Heart Failure.pdf

Heart Failure Overview ○ “Pup failure” Affects nearly 5 million people in the US and is the primary cause for >40,000 deaths/year and a contributing factor in 220,000 deaths/year Overall mortality rate is 8x greater for pa...

Heart Failure Overview ○ “Pup failure” Affects nearly 5 million people in the US and is the primary cause for >40,000 deaths/year and a contributing factor in 220,000 deaths/year Overall mortality rate is 8x greater for patients with HF 5 year mortality rate approaches 50% Pathophysiology ○ HF is the end stage of several cardiovascular disorders that ultimately impair the ability of ventricles to fill with blood or eject blood ○ Ischemic heart disease is the m/cc of HF ○ Other causes include HTN, valvular disorder, viral and congenital CM, arrhythmias, and constrictive pericarditis. ○ Less common causes include severe anemia, thiamine deficiency, and some anti-neoplastic drugs (e.g., doxorubicin) Remodeling ○ Cardiac dilation ○ Ventricular wall thinning ○ Interstitial fibrosis ○ Wall stiffness ○ Results from activation of neuroendocrine systems in response of myocardial ischemia, excessive stretching of muscle fibers, and other pathologic stimuli ○ Includes renin-angiotensin-aldosterone axis, sympathetic NS, inflammatory cytokines, and local mediators like endothelin ○ Activates biochemical pathways that induce myocyte hypertrophy, apoptosis, collagen production, fibrosis Hallmark features ○ Decreased SV, decreased CO Determined by measuring ventricular end-diastolic pressure (preload) Systolic vs. diastolic ○ Systolic dysfunction can result from decreased cardiac contractility secondary dilated or ischemic myocardium ○ Diastolic dysfunction can result from lower compliance (increased stiffness) or ventricular tissue secondary LVH or fibrosis LV failure ○ LV doesn’t adequately pump blood forward → increases pressure in pulmonary circulation → fluid forced into lung interstitium which causes congestion and edema ○ Pulmonary edema decreases diffusion of oxygen and CO2 between alveoli and pulmonary capillaries ○ Results in hypoxemia → dyspnea, exertion orthopnea, PND RV failure ○ RV doesn’t adequately pup blood forward → peripheral vein congestion → pedal (ambulatory) or sacral edema (bed-ridden) ○ Leads to a +HJR  Drug classes used ○ + inotropic drugs (increased contractility) and vasodilators (decreased afterload) can be used to increase CO ○ Vasodilators also decrease venous pressure, circulatory congestion, and edema ○ Diuretics mobilize edematous fluid + decrease plasma volume and decreases circulatory congestion ○ Angiotensin inhibitors favorably influence cardiac remodeling, increase survival + inotropic drugs ○ Digoxin (Digox) → A digitalis glycoside ○ Dobutamine → B-adrenoceptor agonist ○ Milrinone → a phosphodiesterase inhibitor ○ Inotropic agents → produce change in muscle fiber contractility ○ + inotropic agents increase cardiac contractility by increasing calcium levels in cardiac myocytes Properties ○ While a large number of digitalis glycosides have been isolated from the leaves of digitalis plants ( and toad secretions), digoxin is the only digitalis glycoside still used today ○ Adequately absorbed from the gut ○ Long half life → 36 hours ○ Renal excretion ○ Narrow TI Effects ○ + inotropic effect Increases SV, increases CO ○ - chronotropic effect ○ - dromotropic effect Electrophy effects ○ Digoxin causes increase parasympathetic (vagal) tone which decreases HR and decreases AV node conduction ○ Also causes decreases sympathetic tone which decreases sympathetic vasoconstriction Interactions ○ Antacids and cholestyramine can decrease absorption and decrease therapeutic effects, so separate by at least 24 hours ○ Diltiazem, quinidine, and verapamil decreases digoxin clearance and increase serum digoxin levels ○ Loop and thiazide diuretics can cause hypokalemia and precipitate digitalis toxicity Indications ○ Digoxin and other cardiac glycosides have been used for centuries, benefits uncertain, toxicity is substantial Improvement in HF patient probably from inotropic effect and attenuation of neuroendocrine consequences of HF Generally not used to diagnose diastolic disease because contractility is not impaired  Antedote ○ Severe digoxin toxicity is treated with digoxin immune fab (digibind) Made from immunoglobulin fragments taken from sheep immunized with digoxin derivatives Administered IV, can rapidly reverse digoxin toxicity by binding to digoxin Dobutamine ○ Dobutamine is a B- adrenoceptor agonist that selectively stimulates cardiac contractility Causes less tachycardia than other B-agonists Also activates B2-adrenoreceptors in vascular smooth muscle → decreases vascular resistance, decreases afterload which augments CO Neprilysin inhibitor ○ Neprilysin is an endogenous endopeptidase enzyme that degrades peptides such as bradykinin and natriuretic peptides Inhibition raises the levels of these peptides, leading to decrease cardiac remodeling, decreased vasoconstriction and decreased sodium retention Will degrade angiotensin II to inactive products, so much be combined with an inhibitor of RAAS Sacubitril/valsartan ○ Sacubitril/valsartan (entresto) is a 1:1 combo of a neprilysin inhibitor and ARB Sacubitril is a pro-drug that is rapidly converted to active metabolite Combo is the first new drug in >10 years to decrease death rates in patients with systolic HF In a large phase 3 trial, combo decreases CV death and hospitalizations from HF by 20% more than enalapril alone Fewer adverse events in clinical trials Hydralazine and nitrates ○ Isosorbide dinitrate relaxes venous muscle ○ Hydralazine relaxes arterial muscle ○ Combo of both drugs reduces preload and afterload Decreases venous pressure and edema and increases CO Aldosterone antagonists ○ Spironolactone and eplerenone both complete with aldosterone for mineralocorticoid receptor in renal tubules and other tissues Act on kidney to increase Na excretion, decrease K excretion, and exert moderate diuretic effect Spironolactone ○ Spironolactone has unfavorable endocrine side effects (gynecomastia and impotence in men) ○ Eplerenone produces fewer endo side effects but is much more expensive Loop diuretics ○ Loop diuretics (furosemide) have greater natriuretic activity than other diuretics Preferred for reducing plasma volume in HF Use carefully, may cause dehydration, hyponatremia, hypokalemia (increases risk of digoxin toxicity)  ○ Thiazide diuretics Thiazide diuretics (HCTZ) can be used when lesser degree of diuresis is required Can be combined with loop diuretics Standard therapy ○ Drug therapy for HF caused by systolic dysfunction usually includes a diuretic, an angiotensin inhibitor (possibly in combo with sacubitril) and a BB ○ An aldosterone antagonist (spironolactone or eplerenone) can be added when indicated ○ Some patient benefit from addition of digoxin and/or hydrazine and nitrate ○ Anticoagulant and anti-PLT drugs may be needed by some patients