Block 2 Exam Review.docx

I.

Pathophysiology of Heart Failure a. Frank Starling Mechanism i. “The more I get, the more I pump.” ii. Fiber stretch depends on preload. iii. Amount of stretch determines force. iv. Normal: Inc Preload -> Inc SV v. Failure: Inc Preload -> Dec SV b. Types of Heart Failure i. HFpEF – Preserved Ejection Fraction 1. Diastolic HF 2. LVEF ≥50% ii. HFrEF – Reduced Ejection Fraction 1. Systolic HF 2. LVEF ≤40% iii. HFpEF, borderline: 41-49% iv. HFpEF, improved: > 40% c. Compensation i. Neurohormones 1. Angiotensin II – ATII a. Vasoconstriction b. NE & Aldosterone Release c. Ventricular Hypertrophy (VH) d. Cardiac Remodeling (CaR) e. Increases Preload f. Increases Afterload 2. Norepinephrine – NE a. Vasoconstriction b. Tachycardia c. Contractility d. Down regulates beta receptors e. VH f. CaR g. Pro-arrythmic

h. Increases Afterload 3. Aldosterone a. Na & H2O Retention i. Increased fluid volume b. Production of cardiac fibrosis c. Pro-arrythmic d. Increases Preload 4. Brain Natriuretic Peptide – BNP a. Elevated in ventricular injury (MI) b. Natriuresis (Na) c. Diuresis d. Vasodilation e. Lowers Preload 5. Endothelin-1 – ET-1 a. Vasoconstrictor b. Decreases renal blood flow c. VH d. Pro-arrythmic e. Positive inotrope (force) 6. Neprilysin a. Neutral endopeptidase b. Degrades BNP ii. Mechanisms 1. Tachycardia & Increased Contractility a. NE – SNS Activation i. Increased intracellular Ca -> Increased Contractility ii. Increased HR -> Decreased Lusitropy (ventricular relaxation) -> Increased O2 demand iii. Vasocontriction can preserve blood supply 2. Fluid Retention & Increased Preload a. Kidneys detect low perfusion -> Renin Released

b. Renin Cleaves angiotensinogen to AT1 c. AT1 + ACE -> ATII i. NE & Aldosterone Release 3. Vasoconstriction & Increased Afterload a. Reduced CO -> Blood Redistribution b. Vasoconstriction -> Decreased EF i. Decreased EF -> Increased Afterload c. NE, ATII, ET-1 4. Ventricular Hypertrophy & Cardiac Remodeling a. CaR -> VH i. Myocardium walls thicken ii. Ellipse -> Sphere b. Less volume to fill with blood c. NE, ATII, ET-1, Vasopressin, cytokines iii. Symptoms 1. Dyspnea (esp. on exertion) a. Pulmonary congestion 2. Peripheral edema a. Increased Preload -> Less Venous Return 3. Fatigue/weakness/lethargy 4. Orthopnea (pillow orthopnea) 5. SOB 6. Paroxysmal nocturnal dyspnea 7. Exercise intolerance 8. Tachypnea 9. Cough 10.Nocturia/Polyuria 11.Bloating 12.Mental Status Changes iv. Signs 1. Rales or crackles at lower lung base a. SOB, cough, dyspnea b. Pulmonary congestion

2. Tachycardia a. NE -> palpitations 3. Hypotension (postural) a. Low CO -> Poor compensation for position change 4. JVD – Jugular Venous Distention a. Fluid Overload 5. Lab Parameters a. BNP or NT-proBNP i. BNP > 100 pg/mL or NT-proBNP > 300 pg/mL 1. Consider LV dysfunction ii. Non-specific can be elevated in other conditions b. CBC for O2 carrying capacity c. CMP i. Na 1. Volume Overload -> Hyponatremia ii. K goal > 4 mEq/L d. Renal & hepatic function i. Reduced Renal Perfusion -> Increased Creatinine e. Baseline i. Urinalysis, lipid, Glu/A1C, thyroid v. Staging/Classification 1. ACCF/AHA – Evaluates HF Progression a. A-D i. High Risk -> Severe HF Symptoms 2. NYHA – Classifies symptoms a. I-IV i. No Physical Limitation -> Unable to Carry Out Any Physical Activity

II.

Cardiac Stimulants & Inotropes: Pharmacology a. Positive Inotropes: Stronger Force of Contraction i. Digitalis glycoside 1. Digoxin: Na/K/ATPase Inhibitor a. Steroid nucleus, lactone ring, three sugar residues linked by glycosidic bonds b. T1/2 = 36 h i. Renal excretion of parent c. Positive Inotrope, Negative Chronotrope d. Negative dromotrope i. Decrease K -> Decrease Conduction Velocity e. Increases intracellular Ca & Decreases K f. Adverse Effects i. Shortens ST duration 1. Premature ventricular contractions ii. Anorexia, NV iii. Halos around objects, yellow/green color aberrations, blurred vision iv. Quinidine reduces clearance g. Digoxin immune Fab: Digoxin Antidote i. Sheep IG ii. Adrenoreceptor agonist 1. Dobutamine: beta-1 (in heart) and beta-2 (in vascular smooth muscle) agonist a. Catecholamine related to dopamine b. T1/2 = 2 min c. Used for cardiac stim during surgery, acute heart failure, cardio shock d. Reduces vascular resistance -> Reduced Afterload -> Increased CO e. Less tachycardia than other beta agonists f. Increase cAMP by stimulating adenylate cyclase

i. Increase cAMP -> Activate PKA -> Increase iCa

III.

iii. PDE-3 Inhibitor 1. Milrinone a. PDE-3 inactivates cAMP -> AMP b. Increase cAMP -> Activate PKA -> Increase i-Ca i. Heart: inotropic ii. Vascular smooth muscle: vasodilation c. Infants & Children d. Inamrinone was prototype Heart Failure Therapeutics a. Types of HF i. HFpEF – HF with Preserved Ejection Fraction 1. LVEF ≥50% 2. “diastolic HF” 3. Relaxation and filling impaired ii. HFrEF – HF with Reduced Ejection Fraction 1. LCEF ≤40% 2. “systolic HF” 3. Ventricle too weak -> poor perfusion b. FACES – Symptom Mnemonic i. Fatigue ii. Activity Limitation iii. Chest Congestion iv. Edema or ankle swelling v. Shortness of Breath c. Outcomes/Goals i. Reduce morbidity 1. Reduce/relieve symptoms 2. Improve QOL ii. Prevent or minimize hospitalizations iii. Slow progression iv. Reduce Mortality

1. Prolong survival d. Agents i. ACEi 1. 2. 3. 4. 5.

All HFrEF patients unless CI Reduces ATII -> Reduces aldosterone -> Reduces Preload Lowers BP -> Reduces Afterload Reduces CaR Increase bradykinin -> vasodilation -> decreases afterload + cough 6. Adverse Effects a. Hyperkalemia b. Angioedema c. Cough 7. Contraindications a. Pregnancy b. SCr > 3.0 mg/dL c. History of AEs 8. Monitor a. BUN, SCr, K, BP 9. Outcomes a. Survival b. Hospitalizations c. Progression d. Reinfarction 10. Target Doses a. Captopril 50 mg TID b. Enalapril 10-20 mg BID c. Lisinopril 20-40 mg QD d. Ramipril 10 mg QD ii. ARB 1. All HFrEF patients unless CI 2. Can be used after ACE escape or ACE cough 3. AEs & CI same as ACEi

4. Monitor a. BUN, SCr, K, BP 5. Outcomes a. Survival b. Hospitalization c. Progression 6. Target Dose a. Valsartan 160 mg BID b. Candeartan 32 mg QD c. Losartan 50-150 mg QD iii. Beta Blocker 1. All HFrEF patients unless CI 2. Beta-1 antagonism -> Reduce HR and BP a. Decreases load on heart b. Increase filling -> increase CO c. Blocks effects of NE d. Short term: negative inotrope during titration e. Long term: improved contractility >3 months 3. Adverse Events a. Fatigue b. Depression c. Bradycardia (D-D) d. Hypotension (D-D) 4. Contraindications a. Unstable/decompensated HF b. HR < 60 bpm c. SBP < 80 mm Hg d. Sick sinus syndrome e. 2nd or 3rd degree AV block 5. Monitor a. BP, HR, signs of congestion 6. Outcomes a. Survival

b. Hospitalization c. progression 7. Target Dose a. Carvedilol IR 25 mg BID < 85 kg, 50 mg BID > 85 kg with food b. Carvedilol CR 80 mg QD with food c. Metoprolol succinate 200 mg QD i. Tartrate not shown to improve outcomes d. Bisoprolol 10 mg QD iv. MRA 1. HFrEF with symptoms a. NYHA II-IV with EF ≤35% b. Acute MI with EF ≤40% with symptoms or diabetes (eplerenone preferred) 2. Adverse Effects a. Gynecomastia – spironolactone b. Hyperkalemia c. Hyponatremia 3. Contraindications a. ACE + ARB concurrently with MRA b. K < 5.0 mEq/L c. SCr ≤2.5 in men or 2.0 in women d. Spironolactone i. Anuria ii. HyperK iii. CrCl < 10 mL/min e. Eplerenone i. CrCl < 30 mL/min ii. CrCl 50 mL/min with increased SCr iii. T2DM with microalbuminuria 4. Monitor a. BUN, SCr, K 5. Outcomes

a. Survival b. Progression c. Symptoms d. hospitalizations 6. Target Dose a. Spironolactone 50 mg QD i. Renal dose b. Eplerenone 50 mg QD v. Hydralazine/nitrate 1. Black, HFrEF, symptoms despite optimized doses a. Also symptomatic HFrEF who cannot tolerate ACE/ARB 2. Nitrate -> venodilation -> reduces Preload 3. Hydralazine -> arterial dilation -> Reduces Afterload 4. Adverse Effects a. Hypotension b. Headache (nitrate effect) 5. Monitor a. BP, HR 6. Outcomes a. Mortality b. Hospitalizations c. QOL d. Progression 7. Target Doses a. Bidil – hydralazine 37.5/ISDN 20 mg two tablets TID b. Hydralazine 300 mg daily total, divided c. ISDN 120 mg daily total, divided vi. Ivabradine 1. HFrEF, symptomatic at optimized beta blocker dose a. EF ≤ 35% b. HR > 70 bpm

c. Optimized beta blocker dose d. Persistent symptoms 2. Reduces HR 3. Maintains contractility 4. Adverse Effects a. Bradycardia b. Hypertension c. Afib d. Luminous visual phenomena 5. Contraindications a. Pregnancy b. BP < 90/50 mm Hg c. HR < 60 bpm d. AV/SA block e. CYP3A4 inhibitors f. Liver impairment 6. Outcomes a. Hospitalization (SHIFT trial) 7. Target Dose a. Ivabradine (Corlanor) 7.5 mg BID vii. ARNI – Sacubitril/valsartan 1. HFrEF, symptomatic, can tolerate ACEi/ARB 2. Sacubitril – Neprilysin inhibitor a. Increases BNP -> vasodilation, natriuresis, diuresis b. Decreases sympathetic tone, aldosterone, fibrosis, VH, BP 3. Adverse Effects a. Same as ARB/ACE 4. Contraindications a. Pregnancy b. Breast Feeding c. Aliskiren + diabetes + ARNI d. Lithium

5. Monitor a. BUN, SCr, electrolytes, BP 6. Outcomes a. Hospitalizations (PARADIGM-HF Trial) b. CV death (PARADIGM-HF Trial) 7. Target Dose a. Sacubitril/Valsartan 97/102 mg BID b. ACE/ARB naïve, ≥75 YO, low BP, liver impairment start at lowest dose 24/26 mg viii. Digoxin 1. HFrEF, hospitalizations despite optimized doses 2. Positive Inotrope, Negative Chronotrope 3. Negative dromotrope a. Decrease K -> Decrease Conduction Velocity 4. Increases intracellular Ca & Decreases K 5. Adverse Effects a. Shortens ST duration i. Premature ventricular contractions b. Anorexia, NV c. Halos around objects, yellow/green color aberrations, blurred vision d. Quinidine reduces clearance 6. Monitor a. BUN, SCr, K, HR, symptoms 7. Outcomes a. Hospitalizations b. Symptoms c. Exercise tolerance d. Does NOT improve survival 8. Target Dose a. Digoxin 125-250 mcg QD b. Elderly, renal, lean body mass, require lower dose c. Narrow TPI 0.5 to 0.9 ng/mL in blood

ix. Diuretics – Improve symptoms only 1. HFrEF with congestive symptoms 2. Decrease volume -> Decrease Preload 3. Mildly decrease BP, increase HR 4. Monitor a. BUN, SCr, electrolytes, BP i. K > 4.0 mEq/L 5. Outcomes a. Symptoms i. QOL, exercise tolerance b. Does NOT improve survival 6. Target Dose a. Furosemide 20-40-600 mg in divided doses i. IV:PO = 1:2 b. Bumetanide 0.5-10 mg QD or in divided doses c. Torsemide 10-20-200 mg QD d. Metolazone 2.5-10 mg 30 minutes before loop diuretic i. For loop diuretic resistance ii. Inhibits Na reabsorption e. Weight loss 0.5-1 kg daily e. Non-Pharm Treatment i. Na < 2 g/day ii. Fluids < 2 K/day if fluid overloaded iii. Manage comorbidities iv. Weight reduction if overweight v. Physical Activity as tolerated

IV.

Acute Decompensated Heart Failure – ADHF a. Diuretics if PCWP ≥ 18 i. Improves mortality if given within 1 hour of admission 1. REALITY-AHF Trial

ii. Dose 1. Double TOTAL home oral dose a. Furosemide 40 mg po = 40 mg IV i. Furosemide IV:PO = 1:2 b. Bumetanide 1 mg po = 2 mg IV 2. Naïve = Furosemide 40 mg IV 3. IV bolus or continuous infusion 4. Ceiling for Bolus Dose a. Furosemide 40-80 mg IV i. Max infusion rate 4 mg/min ii. Ototoxicity b. Torsemide 20-40 mg c. Bumetanide 1-2 mg d. Ethacrynic Acid 30 mg i. Used for sulfa allergy e. Dose more frequently or use continuous infusion when at ceiling 5. Diuretic Resistance – DOSE Trial a. Decreased kidney perfusion -> reduced drug delivery b. Use higher doses, continuous infusion, second diuretic, Na/fluid restriction, dopamine (renal dose), ultrafiltration dialysis b. Vasodilators if SBP ≥90 mm Hg i. Warm & Wet, Cold & Wet with MAP >50 and SBP >90 ii. Venous dilators 1. Reduce Preload, PCWP, edema iii. Arterial Dilators 1. Reduce Afterload, SVR 2. Increase SV, CO iv. Nitroglycerin 1. Increase cGMP -> vasodilation

a. Venous mostly, arterial at high dose >100 mcg/min b. Dose i. 5 mcg/min IV up to 200 mcg/min ii. T1/2 = 1-4 minutes v. Nesiritide 1. Recombinant BNP a. Increase cGMP -> vasodilation -> Reduce Preload, PCWP, SVR i. Veins and arteries vi. Sodium Nitroprusside 1. NO -> Increase cGMP -> vasodilation a. Veins and arteries 2. Cold & Wet c. Inotropes if PCWP ≥ 15 d. Fluids if PCWP < 15 e. Ventricular Assist Device – VAD i. LVAD – Left VAD 1. LV or LA -> Aorta ii. RVAD – Right VAD 1. RV or RA -> pulmonary artery iii. BiVAD – Left and Right VAD iv. Requires anticoagulation

V.

Dyslipidemia Pathophysiology a. Lipids i. Cholesterol 1. Cell membrane formation 2. Bile Acid precursor 3. Steroid, hormone, Vit D synthesis 4. Sources a. In vivo synthesis – 80% in liver and intestines

i. Mevalonate production is rate limiting step 1. Catalyzed by HMG-CoA reductase – statin target b. Extraction from lipoproteins c. Diet has modest impact ii. Triglycerides 1. Glycerol + fatty acids 2. Derived from food 3. Stored energy in adipose iii. Phospholipids 1. Lipid transport 2. Oxidation of arterial wall lipoproteins b. Lipoproteins Lipoprotein Content Metabolism Function chylomicron 98-99% TG LPL into FFA Transfers TG Bile Acids and remnants and cholesterol gut -> liver VLDL & IDL Mostly TG VLDL + LPL -> LDL Precursor 15-20% of IDL -> LDL serum cholesterol apo B LDL 60-70% of Liver removes VLDL transport serum 70% TG and cholesterol cholesterol PCSK9 inhibition IDL transports -> increase LDL cholesterol metabolism Atherosclerosis by attaching to arterial walls by oxidation

HDL

20-30% of serum cholesterol

Small, dense LDL is worse Removes excess cholesterol CETP allows exchange of TG and cholesterol LCAT allows cholesterol collection

c. Risk Factors i. Non-modifiable 1. Male ≥45 YO, Female ≥ 55 YO 2. Family history 3. Gender 4. Socioeconomic status ii. Modifiable 1. Tobacco 2. Stress 3. Diet 4. Physical Activity 5. Obesity 6. HTN 7. Lipid disorders 8. diabetes d. Pathogenesis i. Injury to endothelium -> inflammation -> fibrous cap -> plaque rupture ii. LDL oxidation triggers inflammation and macrophage activation 1. Foam Cells – lipid filled macrophages 2. Foam cells accumulate to form fatty streak

iii. Fibrous cap – Protects core of lipids, macrophages, collagen 1. Can rupture to release material 2. Forms clot to block vessel e. Secondary Causes i. TC > 200 mg/dL 1. Hypothyroid 2. Liver disease 3. Corticosteroids 4. Protease inhibitors 5. Thiazide diuretics 6. Beta blockers ii. LDL ≥ 190 mg/dL 1. Usually primary cause (FH, apo B-100 defect) iii. TG ≥ 150 mg/dL 1. TG >500 mg/dL -> pancreatitis 2. T2DM 3. Obesity 4. Tobacco 5. Alcohol 6. Physical inactivity 7. High carbohydrate intake 8. Corticosteroids 9. Beta blockers 10.Thiazide diuretics 11. Bile acid sequestrant 12. Atypical antipsychotics iv. HDL < 40 mg/dL 1. Obesity 2. Physical inactivity 3. Tobacco 4. T2DM 5. Beta blockers 6. Anabolic steroids

7. Progestational agents f. Lab Values i. TC <200 mg/dL ii. Non-HDL <130 mg/dL iii. LDL <100 mg/dL iv. HDL >40 in men, >50 in women v. TG <150 mg/dL

VI.

Dyslipidemia Therapeutics a. Lifestyle i. Diet 1. vegetables, fruits, whole grains, legumes, non-tropical vegetable oils (more dense, saturated fats due to warmer climate) 2. Protein: low fat dairy, poultry without skin, fish, nuts 3. Limit red meats, sweet ii. Physical Activity 1. 3-4 sessions/week of aerobic activity a. 40 minutes/session b. Moderate-vigorous intensity iii. Weight loss 1. 10 lb weight loss increases HDL by 1.6 mg/dL iv. Alcohol and smoking cessation b. Lipid Lowering Agents i. Statins – HMG-CoA Reductase Inhibitor 1. Adverse Effects a. Myopathy in large muscles b. LFT Elevations c. Cognitive impairment 2. Contraindications a. CYP3A4 inhibitors i. Simvastatin, lovastatin highest risk

ii. Pravastatin not metabolized by CYP450 b. Gemfibrozil (increase ADR) c. Pregnancy d. Lactation 3. Monitoring a. LFT – Baseline and if abnormal b. Lipid panel c. CPK - myopathy 4. Counseling 5. Place in Therapy a. Outcomes i. Major coronary events ii. Mortality iii. Pleiotropic effects 1. Vasodilation, plaque stability 2. Decrease inflammation, lipoprotein oxidation, coagulation b. Dose i. High – LDL-C Reduction >50% 1. Rosuvastatin 20-40 mg QD 2. Atorvastatin 40-80 mg QD ii. Moderate – LDL-C Reduction 30-50% iii. Low – LDL-C Reduction <30% iv. Duration 1. Long: atorvastatin, rosuvastatin, pitavastatin 2. Short: lovastatin, pravastatin, simvastatin, Fluvastatin a. Dose PM ii. Ezetemibe 1. Adverse Effects a. Myopathy (+ statins) b. Diarrhea

c. URI d. Cough 2. Contraindications a. Moderate-severe liver impairment 3. Monitoring: see statins 4. Outcomes a. CV Outcomes - IMPROVE-IT Trial iii. PCSK9 Inhibitors 1. Agents a. Evolocumab (Repatha) b. Alirocumab (Praluent) c. Approved for FH and clinical ASCVD requiring LDLC reduction 2. Adverse Effects 3. Contraindications 4. Monitoring a. Lipid panel b. LFTs 5. Counseling 6. Place in Therapy a. Outcomes i. CV Outcomes 1. ODYSSEY, FOURIER Trials iv. Bile Acid Sequestrant (BAS) 1. Agents a. Colesevelam b. Colestipol c. Cholestyramine 2. Adverse Effects a. Increase TG b. GI Upset 3. Contraindications a. TG > 400 mg/dL

b. Chronic constipation 4. Monitoring 5. Counseling a. Other drugs 1 hour before or 4 hours after BAS i. Decreased absorption v. Fibric Acid 1. Agents a. Fenofibrate i. ER did not meet primary or secondary CV outcomes ii. Renal dosing iii. Once daily with or without food b. Gemfibrozil i. Myopathy ii. Twice daily with meals 2. Monitor a. Lipid, LFT, CPK vi. Omega-3 Fatty Acids 1. Agents a. Omega-3 acid ethyl esters b. Icosapent – EPA Only i. CV Benefit – ASCEND Trial 2. Adverse Effects a. Fish burps i. Store in freezer ii. Avoid hot liquids iii. Take with meals iv. Use EC b. Diarrhea vii. Niacin (nicotinic acid) 1. Adverse Effects a. Flushing i. Take with food

ii. ASA 325 Pre-medicate iii. Avoid hot liquids, alcohol b. Pruritis c. Myopathy i. LFT Elevations d. Hyperuricemia e. Hyperglycemia i. Caution: DM 2. Monitoring a. Lipid b. LFT c. CPK d. Glu/A1C e. Uric Acid if History of Gout viii. Summary 1. LDL-C Reduction a. Statins b. Ezetemibe c. PCSK9 Inhibitors d. BAS 2. TG Reduction a. Fibrates b. Omega-3 c. Niacin c. Guidelines i. ASCVD 10 Year Risk 1. % Risk of CHD Death, MI, Stroke 2. Baseline lipid panel off statin therapy ii. Patient Groups 1. Secondary Prevention of Clinical ASCVD 2. Primary Hypercholesterolemia, LDL ≥190 mg/dL 3. Diabetes in Adults 4. Risk Based Need for Primary Prevention