Congestive Heart Failure

Question 1

What is congestive heart failure?

Answer 1

● Congestive heart failure is a pathologic state when the heart is unable to meet the metabolic requirements of tissues.

Question 2

Causes of chronic congestive heart failure?

Answer 2

●cardiac:
》coronary artery disease,
》 valvular heart disease,
》 myocarditis,
》 use of cardiotoxic drug
(alcohol, cocaine, tricyclic antidepressants),

》some infections
(diphtheria, Lyme disease)

●extracardiac:
》arterial hypertension,
》pulmonary hypertension,
》hypo or hyperthyroidism.

Question 3

Mechanisms of pathogenesis of congestive heart failure?

Answer 3

Page. 123
(Fig. 32)

Question 4

The effects of the sympathetic nervous system include.

Answer 4

●the increase of the myocardial contractility and the heart rate
(through the activation of beta-1 adrenergic receptors);
it helps to maintain the cardiac output,

contributes to the increased size of the myocardium (myocardial hypertrophy)

●The constriction of the peripheral blood vessels
(through alpha-1adrenergic receptors) and redistribution of the blood flow in favor of the central organs
(the heart, the brain, the liver);

●helps to maintain the arterial blood pressure as well as the blood flow in the most important organs.

●The activation of the renin secretion (through beta-1 adrenergic receptors) resulting in the increased formation of angiotensin II and aldosterone.

●The long-term activation of the sympathetic nervous system leads to
the downregulation of beta-1 adrenergic adrenoceptors
(decrease in their number).

Question 5

The effects of angiotensin II?

Answer 5

●Increase in the size of cardiomyocytes, which directly contributes to myocardial hypertrophy.

●Apoptosis of cardiomyocytes.

●Vasoconstriction and increase in arterial blood pressure.

●Increase in aldosterone secretion

●Activation of the sympathetic nervous system.

●Increased generation of the oxygen free radicals leading to inactivation of NO.

Question 6

The effects of aldosterone.

Answer 6

●retention of Na+ and water (contributes to the increase of the blood
volume, cardiac overload and tissue edema).

●loss of K*
(increases the risk of tachyarrhythmias and sudden death)

●stimulation of proliferation of fibroblasts
(leads to cardiac fibrosis).

The long-term activation of the sympathetic nervous system and
renin-angiotensin-aldosterone system leads to the development of cardiac remodeling that is structural and geometrical changes in the myocardium,
developing in response to the influence of pathologic factors.
Cardiac remodeling includes:

●hypertrophy and later - dilation of the heart.
●apoptosis of some cardiomyocytes.
●proliferation of fibroblasts.
●decrease in the number of beta adrenoceptors.

So, the most important feature of the pathogenesis of heart failure is activation of the sympathetic nervous system and renin-angiotensin-aldosterone system.

At the first stages of chronic congestive heart failure, the sympathetic nervous system and the renin-angiotensin-aldosterone system play a compensatory role helping to maintain normal perfusion of tissues. But
a long-term activation of these systems leads to the remodeling of myocardium and impairment of hemodynamic functions.

The most common symptoms of chronic congestive heart failure are,
●a decreased tolerance to physical activity,
●dyspnea (shortness of breath),
●tissue edema.

Question 7

The approaches of treatment to the congestive heart failure?

Answer 7

The main approaches to the treatment of congestive heart failure.

inhibition of neurohumoral influences (of the sympathetic nervous system and renin-angiotensin-aldosterone system) on the heart:

• ACE inhibitors
  (captopril, enalapril, lisinopril)
• angiotensin II receptor antagonists (losartan, valsartan)
• aldosterone receptor antagonists (spironolactone, eplerenone)
• beta adrenergic receptor antagonists (metoprolol, bisoprolol,carvedilol, nebivolol)

-decrease of cardiac overload:
- diuretics
(hydrochlorothiazide, indapamide, furosemide, torasemide);

• directly acting vasodilators
  (isosorbide dinitrate, hydralazine)
• bradycardic drugs (ivabradine)

increase of cardiac contractility:
- cardiac glycosides (digoxin)
- non-glycoside inotropic drugs (milrinone, levosimendane).

Drugs, which decrease the mortality in a long-term treatment of congestive heart failure:

●ACE inhibitors,
● angiotensin II receptor antagonists
●aldosterone receptor antagonists
●beta adrenergic receptor antagonists;
some directly acting vasodilators (isosorbide dinitrate and hydralazine)
●ivabradine.

So, the most effective approach for the treatment of congestive heart failure is the inhibition of influence of the sympathetic nervous system and
renin-angiotensin-aldosterone system.

Question 8

What are ACE inhibitors?

Answer 8

●These drugs inhibit the formation of angiotensin II from angiotensin I by inhibiting ACE.
●This enzyme is also responsible for the inactivation of bradykinin,
so ACE inhibitors also increase the amount of bradykinin in the tissues and the blood due to the block of inactivation of this peptide.

Question 9

The mechanism of beneficial action of ACE inhibitors in congestive heart
failure?

Answer 9

●The inhibition of ACE leads to a decrease in the amount of angiotensin II and aldosterone.
●This contributes to the vasodilation and decrease in cardiac overload.
●On the other hand, the decrease in the production of angiotensin II and aldosterone prevents the development of the cardiac remodeling and progression of heart failure.

●The increased amount of bradykinin also has the beneficial influence on the heart due to
》the NO-dependent vasodilation,
》Improvement of endothelial function,
》prevention of the cardiac hypertrophy and remodeling.

●Now ACE inhibitors are first-line drugs for the treatment of chronic congestive heart failure.

Question 10

Mechanism of ACE Inhibitors.

Answer 10

Page_126
(Fig.33 & 34)

Question 11

Adverse effects of ACE inhibitors?

Answer 11

●hyperkalemia
(due to the decreased secretion of aldosterone)
● dry cough
●angioedema

》Both dry cough and angioedema develop due to the accumulation
of bradykinin.

in the case of these adverse effects, angiotensin II receptor antagonists must be administered
instead of ACE inhibitors.

Question 12

Angiotensin II receptor antagonists.
The mechanism of the beneficial effect in congestive heart failure
&
Adverse effects.

Answer 12

●These drugs block angiotensin AT₁ receptors and by thus block all the above-mentioned effects of
angiotensin II
involved in the pathogenesis of congestive heart failure.
The effects of angiotensin II receptor antagonists are almost similar to the effects of ACE inhibitors

(vasodilation,
inhibition of cardiac hypertrophy and apoptosis of cardiomyocytes,
the decrease of aldosterone,
the increase of K,
the prevention of the development of the cardiac fibrosis),

but they do not increase the level of bradykinin and do not cause dry cough and angio-edema.

Like ACE inhibitors, angiotensin II receptor antagonists also prevent
the progression of heart failure and decrease the mortality of the patients.

Adverse effects include

●hyperkalemia.
●dizziness.
●headache.

Question 13

Aldosterone receptor antagonists
Mechanism & Adverse effects.

Answer 13

●Aldosterone receptor antagonists block a negative influence of aldosterone on the heart,
preventing the development of fibrosis in the heart;
also induce a mild diuretic effect with the increase of K+ in the blood.

The most typical adverse effect of aldosterone receptor antagonists
is hyperkalemia.

Spironolactone can block the receptors for other steroidal hormones
(including sex hormones),
so it can cause sexual disorders,

gynecomastia (breast enlargement) men.

Eplerenone is a selective antagonist of aldosterone receptors and does not impair the sexual function.

Question 14

Beta adrenergic receptor antagonists?

Answer 14

●Among beta adrenergic receptor
antagonists only four drugs are approved for the treatment of congestive heart failure:

》selective antagonists of
beta-1 adrenergic receptors
metoprolol,
bisoprolol,
nebivolol and

》antagonist of beta and alpha adrenergic receptors - carvedilol.

●These drugs decreased the mortality of patients with congestive heart failure in randomized clinical trials.

Question 15

The mechanism of beneficial effect in congestive heart failure.

Answer 15

●is a block of the excessive influence of the sympathetic nervous system on the heart.

●As a result, beta adrenergic receptor antagonists attenuate remodeling of the heart.

●Antiarrhythmic and antianginal properties of these drugs also
have a positive impact on the course of the disease and mortality.

》An additional beneficial effect of nebivolol is its ability to stimulate the generation of endothelial NO leading to vasodilation and improvement of endothelial function.

Question 16

Diuretics used for congestive heart failure?

Answer 16

●loop diuretics
(furosemide, torasemide);

●thiazide diuretics (hydrochlorothiazide, indapamide);

●K*-sparing diuretics
(triamterene,
aldosterone receptor antagonists).

Question 17

The mechanism of the beneficial effect in congestive heart failure. (Diuretics)

Answer 17

●Decrease of the blood volume and,
as a result,
the decrease of the cardiac overload.

The diuretics contribute to the disappearance of such common
symptom of heart failure as edema.

●The most important disadvantage of loop and thiazide diuretics is their
ability to induce hypokalemia.

Torasemide (torsemide - USAN) has some advantages over another loop diuretic furosemide:
• low risk of hypokalemia;
• ability to reduce cardiac fibrosis.

●It is not known exactly why torasemide have such advantages, but it supposed to interact with the renin-angiotensin-aldosterone system.

Question 18

Directly acting vasodilators and their mechanism, Adverse effects.

Answer 18

●Some of the directly acting vasodilators
(isosorbide dinitrate,
hydralazine)
also showed positive influence on the
mortality in congestive heart failure.

●The mechanism of the beneficial effect:
they dilate the vessels
(NO donor isosorbide dinitrate
dilates mainly the venous and to a lesser extent the arterial vessels;

hydralazine dilates mainly the arterial vessels).

As a consequence,
they decrease preload, afterload and the cardiac work.

●These drugs have a relatively minor place in the treatment of congestive
heart failure.

Common adverse effects of vasodilators are,
hypotension,
reflex tachycardia,
headache.

Question 19

Bradycardic drugs.

Answer 19

●Ivabradine causes bradycardia due to the block
of the Na+ & If channels
(see “Antianginal drugs”).

As a consequence,
●the diastolic phase of the cardiac cycle is prolonged,
and the heart has more time for the heart rate.

●Ivabradine is used only for patients with no less than 70 beats per minute.

Question 20

Cardiac glycosides?

Answer 20

●They are drugs of a plant origin,
which increase contractility of the cardiac muscle.

●The most known of them is digoxin
(derived from the plant Digitalis lanata).

●In some countries digitoxin
(from Digitalis purpurea) &
ouabaine (from Strophanthus gratus) are also used (now rarely).

Question 21

The main effects of cardiac glycosides.

Answer 21

● positive inotropic (increased contractility)
●positive bathmotropic (increased automaticity);
●negative chronotropic (decreased heart rate);
●negative dromotropic (decreased AV conduction).

》A unique feature of cardiac glycosides is that the increase of the cardiac
contractility is accompanied by the increase of the duration of diastole.

the heart has more time for the rest and accumulation of energy.

Question 22

The mechanism of the action,
The cardiac glycosides

Answer 22

●Block Na+/K+ ATPase.

This leads to decrease of K* amount and increase of Na+ amount into cardiomyocytes.

The increased intracellular Na+ concentration contributes to the inhibition of Na/Cat exchanger and the increase in the intracellular amount of Ca++.

As a result, more Ca+ is accumulated in the
sarcoplasmic reticulum and more Ca+ is released during the electric systole leading to the stimulation of the cardiac contractility.

The negative chronotropic and dromotropic effects have a reflex mechanism.

The increase of the cardiac contractility leads to the activation of baroreceptors in the aorta.

The signals from the baroreceptors activate parasympathetic centers
causing the
decrease of the heart rate and slowing
the atrioventricular conduction.

●Digoxin is used not only in the congestive heart failure,
but also supraventricular tachyarrhythmias

(due to the decrease of atrioventricular
conduction).

Question 23

The main disadvantage of the cardiac glycosides?

Answer 23

●low therapeutic index
(a small interval between therapeutic and toxic doses).

According to the clinical data,
●cardiac glycosides do not decrease mortality in patients with congestive heart failure,
but slower progression of the disease and improve the quality of life.

Question 24

The factors predisposing to toxicity of the cardiac glycosides?

Answer 24

●hypokalemia (may be induced by thiazides and loop diuretics)
● hypomagnesemia
● hypercalcemia
●acidosis
●interaction with some drugs
(diuretics, quinidine).

Antiarrhythmic drug quinidine can increase the plasma concentration of digoxin due to the inhibition of the secretion of digoxin in the kidneys
and due to inhibition of intestinal efflux of digoxin by the P-glycoprotein.

Other drugs,
which can increase the concentration of digoxin, are
》amiodarone,
》clarithromycin,
》saquinavir.

Question 25

The symptoms of intoxication by the cardiac glycosides are?

Answer 25

● extracardiac:
gastrointestinal disorders
(nausea, vomity, diarrhea)

visual disorders 
(xantopsia, i.e. vision in yellow colour) 
   
CNS disorders
(disorientation, hallucinations)

●cardiac:

》arrhythmias
(both brady- and tachyarrhythmias are possible)
for example, AV block
(an early symptom is significant prolongation of PQ interval)
ectopic beats, paroxysmal tachycardia.

Question 26

Treatment of intoxication by the cardiac glycosides?

Answer 26

• preparations of K+ and Mg++

• antiarrhythmics
(lidocaine or phenytoin in tachyarrhythmias, others
are contraindicated
atropine in bradyarrhythmias)

• antibodies for digoxin - digoxin immune fab (digibind).

Question 27

Non-glycoside inotropic drugs?

Answer 27

● They are drugs with the positive inotropic effect
(the increase of the cardiac contractility) not related to cardiac glycosides.

●They are used mainly in acute heart failure
or
in the severe decompensation of chronic heart failure.

Question 28

Phosphodiesterase-3 inhibitors,
(MOA, Effects, Adverse effects)

Answer 28

● amrinone
(inamrinone - USAN, milrinone).

■The mechanism of the action,
is the increase intracellular cAMP by blocking its metabolism by phosphodiesterase-3;
increased cAMP in cardiomyocytes leads to the increased Ca** influx through the L-type Ca2* channels
and increased force of contraction.

●Effects of phosphodiesterase-3 inhibitors:
》the increase of the cardiac contractility and the slight increase of the heart rate,
》peripheral vasodilation
(the decrease of the cardiac overload).

●Adverse effects
include arrhythmias
(more prominent for milrinone),

hepatotoxicity and thrombocytopenia (more prominent for amrinone).

These drugs increase the mortality in a long-term administration.

They may be administered (intravenously) only by short-term courses in acute heart failure or the severe decompensation of chronic heart failure.

Question 29

Beta adrenergic receptor agonists.

Answer 29

》dopamine, dobutamine.

●The mechanism of the action - activation of beta-1 adrenergic receptors
in cardiomyocytes leading to the increase of intracellular cAMP and increased Ca influx through the L-type Ca2+ channels.

●Adverse effects:
tachycardia, arrhythmias
beta-1 adrenergic receptor agonists increase the oxygen demand of myocardium,
》so in the patients with coronary artery disease, they can contribute to the development of cardiac ischemia. (For more information see “Adrenergic agonists”.)

Question 30

Ca2+ sensitizer?

Answer 30

●levosimendan

》It increases cardiac contractility due to the increase in the sensitivity of cardiomyocytes to Ca also it dilates the peripheral vessels by the opening
of ATP-dependent K+ channels.

》 it can cause arrhythmia.

》It is also used intravenously in acute heart failure or the severe decompensation of chronic heart failure.

Question 31

Treatment of acute heart failure?

Answer 31

■In this case,
the decrease of the cardiac contractility and
the symptoms of the cardiac congestion (especially shortness of breath)
develop and progress rapidly
》 pulmonary edema can occur in the severe left ventricular failure
the significant decrease of the blood pressure can be observed in the case of the significant decrease of the cardiac contractility.

》The following drugs are administered in acute heart failure
(intravenously)

• non-glycoside inotropic drugs (milrinone,
levosimendan,
dopamine,
dobutamine)
are used to increase cardiac contractility.

● dopamine and dobutamine are especially useful in severe hypotension.

• diuretics (furosemide) are used to decrease the blood volume and, as a
consequence, to decrease cardiac overload.

• vasodilators
(sodium nitroprusside, nitroglycerine, nesiritide)
reduce the peripheral resistance and, as a consequence, decrease the cardiac overload.

》They are contraindicated in case of hypotension.