Study materials of HF

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Introduction
Heart failure (HF) is a complex cardiac syndrome characterized by an inability of the
heart to fill with or pump out blood under normal circumstances, due to structural or
functional abnormalities.
HF is characterized by reduced cardiac output (<5 litres/min), impaired venous return to
the heart and systemic venous congestion, which may lead to oedema. At this stage it is
termed as congestive heart failure (CHF).
However, reduced cardiac output due to severe blood loss and venous congestion from
other causes are not considered as CHF.
Definitions
Preload: Degree of tension within the myocardial fibers at the onset of systole, usually
denoted as the end-diastolic pressure.
Afterload: The load which the ventricular contractions must overcome to pump blood
into the circulation, denoted as the blood pressure (BP) in arteries leading from the
ventricles.
Stroke volume (SV): Amount of blood ejected from the left ventricle during systole.
Ejection Fraction (EF): Fraction of blood ejected from the ventricles during systole.
Cardiac output (CO): Total volume of blood ejected from the ventricles per minute.
Classification
The more common classifications of CHF are outlined as follows:
Contractile dysfunction
Cardiac contractile abnormalities are divided into two groups: systolic
dysfunction and diastolic dysfunction, which will be discussed later.

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Anatomical division
The anatomical location of CHF has great clinical significance because signs and
symptoms vary accordingly.
Left-ventricular (LV) failure usually results in pulmonary dysfunction and reduced CO.
Right ventricular (RV) failure causes congestion and peripheral oedema.
Functional classification
The New York Heart Association (NYHA) classifies the severity of CHF as:
Class Physical Activity Example
I (none)
Normal physical activity does not cause fatigue,
palpitations and dyspnoea
Jog/walk 8km/h
II (slight)
Normal physical activity causes fatigue,
dyspnoea and palpitations/angina
Walk 7km/h on level
ground
III (moderate)
Comfortable at rest, light physical activity causes
fatigue, dyspnoea and palpitations/angina
Walk 4km/h
IV (Severe)
Symptoms present at rest; any physical activity
increases discomfort
Unable to perform any
of the above activities
Pathogenesis
CHF is a common end-stage condition for many cardiovascular disease processes.
Most cases of CHFs result from a progressive decline in myocardial contractility, with
20-50% of cases resulting from diastolic dysfunction.
Etiology
Diseases leading to CHF are categorized into the following:

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Impaired myocardial
contractility
Ischemic heart disease, myocardial infarction,
myocardiomyopathy, poisons, infections, genetic mutations of
myocardial cellular contractile proteins
Volume overload Regurgitant valves (aortic/mitral)
Pressure overload Hypertension, aortic stenosis, pulmonary embolism
Increased metabolic
demands
Thyrotoxicosis, anemia, pregnancy, infections
Restricted filling of
the heart chambers
Mitral stenosis, constrictive pericarditis, cardiac tamponade,
haemochromatosis, amyloidosis, myocarditis
Electrical
dysfunction of the
heart
Pathological tachycardia, heart block
Table 1: Summary of the various aetiologies of CHF
Pathophysiology
In HF, the heart suffers an insult that severely affects its ability to pump blood into the
peripheral circulation, thus it is unable to provide sufficient perfusion to the periphery.
With reduced CO and SV, the heart is now pumping out less blood, thus more blood
accumulates within the heart chambers, causing pressure overload. As pressure builds
up in the heart and the veins connected to it, systemic venous pressure increases,
causing systemic and pulmonary venous congestion.
Venous congestion impairs venous return to the heart, eventually leading to congestion
of blood in the heart, lungs and peripheral organs (Figure 2). This usually leads to
pulmonary and peripheral oedema. This is usually attributed to systolic and diastolic
abnormalities of the heart.

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Figure 1: The pathophysiology of systolic and diastolic dysfunction in CHF
Systolic dysfunction
Most CHF occurs due to systolic dysfunction, which is a gradual decline in myocardial
contractility, defined by left ventricular EF of less than 50%.
Decrease contractile force results in incomplete ventricular ejection, thus decreasing SV
and CO. With reduced ventricular ejection, relative accumulation of blood raises end-
systolic volume and end-systolic pressure in the ventricles, thus reducing EF (Figure 1).
Systolic dysfunction commonly occurs due to myocardial infarction, myocarditis or
cardiomyopathy, leading to LV or RV failure. LV failure is commonly preceded by RV
failure. LV failure can cause congestion of blood within the pulmonary circulation and
ultimately into the right side of the heart, causing RV failure.
Diastolic dysfunction

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In diastolic dysfunction, normal relaxation of the heart is impaired, decreasing
ventricular filling and CO. This is due to reduced myocardial fibre elasticity and
increased ventricular stiffness.
Impaired ventricular relaxation compromises ventricular re-filling. Consequently, end-
diastolic volume is reduced but end-diastolic pressure is increased. Overall, SV and CO
are reduced (figure 1). However, EF increases as the ventricles contract more forcibly to
maintain sufficient CO.
Diastolic dysfunction is present in hypertrophic myocardiopathy and myocardial
infarction. In the elderly, age-related loss of myocytes and deposition of collagen within
the myocardium increases its stiffness, causing diastolic dysfunction.
Vascular congestion and peripheral oedema
CHF usually causes vascular congestion in organs and fluid extravasation into
peripheral tissues.
Considering the Starling equation, systemic venous congestion increases Pc within
tissue capillary beds, causing Pc to exceed Pi, while πc and πi remain constant. Thus
net driving force (NDF) is altered such that there is a positive pressure gradient(NDF>0)
driving fluid out of capillaries into the interstitium. Net accumulation of fluid within the
interstitium causes peripheral oedema.
Compensatory responses
In CHF, compensatory mechanisms are activated to alter preload, afterload and
myocardial contractility to augment SV.
In acute CHF, sudden onset of insult triggers a fall in CO and BP. Within minutes,
peripheral baroreceptors and chemoreceptors are activated to increase the sympathetic
tone, which causes reflex tachycardia, peripheral vasoconstriction, and increased
cardiac inotropy to restore normal BP and CO.
In chronic CHF, long-term compensatory responses are activated, as discussed below.
Cardiac responses

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Increased end-diastolic pressure causes gradual ventricular remodeling. The LV and
RV becomes hypertrophic, spherical and dilated to generate a greater contractile force
to pump blood into the circulation, so as to augment CO (Figure 2). However, these
changes increases ventricular stiffness and wall stress during diastole, compromising
cardiac function.
However, atrio-ventricular valve regurgitation and accelerated myocyte apoptosis can
occur as the ventricles become dilated and subjected to greater tensional forces from
the pressure overload]
Neurohumoral Responses
Figure 2: Downstream effects on activation of the sympathetic nervous system

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Decreasing CO causes a reflex increase in the sympathetic tone, activating multiple
downstream effects to boost CO.
As BP decreases, it activates arterial baroreceptor reflexes, which increases
sympathetic tone. Cardiac nerves release noradrenaline to increase contractility and
heart rate.
Increased sympathetic tone has a direct cardiotoxic effect on the heart, damaging
myocytes.. It also activates renin-angiotensin-aldosterone system, causing multiple
downstream effects which are discussed later.
Strong sympathetic tone causes prolonged peripheral vasoconstriction, which increases
preload and afterload. However, the dysfunctional myocardium cannot cope with
elevated preload and afterload, thus exacerbating vascular congestion and dysfunction
in chronic CHF.
Renin-angiotensin-aldosterone system
On activation of the renin-angiotensinogen-aldosterone (RAS) system (Figure 3), the
kidneys releases renin, which converts angiotensinogen to angiotensin I(AI), which is
then converted to Angiotensin II(AII) by Angiotensin-converting enzyme(ACE) that is
released by the lungs.

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Figure 3: Activation of the renin-angiotensin-aldosterone system.
Angiotensin II has multiple downstream effects - inducing myocardial hypertrophy,
stimulating aldosterone and anti-diuretic hormone (ADH) release, promoting sodium and
water retention and peripheral vasoconstriction (Figure 6).
These changes increase BP and blood volume, elevating preload and afterload to
maintain normal CO.
However, aldosterone increases collagen deposition and myocardial fibrosis,
compromising cardiac contractility.
Frank-Starling Mechanism

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Figure 4: Frank-Starling relationship in various cardiac conditions
The Frank-Starling Mechanism refers to the ability of the heart to alter its contractility
and SV in response to changes in stretching of the myocardial fibres.
In CHF, blood congestion leads to ventricular distension, increasing end-diastolic
pressure. By the Frank-Starling relationship, the myocardial fibres will now contract
more forcibly to pump more blood out into the circulation.
With gradual worsening of CHF, as the adaptive mechanisms are exceeded, myocardial
contractility deviates from the Frank-Starling relationship (Figure 7). The fibres become
stretched beyond their limits, decreasing inotropy and SV.
Atrial Natriuretic Peptide
In CHF, systemic venous congestion and elevated end-diastolic pressure increases
intra-atrial pressure. On excessive atrial distension, the atria secretes atrial natriuretic
peptide,a hormone that promotes excretion of salt and water in the kidneys, thus
alleviating the congestive symptoms of HF.
Initially, when the above changes are able to maintain adequate CO despite the
contractile abnormalities, it is termed as compensated heart failure. With time, as
these compensatory mechanisms are exceeded, CO falls drastically, leading
to decompensated cardiac failure.
Clinical manifestations and underlying aetiology
Common clinical manifestations of CHF are presented below:
Signs Aetiology
Dyspnoea
Pulmonary venous congestion causes inadequate blood
oxygenation and fluid extravasation into pulmonary tissues with
secondary pleural effusion causing symptoms.
Orthopnoea
Recumbent position reduces blood pooling in the extremities,
improving venous return that exacerbates pulmonary congestion.
Paroxysmal Improved venous return, reduced ventricular adrenergic innervation

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nocturnal
dyspnoea
during sleep and nocturnal depression of respiratory center.
Fatigue Reduced CO - poor perfusion of skeletal muscles leads to fatigue
Nocturia
Underperfusion of kidneys during the day, adequate perfusion
restored by supine position at night.
Symptoms Aetiology
Ascites
Venous congestion of abdominal viscera leads to fluid
extravasation into peritoneal cavity.
Generalised oedema
(anasarca), dependent
oedema
Peripheral vascular congestion alters Starling forces in
tissues, causing fluid extravasation into interstitial
spaces.
Right upper quadrant pain
Hepatic congestion and fluid extravasation cause
hepatomegaly, stretching the hepatic capsule, causing
pain.
Elevated Jugular venous
pressure (JVP)
Blood congestion and decreased right ventricular output
increases atrial filling, giving a higher JVP.
Management:
Drug Therapy of CHF
1. Digoxin
2. Diuretics
3. Aldosterone Antagonists
4. Beta Blockers
5. Angiotensin 2-Receptor Blockers
Treatment

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• Various drugs are used to treat congestive heart failure.
• They perform different functions.
• ACE inhibitors and vasodilators expand blood vessels and decrease resistance.
• This allows blood to flow more easily and makes the heart's work easier or more
efficient.
• Beta blockers can improve how well the heart's left lower chamber (left ventricle)
pumps.
• Digitalis increases the pumping action of the heart.
• Diuretics help the body eliminate excess salt and water.
CARCA
• Carvedilol is a third generation, nonselective b-adrenoceptor antagonist with
vasodilating properties exerted primarily through a1-blockade
• It also has cardioprotective and neuroprotective properties, but lacks
sympathomimetic activity
• Additionally, it has free radical scavenging activity, and an antiproliferative
activity on smooth muscle cells
Mechanism of action
Carvedilol is a vasodilating, non-selective beta-blocking agent with vasodilator &
antioxidant properties.
• Vasodilatation has been shown to be mediated primarily by selective
blockade of alpha1 adrenoceptors
• Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it
has membrane stabilizing properties

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Pharmacodynamics
• Potent and competitive blockage of beta1, beta2 and alpha 1 receptors
without intrinsic sympathomimetic activity and with membrane stabilizing activity
• Unique haemodynamic profile
• Cardio-protective action
• Favorable effect on renal hemodynamics
• Anti-oxidant property
• Anti-proliferative effects providing benefits against atherosclerosis
• Favorable effect on lipid profile
• Improves insulin sensitivity
Pharmacokinetics
• After oral administration of 25mg and 50mg doses, carvedilol is rapidly
absorbed
• Tmax 1-2 hours after oral administration
• Oral bioavailability is 20-25% due to extensive first-pass hepatic metabolism,
which is not influenced by food
• Carvedilol is lipophilic and is highly bound (95%) to plasma protein
• It is extensively metabolized in liver by cytochrome P 450 enzymes
• Most metabolites are secreted into bile & eliminated in faeces (60%) and urine
(16%)

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• Carvedilol has a terminal elimination half-life of 2 to 8 hours
• Carvedilol 12.5 to 50 mg/day has been shown to be safe and effective in
hypertensive patients with chronic renal failure (even those using hemodialysis)
without dose alteration
Therapeutic Uses
Carvedilol has been approved in India for the treatment of:
• Mild to moderate hypertension (prehypertension to hypertension, stage 1)
 Left ventricular dysfunction following myocardial infarction
• CCF, in addition to ACE inhibitors, diuretics and/or digitalis
Contraindications
• Decompensated heart failure requiring intravenous inotropic support
• Bronchial asthma & COPD
• Sinus bradycardia, 2nd & 3rd degree AV block, sick sinus syndrome,
hypotension & shock
• Known hypersensitivity to the drug
• Hepatic impairment
Dosage and Administration
• The recommended dose for initiation of therapy is 12.5mg once a day for
the first 2 days
• If needed, increase to 25mg once a day. The dosage may subsequently be
increased at intervals of at least 2 weeks up to the recommended maximum daily
dose of 50 mg given once a day or in two divided doses

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• The maximum recommended dose is 25mg twice daily in patients weighing
less than 85kg and 50mg twice daily in those weighing more than 85kg
• In symptomatic congestive heart failure :
o It is recommended that carvedilol be taken with food to slow the rate of
absorption and to reduce the risk of orthostatic effects
o The recommended starting dose in patient with compensated CCF is 3.125 mg
twice daily
o If tolerated, increase at intervals of not less than two weeks, to 6.25 mg ,
12.5mg & 25mg twice daily
o The maximum recommended dose is 25mg twice daily in patients weighing
less than 85kg and 50mg twice daily in those weighing more than 85kg.
CARCA CR
(CARVEDILOL CONTROLLED RELEASE FORMULATION)
Carvedilol profile:
Carvedilol is a non-selective β blocker. it is available as a phosphate salt. It is a racemic
mixture of R (+) and S(-) enantiomers. It is widely used in management of heart failure.
A nonselective β-adrenergic blocking agent with α1-blocking activity. Β-adrenoreceptor
blocking activity present in S (-) enantiomer.
Mode of action:
α1 blockage: leads to vasodilation thereby reducing preload
β1 blockage: leads to decreased force of contraction & heart rate thereby reducing
afterload
β2 blockage: leads to bronchoconstriction (So contraindicated in asthma)

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Pharmacological effects:
Carvedilol provides beneficial effects in patients with heart failure and in patients with
left ventricular dysfunction following an acute myocardial infarction. The concentration-
response relationship for β1-blockade following administration of Carvedilol CR is
equivalent to immediate-release carvedilol tablets. By blocking β-adrenoreceptor,
carvedilol reduces cardiac output, reduces exercise- and/or isoproterenol-induced
tachycardia, and reduces reflex orthostatic tachycardia. These effects are usually seen
within 1 hour of drug administration. It has a little effect on plasma catecholamines,
aldosterone, or electrolyte levels; significantly reduce plasma renin activity when given
for at least 4 weeks.
Increases levels of atrial natriuretic peptide.
Pharmacokinetics:
• Absorption: Slower and more prolonged compared to the immediate-release
formulation. Tmax – 5hrs. Bioavailability of CR formulation – 85% of bioavailability of IR
formulation.
• Effect of Food:
Administration of carvedilol CR formulation with a high-fat meal resulted in increase
(~20%) in AUC and Cmax compared to standard meal. Decrease in AUC (27%) and
Cmax (43%) were observed when Carvedilol CR was administered in the fasted state
compared to administration after a standard meal. Carvedilol CR formulation should be
taken with food.
• Distribution: Plasma proteins binding - > 98%. Volume of distribution - 115 L
• Metabolism: Stereoselective first-pass metabolism through CYP450 Enzymes.
Active metabolites with weak vasodilating activity. Apparent 90 L/h for R(+)-carvedilol.
Clearance is 213 L/h for S(-)-carvedilol
• Excretion: Primarily via the bile into the feces.
Indications:

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• Heart failure
• LV dysfunction following MI
• Hypertension
Contraindications:
• Bronchial asthma or related bronchospastic conditions.
• Sick sinus syndrome.
• Second- or third-degree AV block.
• Patients with cardiogenic shock or who have decompensated heart failure
requiring the use of intravenous inotropic therapy.
• Such patients should first be weaned from intravenous therapy before initiating
Carvedilol CR.
• Severe bradycardia (unless a permanent pacemaker is in place).
• Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-
Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the
components of Carvedilol CR.
• Patients with severe hepatic impairment.

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Dosage:
Condition
Recommended
Starting Dose/ Day
Heart Failure 10 mg
Left Ventricular Dysfunction Following
Myocardial Infarction
20 mg
Hypertension 20 mg
Daily Dose of Immediate-
Release Carvedilol Tablets
Daily Dose of Controlled Release
Carvedilol phosphate Tablets
6.25 mg
(3.125 mg twice daily)
10 mg once daily
12.5 mg
(6.25 mg twice daily)
20 mg once daily
25 mg
(12.5 mg twice daily)
40 mg once daily
50 mg
(25 mg twice daily)
80 mg once daily

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Drug-Drug Interaction:
CYP2D6 Inhibitors and Poor Metabolizers
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as
quinidine, fluoxetine, paroxetine, and propafenone) would be expected to increase
blood levels of the R (+) enantiomer of carvedilol.
Hypotensive Agents
Patients taking both carvedilol and reserpine/monoamine oxidase inhibitors should be
observed closely for signs of hypotension and/or severe bradycardia.
Concomitant administration of clonidine with carvedilol may potentiate blood-pressure-
and heart-rate-lowering effects.
Cyclosporine
As Carvedilol increases cyclosporine concentration, cyclosporine concentrations be
monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine
be adjusted as appropriate.
Inducers/Inhibitors of Hepatic Metabolism
Rifampin reduces plasma concentrations of carvedilol by about 70%. Cimetidine
increases area under the curve (AUC) by about 30% but caused no change in Cmax.
Digitalis Glycosides
Concomitant use of digoxin and carvedilol increases digoxin concentrations by about
15% and can increase the risk of bradycardia.
Amiodarone
The concomitant administration of amiodarone or other CYP2C9 inhibitors such as
fluconazole with Carvedilol may enhance the β-blocking properties of carvedilol
resulting in further slowing of the heart rate or cardiac conduction.

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Calcium Channel Blockers
Conduction disturbance (rarely with hemodynamic compromise) may occur when
carvedilol is co-administered with calcium channel blocker.
Insulin or Oral Hypoglycemics
Carvedilol (β-blocking properties) may enhance the blood-sugar-reducing effect of
insulin and oral hypoglycemics.
Side effects: Postural hypotension diminished peripheral circulation, dry eyes,
headache, fatigue, dizziness.
Clinical trials on Carvedilol:
DRUG CLINICAL TRIALS
NYHA Class
(Heart Failure)
MORTALITY
REDUCTION
Carvedilol
COPERNICUS -
Carvedilol vs. Placebo
IV 35 %
CAPRICORN - Carvedilol
vs. Placebo
I 23 %
COMET – Carvedilol vs.
Metoprolol
I-II 17 %
US CARVEDILOL HF
STUDY – Carvedilol vs.
Placebo
I-II 65 %

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