiotensinogen Renin Angiotensin I COW HERE Angiotensinogen Renin Angiotensin I Angiotensin I Angiotensinogen Renin ACE Angiotensin II Angiotensin I Angiotensinogen Renin ACE Angiotensin II Na+ Retained Aldosterone K+ Lost Vasoconstriction Angiotensin I Angiotensinogen Renin ACE ACE I Angiotensin II Aldosterone Aldosterone K+ Retained Vasoconstriction Angiotensin I Angiotensinogen Renin ACE Kinins Kinins ACE I Angiotensin II Aldosterone Breakdown Vasoconstriction OK, So how does this benefit the fluid overloaded, under-perfused CHF patient insert preload diagram here Whew !!! I Can Breathe !! Low Pressure High Pressure: Afterload Left Ventricle Arteries High Pressure: Post Dilation Left Ventricle Arteries OK, So how does this benefit the fluid overloaded, under-perfused CHF patient Ace Inhibitors: Efficacy Breathing and fluid improved Exercise capacity improved Mental Status Improved B. P. Ace I: Adverse Effects BUN / Creatinine Potassium Hypotension (dizziness) Cough Angioedema ACE & Kidneys Ace Inhibitors:Warning Signs Impaired Renal Perfusion Diuretic CHF – Especially w/ Hyponatremia Ascites Ace Inhibitors : Dosing CHF vs HTN Caution: Hyponatremia Ace Inhibitors : Drug Intx Potassium Sparing Diuretics NSAIDS What is the intx with ACE Inhibitors and NSAIDS? V-HeFT I Enalapril vs. Placebo Class II & III Mortality – 34.3 vs 25.6 @ 2 years NNT – 53.6 vs 49.7 @ 4 years NNT (benefit diminishes w/ time) 11.5 25.6 CONSENSUS I Class IV Mortality at one year 52% vs 36% NNT 6 !!! Average dose 18.4 mg /day SOLVD-Treatment Class II & III Mortality at 4 years 39.7 % vs 35.2 % NNT 22 Mean daily dose of enalapril= 16.6 mg Penelope : Increase Zestril to 10 mg daily Because : Ace Inhibitors Save Lives Penelope : Episode 2 One month later… Develops an intractable cough Your questions? Your recommendation? Angiotensin I Angiotensinogen Renin Kinins Chymase Angiotensin II Breakdown Na+ Aldosterone Aldosterone K+ Retained Vasoconstriction Vasoconstriction AT3 AT4 AT2 Feedback Fetal effects Many others Angiotensin II II Angiotensin AT1 Aldosterone AT1 Vasoconstriction ARBs Similar to ACE inhibitors but also many differences Highly variable half lives Highly variable AT1 receptor affinity RESOLVD Candesartan vs. candesartan +enalapril vs. enalapril alone Class II – IV Terminated early due to candesartan groups doing worse. Difficult to interpret due to unusually low mortality and morbidity in enalapril group RESOLVD Because the study wasn’t powered to show mortality, the authors conclusion didn’t mention higher mortality in the candesartan groups! “Candesartan was as effective, safe, and tolerable as enalapril” “The Combination… was more beneficial for preventing left ventricular remodeling” Elite II Losartan 50mg / d vs. placebo Class III & IV Mortality: No difference ValHeft Valsartan Class II-IV Some benefit added to ACE OR to a Beta Blocker INCREASED MORTALITY When added to both !! CHARM (as in snake?) Alternative Added Preserved Overall – In ACE intolerant patients – Improved outcomes moderately – Improved outcomes minimally – Beta blocker would be better (opinion) – No statistical improvement – Statistical improvement Penelope Cozaar 50mg daily Continue Lasix etc. Penelope: Episode 3 Four months later… There has been trouble getting weights in the nursing home Another episode of SOB, 02 saturation 85% Weight 178 pounds BUN / Cr: 40 / 1.4 Penelope Treatment now? Right Again! Treatment: Lasix 80 mg BID What will that do to the BUN / Cr? Vitamin L Penelope: Two weeks later… Wt. 175 pounds Breathing improved but not good No CXR or ausculation BUN / Cr 50 / 1.5 What do you recommend ? My Momma Always Said: Patience is a Virtue Penelope Weight decreases to 158 over the next 2 months. Breathing greatly improved in the last month. BP: 110 / 70 Guesses on the BUN and Creat?? 90 / 2.0 Penelope: Episode 5 What next?? Decline in mental status. Sleeping 18 to 20 hours per day. Confused, wild delusions. What do you do now? The Hemodynamic Duo!! Nitrates / Hydralazine: Mechanisms Hemodynamic effects similar to Ace Inhibitors Nitrates decrease Preload Hydralazine decreases afterload Nitrates / Hydralazine PERHAPS a little: – less mortality benefit – more symptom benefit Less renal impairment risk Nitrates / Hydralazine: Efficacy Similar to Ace Inhibitors Better in African Americans? Nitrates / Hydralazine: Adverse Effects P.O.S. (Pill overload syndrome) Headache Nausea Hypotension Nitrates / Hydralazine: BIDIL® Could we use digoxin? Digimon Digoxin: Mechanisms Increased force of contraction Decreased hospitalizations No mortality benefit or harm Digoxin: Efficacy Urine Output Mental Status Exercise capacity improved Digoxin: Adverse Effects Potassium Mental Status Pulse / EKG Nausea / Vomiting Digoxin: Evidence The Dig Trial No difference in mortality 67.1% vs 64.3% hospitalization 1% vs 2 % hospitalized for suspected dig toxicity Digoxin Pharmacology? Clinical Effect? Meanwhile, Penelope is still on the Railroad Tracks Increase Cozaar BUN goes to 120 (oops) Decrease Cozaar Add Hydralazine and Nitrates Titrate up to 50 mg TID and 20 mg TID Penelope Result? Somnolence improves Delusions resolve BUN / Cr 80 / 1.8 Weight 158 BP: 100/60 Add a beta blocker? Sir Blocksalot Adrenergic Receptors in Normal vs Failing Left Ventricles 80 1 2 Receptor density (fmol/mg protein) 70 60 50 *P<.05 vs normal function 40 1 * 30 20 10 0 Mean + SD. Normal function (n=12) Cardiomyopathy (n=54) 1: 2 80%:20% 1: 2 65%:35% Adapted from Bristow M. J Am Coll Cardiol. 1993;22(4 Suppl A):61A–71A. Beta Blockers Improve Cardiac Function ?? Decreased Mortality Don’t Use Unless CHF is stable Beta Blockers Block Death Beta Blockers: MERIT-HF Metoprolol XL Mostly Class II & III Mortality over one year – 11% vs. 7.2% NNT 26 Dosing Beta Blockers:Carvedilol Trial Mostly Class II & III Mortality over 6 months – 3.2% vs. 7.8% NNT 21 hospitalization 14% vs 19% NNT 20 2% died or deteriorated during run in Which beta blockers are proven in CHF? Penelope She does well for 3 months Penelope died July 9, 1998 Penelope What do we know now that we didn’t know then? Spiro the Super Mouse CHF: Vicious Cycle Strain Cardiac Output Preload and Pulmonary Edema Na+ and H2O retention Kidney Perfusion Renin Angiotensin Aldosterone Aldosterone Aldosterone Sodium Retention Magnesium and Potassium Loss Sympathetic Activation Parasympathetic Inhibition Myocardial fibrosis Vascular Fibrosis Impairs arterial compliance RALES Spironolactone 25 mg / d vs. Placebo Class III & IV Mortality at 11 months (stopped early) 46% vs 35 % NNT: 9 Newbies Tezosentan endothelin receptor antagonist Who knows Levosimendan Calcium sensitizer on troponin C may increase force of contraction without increasing myocardial oxygen consumption. Nesiritide - Origin Stretch receptors in the Atria (ANP) and the Ventricles (BNP) Cause natriuresis and vasodilation Makes perfect sense Easy to Market Benefit?? Nesiritide This is also known as BNP and causes diuresis and vasodilation. Studies show it superior to placebo and equal to conventional therapy. If you don’t count mortality It costs about $1 million per dose, may be useful in highly specific cases Nesiritide – On the Other Hand BNP is a good test in diagnosing CHF <100 mcg/ml NOT CHF 101 to 999 NOT normal, but probably not CHF 1000 to 4000 CHF or related condition >4000 almost certainly CHF Seven Roles for Rx Man Sell them a scale Poke at their ankles Ensure labs (K+) Teach them to take their pulse NSAIDS Salt Police Cough Syrup patrol Clinical Signs and Sx of CHF Fluid Overload Shortness of Breath DOE Orthopnea / PND Pedal Edema CXR Clinical Signs and Sx of CHF Inadequate Perfusion Decreased Urine Output Increased BUN/Cr ratio Impaired Mental Status Cool, Clammy Skin Fatigue Recap: AHA/ACC Heart Failure Guidelines J Heart Lung Transplant Feb, 2005 Class I Recommendations – Diuretics for patients with fluid retention (A) – ACEI for all patients unless contraindicated (A) – Beta-blockers for all stable patients unless contraindicated (A) – Digitalis for treatment of symptoms (A) – Withdrawal of drugs that may adverse the status of heart failure patients (NSAIDs, most antiarrhythmics, most calcium channel blockers) (B) Recap: AHA/ACC Heart Failure Guidelines J Heart Lung Transplant Feb, 2005 Class I Recommendations (cont’d) • Exercise training • Implantable defibrillator if history of arrest, V Fib or bad V. Tach • Resynchronization therapy where indicated Recap: AHA/ACC Heart Failure Guidelines J Heart Lung Transplant Feb, 2005 Class IIa Recommendations (conflicting evidence/opinion but evidence favors) – Spironolactone for recent Class IV symptoms (B) – ARBs for patients not tolerating ACEI due to cough or angioedema (A) – Combination of hydralazine + nitrate in patients not an ACEI candidate due to hypotension/renal insufficiency (B) • Digitalis for treatment of symptoms (A) • Use of a CCB with negative inotropic effect may be harmful low ejection fraction (A) Class IIb Recommendations (conflicting evidence/opinion with less evidence to support) – Addition of an ARB to an ACEI (B) – Addition of nitrate +/- hydralazine to patients on ACEI (B) Recap: AHA/ACC Heart Failure Guidelines J Heart Lung Transplant Feb, 2002 Class III Recommendations (no data or harmful) – Intermittent IV positive inotropes (C) – ARB instead of an ACEI in patients never tried on or could tolerate an ACEI (B) – Use of an ARB before beta-blocker in a patient on an ACEI – Use of a CCB to treat CHF (B) – Routine use of nutritional supplements (CoQ10, etc.) or hormones (thyroid, growth) (C) Case #1 KK is a 71 year old male with known history of CHF admitted for hypotension and shortness of breath Case #1 Albuterol Ipratropium Phenytoin Neurontin Levothyroxine Protonix Lasix 20mg /day Amiodarone Verapamil 240mg/day Labs BNP 995 Troponin <0.3 LDL <100 Na 137 K 4.1 Cl 101 TCO2 29 BUN 33 Creat 1.3 x 3 Weight on admission= 84 kg BP 102/63 Heart Rate 58 TSH 2.2 #1 Monitoring Parameter? 84 Kg on admission Day 1: 83.5 Day 2: 83.3 Day 3: 83.1 Case #1