What are the 3 cardinal manifestations of heart failure?
Dyspnea (shortness of breath)
Fatigue
Fluid Retention
In most conditions, heart failure is associated with decreased cardiac output. What are 4 examples where cardiac output is high, but metabolic demands are also high, resulting in heart failure?
Hyperthyroidism
Beri Beri
Anemia
Major AV shunts
What are the 4 levels of heart failure?
• I – only at levels of exertion that would limit normal individuals • II – on ordinary exertion • III – on less-than ordinary exertion • IV – symptoms of heart failure at rest
What is the major determinant of contraction force?
Sarcomere length during diastole
What is the major determinant of sarcomere length?
End diastolic filling pressure (pre-load)
What are preload and afterload relative to cardiac function?
Pre - Diastolic filling pressure
After - Arterial pressure (resistance heart pumps against)
Cardiac myocyte depolarization results in _ (ion) influx into the cell. This influx causing a change in membrane potential, stimulating calcium influx through _ type calcium channels. This influx causes more calcium release from the sarcoplasmic reticulum via _ receptors
Sodium
L-type
Ryanodine receptors
What happens to the Na/Ca exchanger during depolarization? How is calcium removed to the sarcoplasmic reticulum? How is the remaining calcium removed?
Briefly reverse, now calcium pumped into cell
SERCA, Calcium ATPase
Sarcolemmal Calcium ATPase
What are 2 components of heart failure that may be present individually or in combination?
Systolic dysfunction: Weak contraction
Diastolic dysfunction: Incomplete relaxation (not enough filling)
One of the earliest steps in heart failure is a reduction in cardiac output. What are 2 compensatory systems activated as a result of this reduction?
Sympathetic NS
Renin Angiotensin System
What are the major forces that cause cardiac remodeling during heart failure?
Increased intravascular and ventricular volume, leading to increased diastolic and systolic wall stress
What are 3 neurohumoral factors that act directly on the myocardium to promote unfavorable remodeling?
Sympathetic NS
Ang II
Aldosterone
What happens to the baroreceptor reflex during heart failure? What is increased as a consequence (3)?
Reduced function (reads high pressures as normal) Sympathetic NS, Renin-Ang system, vasopressin
Cardiac hypertrophy occurs during heart failure. Why is a larger heart deleterious?
A bigger heart operates at a reduced ionotropic state
How is the renin angiotensin system altered during heart failure? Why?
Increased renin release
Increased symp. NS shunts blood from glomeruli, stimulating renin release
What are 3 systems at work to sustain arterial pressure, despite decreased cardiac output during heart failure?
Symp NS
Renin Ang System
Vasopressin
What is the effect of increased venous pressure during heart failure?
Reduced capillary return, edema
What is the difference between stage A/B and stage C/D of heart failure?
Stage A/B - At risk for heart failure
Stage C/D - Have heart failure
How are stage A and stage B heart failures different? How do their treatments differ?
A - Risk, no symptoms (ACE inhib., Ang receptor Blockers)
B - Structural disease, no symptoms (ACE inhib., Ang receptor Blockers, beta blockers)
What is stage C heart failure? How is it treated?
Structural disease with current / prior symptoms
Diuretics, ACE inhibs, beta blockers
What is stage D heart failure? How is it treated?
Refractory heart failure
Requires extraordinary measures (transplant, mechanical support, etc)
What are 3 drug classes that can be used to reduce afterload?
ACE inhib.
Ang Receptor blockers
Isosorbide dinitrate / hydralazine
For diuresis during HF, what 2 types of diuretics are used?
Loop diruretics
Spironolactone
For positive ionotropy, what 3 types of drugs are used?
Adrenergic agonists
cAMP phosphodiesterase inhibitors
Digitalis glycosides
What are 3 drug classes that are known to reduce mortality when used alone?
- ACEI
- ARB
- beta-blockers
What are the 2 major peptides upregulated by ACE inhibitors?
Ang I (Ang 1-7, opposes classical RAS actions) Bradykinin (potent vasodilator)
What property of ace inhibitors allow them to reduce afterload, Increase stroke volume and cardiac output?
More potent dialators or arterial vessels vs. venous vessels
Captopril, enalapril, ramipril, lisinopril, quinapril
and fosinipril are all examples of _
ACE inhibitors
What is the first line treatment for heart failure / reduced LVEF? What is this usually administered with?
ACE inhibitors
Beta blockers
Angiotensin receptors mainly block what receptor subtype? What subtype is largely unaffected and what is its effect? What peptide is directly increased by this class of drug?
AT1
AT2 - promotes vasodilation and naturesis
Increases Ang II
What are 3 angiotensin receptor blockers used in the treatment of heart failure?
Losartan
Valsartan
Candesartan
Which has better survival in heart failure patients, ACE inhibitors or Angiotensin receptor blockers? What happen to survival when both are combined?
Comparable survival rates for both
No additive benefit when both are combined
What is the preferred class of diuretics for treatment of heart failure? What class may be used in patients with hypertension?
Loop diuretics
THiazides in hypertensive patients
What class of drug will provide the fastest relief of symptoms in patients with heart failure?
Diuretics
How should diuretics be used in treatment of stage C heart failure?
Should be used in combination with another agent, shouldn’t be used alone
How do diuretics affect survival in heart failure patients?
No mortality benefit, address symptoms
How are sympatomimetics used in the treatment of heart failure? Why?
Used only for short term
Increase mortality in patients
What are 3 benefits of beta blockers in heart failure patients?
improve symptoms
improve exercise tolerance
increase LVEF
What is the effect of phosphorylation of the ryanodine receptor? What drug class is blocks / reduces this phosphorylation?
Increased phospho. causes calcium leak from sarcoplasmic reticulum, decreased contractility
Beta blockers
What is the effect of beta blockers on cardiac remodeling?
Blocks remodeling
What types of heart failure patients should get beta blockers? What is the exception?
All patients with HF due to LVEF
No beta blockers if contraindicated (reactive airway disease, bradycardia)
What are 3 beta blockers used in heart disease and what are their receptor targets?
Bisoprolol
Metoprolol - selective beta 1 block
Carvedilol - blocks alpha 1, beta 1 and 2
What is the effect of Metoprolol, carvedilol and bisoprolol on mortality?
All three reduce mortality
What are the 3 cardiac glycosides used in the treatment of heart failure?
Digoxin
Digitoxin
Ouabain
In addition of heart failure, what is another use for digoxin?
Arrythmias
What is the mechanism of action of digoxin? What is its receptor target? What are 2 by products of improved contractility following digoxin treatment?
Increases contraction force by increasing intracell. calcium.
Sodium/ potassium ATPase
Reduced symp. NS activity, increased renal perfusion
How does digoxin reduce the sodium gradient within the cell? What is the main channel affected? How does this affect calcium In the cell?
Reduces the gradient
Blocks activity of the sodium calcium exchanger
Increased calcium in cell, increase calcium uptake into sarcoplasmic reticulum, increase calcium release with depolarization, increased contractile force
What is the effect of digoxin on cardiac baroreceptors? Why is this significant?
It resensitizes these receptors
It leads to decreased sympathetic and increased parasymp input to heart
What is the receptor target of digoxin in the kidney? What is the significance?
It inhibits the sodium/potasium ATPase
Reduces sodium reabsorption in proximal tubule, leading to increase sodium in distal tubule, decreased renin release
What are the glycosides approved for use clinically?
Only digoxin
Digoxin is no longer a first line treatment for heart failure. What patients may be prescribed digoxin? (2)
Heart failure with atrial fibrillation
Patients refrctory to diuretcis, ACE inhib, ang inhib and beta blockers
What is the major toxicity associated with digoxin? What use of digoxin predisposes a patient to toxicity? How can toxicity be countered?
Arrhythmias, cardiac block
Long term use
Digoxin immunotherapy
What is the effect of digoxin on survival? What are risk associated with higher doses of digoxin?
No effect on survival
Increased risk of death from MI and arrhythmias
What are the 2 examples of aldosterone antagonists provided? What 2 classes of drug must be prescribed with the?
Spironolactone and Eplerenone
1) ACE inhib or ang receptor blocker and 2) diuretic
What is the effect of aldosterone on the heart?
Negative cardiac remodeling effects
What would be the effects of venodilators on heart function? (2)
Decrease filling pressure
Decrease intracardiac pressure
Arteriodilator [increase/decrease] vascular resistance and [increase/decrease] renal perfusion which [promotes / prevents] diuresis
Decrease
Increase
Promotes
Nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. Among the preceding, which is Short acting? quick acting? Long acting?
Short acting - iso dinitrate
Quick - Nitroglycerin
Long - Iso mono-nitrate
Isosorbide dinitrate preferentially works on [arteries / veins]. Its major action is to therefore decrease [preload / afterload]. It is usually used in concert with _
Veins
Preload
Hydralazine
Hydralazine preferentially works on [arteries / veins]. Its major effect is to increase perfusion of _ [organ]. What is the drug that is a combo of isosorbide dinitrate and hydralazine?
Arteries
Kidneys
BiDil
What is the major drug for use during decompensated heart failure? What are the 2 heart function related parameters it reduces?
IV Sodium Nitroprusside
Ventricular filling pressure, systemic vascular resistance
To treat acute MI or quickly reduce ventricular filling pressure, what is the drug of choice? What type of vessel is it selective for?
IV notroglycerin
Venous capacitance vessels
What are 3 parenteral positive ionotropic agents that can be used to treat refractory heart failure patients?
Dobutamine
Dopamine
Milrinone
With regards to the heart and vasculature, what are the target receptors and effects of dopamine?
Beta adrenergic receptors (stimulation) - increased contractility
Alpha adrenergic receptors (stimulation) - increases vascular pressure (good if patient has low BP)
What is the receptor target for dobutamine? It is the drug of choice for what cardiac disorders?
Beta agonist
Systolic dysfunction and congestion
What is the major effect of dobutamine, positive ionotropy or chronotropy? What are the 2 major side effects?
Positive ionotropy
Tachycardia and arrhythmias
What are 2 cAMP phosphodiesterase inhibitors that can be used to treat advanced heart failure? What is the main ion affected? Where is this ion affected?
Inamrinone and Milrinone
Calcium
Increased cytoplasmic calcium
Between Inamrinone and Milrinone , which has more favorable side effect profile, shorter half live, and more selective for PDE3?
Milrinone