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69 Cards in this Set

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  • Back
What are the clinical hallmarks of heart failure caused by systolic dysfxn?
"fills fine, but can't pump"

- decrease in EF and SV in association w/ venous congestion (peripheral and pulmonary edema)

- causes symptoms of fatigue, tachycardia, hypotension, and the decreased ability to exercise
Explain how "forward" failure of systolic dysfxn eventually becomes "backward" failure.
1. b/c venous return and cardiac filling greatly exceeds the SV, blood backs up in the pulmonary circuit

2. increased hydrostatic pressure in the lungs causes net secretion of fluid resulting in dyspnea and pulmonary edema

3. Eventually, right heart failure develops

4. Finally, decreased SV and increased ECF volume cause peripheral edema

5. The "backward" failure causes dyspnea, pulmonary edema, right heart failure, and peripheral edema
How do the kidneys exascerbate heart failure?
Renal hypoperfusion results in salt/water retention and increased ECF volume and thus exascerbates both the forward and backward failure
Describe the old etiology about heart failure.
1. cardiac volume and pressure overload were considered to be the causative factors in systolic dysfxn

2. This volume-pressure overload caused increased ventricular wall tension leading to LVH
Give a general idea of the new etiology regarding heart failure.
Neurohumoral activation in response to systolic heart failure causes volume overload (old idea) and cardiac remodeling (new idea)

-- activation of the RAAS in systolic dysfxn results in further volume overload and remodeling of the CV system
What is cardiac remodeling, and what factors play a role?
Remodeling includes hypertrophy of the myocytes as well as increased deposition of fibrillar collagen in the ECM (fibrosis which stiffens ventricular wall)

AngII, a product of the RAAS system, stimulates:
- mitogenesis
- secondary hyperaldosteronism

Aldo stimulates:
- deposition of fibrillar collagen in the ECM of the heart, causing the ventricular muscle to stiffen

Chronic increase in sympathetic tone to the myocardium:
-- exerts a "toxic" effect on contractility
-- exact mech unknown

Increase cardiac preload and TPR produce ventricular dilation and increased wall stress
-- "pressure overload" stims collagen synthesis in the ECM
What is the effect of
1. increased preload
2. increased dp/dt
3. increased afterload
on SV in heart failure associated w/ systolic dysfxn?
1. SV decreases
2. stroke volume increases
3. SV largely decreases

The failing heart cannot maintain SV in the face of an increase in afterload b/c the Starling mechanism no longer applies
What are our strategies in treatment of systolic heart failure?
1. Improve symptoms (may or may not reverse CV remodeling and increase longevity)

2. Reverse CV remodeling and increase longevity
How can we attempt to improve symptoms of systolic heart failure?
1. Decrease preload w/ diuretic drugs or nitrate vasodilators

2. Decrease afterload w/ an arteriolar vasodilator

3. Decrease both preload and afterload w/ "balanced" vasodilation of arterioles and venules

4. Increase ventricular contractility via a direct positive ionotropic action
How can we reverse CV remodeling and increase longevity in a patient w/ systolic heart failure?
Block ATII, aldosterone and cardiac adrenergic (B1, B2, a1) receptors
What drug can decrease congestive symptoms, but does not increase SV, or reverse cardiac remodeling?
LOOP DIURETICS -- furosemide

NITRATE VASODILATORS -- isosorbide mono/dinitrate
Clinical effects of furosemide on systolic HF?
1. saluresis decreases ECF volume, so venous return (preload) and thus left ventricular filling pressure are decreased

2. decreased preload alleviates the congestive symptoms of "backward" failure

3. Pt is still on the same Starling curve, so SV may not increase

4. The "loop" diuretic drugs relieve congestive symptoms, but they do NOT improve survival!
How do we use furosemide when treating systolic HF?
1. must dose 2-3xday because of short duration of action and the compensatory increase in salt and water reabsorption which occurs after each treatment

2. Use the smallest dose possible to prevent congestive symptoms

3. Should be given w/ a K-sparing diuretic to prevent hypokalemia

**In future, spironolactone may become the preferred K-sparing diuretic to give w/ loop diuretic
How do we use isosorbide mono- and dinitrate to treat systolic HF?
It can be given p.o. to selectively dilate venules and thus decrease cardiac preload
What drugs can reverse cardiac remodeling and increase longevity in patients w/ systolic HF?

1. ACEi
- captopril
- enalapril
- lisinopril

2. ARBs
- losartan
- valsartan

3. Combined nitrate venodilator and arterial vasodilator
- isosorbide dinitrate
- hydralazine
What are the hemodynamic effects of balanced vasodilation on patients w/ systolic HF?
1. decreased TPR and pulmonary vascular resistance
2. decreased venous return via increased venous capacitance
3. increased SV and EF
4. increased SV results in decreases in LV-EDV, LV-EDP, ventricular wall stress, and pulmonary congestion
5. Both RBF and GFR are increased, but RBF increases proportionally more. This decreases the FF which results in a diuresis
6. MAP = no change or slight decrease
7. HR = no change or slight decrease

This moves the HF patient to a new Starling curve --> increased EF and SV fixes forward and backward failure
Why should we treat all HF pts with an ACEi?
1. prevent/reverse cardiac remodeling caused by ATII

2. improve fxnal status and quality of life

3. decrease hospitalization and mortality

** used larger doses than those used to treat HTN
When treating a patient w/ and ACEi, what do we want to monitor?
Plasma K and serum creatinine, especially if renal fxn is poor
-- poor kidney fxn tends to cause hyperK which is not good for the electro-status of the heart
Treatment w/ an ACEi after MI...
decreases incidence of systolic HF and death
How do ARBs help patients w/ systolic HF?
These drugs cause almost the same hemodynamic changes as those caused by ACEi, but they have not yet been approved for trtmt of HF
-- substitue for an ACEi if the patient develops a dry cough while taking the ACEi
Explain how balanced venodilation can be achieved by a nitrate venodilator and an arterial venodilator?
Combined therapy w/ nitroglycerine (venous) and hydralazine (arterial) increases SV, EF, and exercise tolerance and decreases RV and LV filling pressure, LV-EDV, LV-EDP, ventricular wall stress, and pulmonary congestion

- trtmt w/ isosorbide dinitrate (venous) + hydralazine decreases mortality, espec in black pts when added to standard therapy for heart failure

-- NO protects against cardiac remodeling (nitroglycerine is donor)
-- hydralazine has antioxidant properties that protect the NO from degradation and prevents development of nitrate tolerance

**prolonged trtmt w/ hydralazine can cause SLE-like syndrome
If your patient has a poor response to ACEi/diuretics, you might try...?
nitroglycerine (or other NO donor) + hydralazine

ESPECIALLY if they are black, better response
Which drugs can decrease backward failure and reverse cardiac remodeling? How do they do this?
Aldo receptor antagonists


They prevent and/or reverse cardiac remodeling caused by Aldo by decreasing the turnover of collagen in the ECM of the ventricles
Explain how spironolactone and eplerenone improve survival.
1. trtmt w/ spironolactone has been shown to improve the clinical status and to decrease symptoms, hospitalization and death (-30%) in patients w/ NYHA class III and IV heart failure

2. Results in large clinical trial with eplerenone showed that the drug signif reduced morbidity/mortality when added to "optimal medical therapy"
Spironolactone and eplerenone can increase the incidence of...?

- incidence increases as dose increases

- May cause severe hyperK in pts w/ poor renal fxn, especially if also taking an ACEi other than captopril
Why does taking Captopril decrease the incidence of hyperK when taken w/ Spironolactone and Eplerenone?
- captopril has half life of only 2h, whereas other ACEi have half-lives of 12+h

- patients w/ HF have increased sympathetic activity and renal perfusion, so renin secretion is elevated

- Intrarenally-generated ATII maintains GFR by preferential constriction of the renal efferent arteriole

- ACEi block this compensatory effect of ATII and thus can impair renal fxn in some pts

- in these pts, captopril is preferred b/c if prevents ATII formation for only part of the day

**small doses spironolactone are effective in blocking Aldo receptors and usually do not pose a risk for hyperK as long as serum creatinine is below 2.5mg/dl
Why is eplerenone preferred over spironolactone?
It is NOT a partial agonist at androgen and progesterone receptors, and thus does not cause gynecomastia or breast pain
Name drugs which reverse cardiac remodeling leading to an increase in EF and SV

- carvedilol
- metoprolol
- bisoprolol
B-blocker MOA regarding reversal of cardiac remodeling?
prevent remodeling of the myocardium caused by excessive sympathetic stimulation

- decrease sudden death by preventing ventricular dysrhythmias

- antianginal effect
Carvedilol use?
-- Blocks B1, B2, and a1-adrenoceptors (myocardium also has B2 and a1 receptors)

-- Approved for use in pts w. NYHAII and III HF and EF less than 35%

-- used to treat pts who are already taking an ACEi and diuretic drugs (poss digoxin)

-- decreases death from LV failure by 50%

-- beneficial effects are dose-related; use largest dose which can be tolerated!!
Time course of response to Carvedilol in pts w/ systolic dysfxn?
1. pt should be w/in 2-3lbs of "dry weight" and therapy is started w/ small doses which are slowly increased = "START LOW, GO SLOW"
-- dry out by getting rid of excess fluid via diuretic so B-block won't cause pulmonary edema

2. Cardiac B-blocker will cause EF to fall and pt will feel much worse for several months

3. After several months, EF will increase above pre-treatment value and patient will feel better and have increased ability to exercise b/c of reversal of heart remodeling
Drug which increases EF and SV and has marginal effect to increase longevity, but does NOT reverse cardiac remodeling?
Normal apparatus for Ca release, reuptake and use in a myocyte?
-- during systole, the intracellular free Ca conc rapidly increases and then rapidly decreases
-- depol of myocardium via increased Na conductance opens voltage-sensitive L-type Ca channels, and Ca in the T-tubules flows down its conc gradient into the myocyte
-- Ca stimulates excitation-contraction coupling btwn actin and myosin
-- In addition, some Ca entering the myocyte via L-type channels "triggers" release of additional Ca from the SR
-- end of systole, free intracellular Ca conc falls b/c Ca sequestered inside the SR and extruded from myocyte by Na/Ca exchanger
-- Na/Cs exchange driven by extracellular Na gradient, which is in turn maintained by Na/K ATPase in the cell mbrn
Digoxin MOA?
***direct positive ionotropic effect = GOOD EFFECT

-- DIGOXIN INHIBITS the Na/K ATPase by binding to a phosphorylated aspartate of the enzyme
-- Inhib of the Na/K ATPase increases intracellular Na
-- Decrease in Na gradient slows extrusion of Ca via exchanger
-- Ca not extruded via exchanger is sequestered in the SR, so total amt of Ca in the SR increases
-- thus, the "trigger" Ca releases a greater amt of Ca from the SR, resulting in INCREASE in myocardial contractility
Indirect electrical effects of digoxin?

1. acts w/in CNS to enhance efferent vagal activity and reduce sympathetic activity

2. Increase vagal activity
-- slows HR
-- decreases number of signals passing thorugh the AV node by decreasing conduction velocity and increasing ERP

3. Decreased sympathetic activity:
-- decreases automaticity
-- increases ERP in the myocardium
Direct electrical effects of digoxin?

1. Inhibition of Na/K ATPase decreases the phase 4 mbrn potential difference
-- cell is less electroneg and thus closer to the threshold voltage

2. Inhibition of the Na/K ATPase produces spontaneous depol (automaticity) in phase 4, leading to PACs and PVCs
-- increased intracellular Ca increases probability of phase 4 automaticity

3. increased intracellular Ca also increases possibility of having delayed after-depol which trigger dysrhythmias
Therapeutic uses digoxin?

- used to treat HF assoc w/ systolic dysfxn when a patient being treated w/ and ACEi and diuretic drugs is still symptomatic

- used to treat HF in pts w/ A.fib b/c the increase in vagal tone controls ventricular HR in presence of a high atrial rate, and digoxin enhances ventricular contractility
digoxin pharmacokinetics?
-- Therapeutic window is miniscule (1-2ng/ml)

-- half-life of 24-48h

-- excreted unchanged and clearance proportional to GFR

-- stored in skeletal muscle, so dose should be based on lean body mass
digoxin drug-drug interactions?
1. Cholestyramine, colestipol and antacids decrease GI absorption

2. Spironolactone decreases renal clearance and interferes w/ radioimmunoassay of digoxin
Digoxin adverse cardio effects?
1. sinus bradycardia from increased vagal tone

2. AV block via increased vagal tone (toxic plasma conc also directly suppress AV conduction)

3. PACs

4. PVCs and late after-depol
DIGOXIN: Factors which may precipitate adverse electrical effects in the heart
1. hypokalemia
-- binding of digoxin to ATPase is enhanced when aspartate on cytoplasmic side of enzyme is phosphorylated, and extracellular K facilitates the dephosphorylation of this aspartate
-- low EC potassium favors the phosphorylated state of the enzyme and thus increases the binding of digoxin to the ATPase

2. Hypercalcemia
-- increased plasma Ca causes digoxin to "overload" the intracellular storage sites

3. hypomagnesemia
Other adverse effects of digoxin?
abnormalities of yellow-green vision
Pharmacodynamic drug-drug interactions?
1. drugs which cause hypokalemia (furosemide, HCTZ) potentiate the adverse cardiac effects of digoxin

2. CCAs verapamil and diltiazem and B-blockers enhance the bradycardia and decrease in AV conduction
Explain diastolic dysfxn.

-- abnormal mechanical fxn during diastole; inability of LV to relax correctly

-- HTN, CAD, and aortic stenosis are major diseases which cause diastolic dysfxn

-- can occur in absence or presence of systolic dysfxn or the symptoms of heart failure

-- pts w/ systolic dysfxn always have some sort of diastolic dysfxn

-- E and A waves representing transmitral inflow velocity are normal
How can diastolic dysfxn be prevented?
1. treat HTN or reverse HT heart disease (LVH)

2. treat ischemia caused by CAD w/ antilipemic drugs, antianginal drugs, or CABG

3. valve replacement in aortic stenosis
Therapy for diastolic dysfxn aimed at...?
Therapy aimed at increasing ability of left ventricle to relax correctly and fill w/ blood at normal filling pressure
How is diastolic dysfxn diagnosed?
Based on doppler echo
What are the clinical hallmarks of HF caused by diastolic dysfxn?
-- Pulmonary congestion (dyspnea)

-- Decreased exercise tolerance despite EF greater than 50%
How is diastolic relaxation impaired and how does that affect the heart?
-- both active and passive phases of diastolic relaxation are impaired by increased deposition of fibrillar collagen in the ECM of the heart
-- decreased LV compliance dictates that higher than normal pressure req'd to fill ventricle w/ normal systolic vol
-- At end of diastole, LVP is abnormally high despite normal volume
-- Increased LVDP eventually leads to pulm congestion, dyspnea
-- also decreses exercise tolerance b/c Starling doesn't work
How does diastolic dysfxn decrease CO via the Starling mechanism?
1. diastolic relaxation does not speed up as HR increases

2. ventricular stiffness prevents increased preload from increaseing LV-EDV, so SV cannot increase
Treatment for diastolic HF is aimed at...?
1. treating the diseases that cause the dysfxn
-- CAD
-- HTN
-- Aortic stenosis

2. relieving symptoms by decreasing pulmonary venous pressure at rest and during exercise

3. reversing the remodeling of the ECM of the LV
Why must we use diuretic drugs and nitrate vasodilators w/ great care to decrease LVDP?
1. small doses must be used to prevent HTN and fatigue

2. pts have high filling pressure or increased blood vol in order to fill LV normally and thus provide a normal preload to maintain CO

4. If LA pressure is decresed too much (nitrates), or if blood volume decreased too much (diuretics), then inadequate LV filling results in decreased CO which in turn causes hypotension and fatigue
How do we prolong diastolic filling?
Use B-blockers to decrease HR and thus prolong filling

-- diastolic dysfxn results in slowed and incomplete relaxation during diastole and inability of heart to accelerate relaxation when HR increases

-- B-blocker trtmt decreases basal HR and impedes tachy caused by exercise

-- prolongation of diastole allows more complete relaxation of LV and decreases end-diastolic P

Will CCAs like verapamil also work? Probably.
verapamil: systolic vs. diastolic dysfxn?
may improve cardiac fxn in a pt w/ pure diastolic dysfxn, but can have the opposite effect in a patient w/ a mixture of diastolic and systolic dysfxn
Every patient w/ HF should be treated with...?
An ACEi, regardless if their dysfxn is diastolic or systolic
Drugs for the treatment of acute heart failure (post-MI and end-stage HF)?
sodium nitroprusside
morphine use?
1. pain increases bp by enhancing sympathetic tone

2. decrease in sympathetic activity produced by morphine results from its analgesic effect and inhibition of carotid baroreflex

3. Decrease in sympathetic tone
-- decreases cardiac preload and afterload = increased SV
-- decreases HR and cardiac automaticity
-- decreases cardiac oxygen demand

4. recent study of pts w/ non-ST elevation acute coronary syndrome revealed that morphine use, either alone, or in combination with NTG, was associated w/ higher mortality
Dopamine use -- low dose?
-- stimulates D1-dopamine receptors in the renal arterioles and causes vasodilation

-- increased RBF via dilation of afferent arterioles

-- increased RBF increases GFR and renal sodium excretion

-- DBP usually remains unchanged, but may decrease slightly
Dopamine use -- intermediate doses?

-- increased dp/dt

-- only small increase in HR

-- increased SV/CO lead to a further increase in GFR
Dopamine use -- large doses?
-- Increased TPR, DBP, and arterial impedence

-- Increased arterial impediance decreases SV/CO

-- Venoconstriction increases venous return and filling pressure, and the resultant increase in wall stress negatively affects myocardial energetics
NB: after MI, venous return is at its maximal value b/c the EF is severely decreased

-- decreasee in SV/CO caused by increased afterload and the increase in filling pressure caysed by venoconstriction can be reversed by i.v. infusion of DOBUTAMINE or SODIUM NITROPRUSSIDE
At larger doses, dopamine can cause...?
tachycardia (which wastes oxygen and worsens ischemia)

may produce cardiac dysrhythmias
Dobutamine action?
**a racemic mix of (+) and (-) enantiomers

-- Both enantiomers stimulate B1 and B2 receptors
-- One enantiomer is a partial agonist at a-adrenoceptors, and the other enantiomer is an agonist at a-adrenoceptors
-- Two enantiomers cancel each others effects at a-adrenoceptors, so any vasodilatory effects are caused by stimulation of vascular B2-adrenoceptors
Dobutamine pharm effects?
1. positive ionotropic effect via B1-adrenoceptors increases SV

2. Arteriodilation via B2-adrenoceptors lowers TPR (afterload) so DBP falls

3. venodilation via B2-adrenoceptors decreases venous return and cardiac filling pressure

4. unlike DOPA, dobutamine has little effect on heart rate at most clinical doses; excessive doses can cause tachy or cardiac dysrhythmias

5. Increase in GFR results solely from increase in CO
Describe the distinct effects of dobutamine over dopamine.
1. Dobuta does not increase DBP (afterload)

2. Dobuta is less likely to cause tachy

3. Dobuta causes venodilation which decreases venous return (preload) so ventricular filling pressure is decreased

**Pts may develop tolerance to the positive ionotropic effects of both dopa and dobuta
Phosphodiesterase inhibitors and their use?

MOA: Type III PDEase increases CAMP in cardiac myocytes

1. increased dp/dt
2. Faster myocardial relaxation during diastole
3. Balanced vasodilation decreases preload (filling pressure) and afterload (DBP)
4. Pulmonary vascular resistance falls
5. SV increases as a result of increased dp/dt and decreased preload and afterload

Trtmt does not decrease CV mortality
Use of diuretics in acute heart failure?
"Loop diuretics" are given to prevent volume expansion

FUROSEMIDE also increases venous capacitance via increase renal production of vasodilatory prostaglandins
Nitroglycerine use with acute heart failure?
-- given by i.v. infusion

-- small doses selectively dilate veins to increase venous capacitance and thus lower cardiac filling pressure

-- Decreases preload:
1. decreases wall stress
2. increases subendocardial perfusion during diastole

-- larger doses also dilate arterioles leading to a decrease in afterload

-- tolerance is always a problem
Sodium nitroprusside
-- rapidly converted to NO, which causes balanced vasodilation

-- increased venous capacitance decreases cardiac filling pressure

-- decreased arterial impedance (DBP) enhances CO

-- decreased filling pressure and wall stress and thus improves myocardial energetics as SV is increased

-- dilation of pulmonary arterioles decreases RV afterload

-- a large fall in DBP can activate the sympathetic nervous system via the carotid baroreflex and/or compromise myocardial perfusion
Overview: how do we treat HF associated w/ acute coronary syndrome (evolving MI)?
M = morphine
O = oxygen
A = aspirin (sublingual)

And EVERY patient in ACEi if HF (also DMII even in normotensive)