Transcript Left heart failure

CONGESTIVE HEART FAILURE
DEFINITION
1920's - "organ physiology" paradigm - interplay between the abnormal heart and the
circulation. The focus on circulatory abnormalities
1960's - "cell biochemistry" paradigm - depressed contractility and impaired relaxation
1980's - "gene expression" paradigm - molecular alterations in the myocardial cells
Heart failure is a clinical syndrome in which impaired cardiac pumping decreases ejection and
impedes venous return. These haemodynamic abnormalities are generally complicated by
depressed myocardial contractility and relaxation, which reflect biochemical and biophysical
disorders in the myocardial cells. This latter, in turn, are due to partly to molecular
abnormalities that not only impair the heart's performance, but also acceletrate the
deterioration of the myocardium and hastens myocardial cell death.
PATHOPHYSIOLOGY OF HEART FAILURE
Heart failure can develop:
a.) Acutely
• resulting from acute myocardial infarction
• secondary to an infectious or infiltrating process (virus, bacterial, rotozoal)
b.) Chronically (over months or years) as the end-stage of different heart diseases.
This low output failure can result from:
a.) decrease in myocardial contractile reserve, due to:
• myocardial infarction
• cardiomyopathy
• increased afterload (eg. hypertension)
b.) valvular disease (eg. aortic stenosis or mitral regurgitation)
c.) prolonged rhythm disturbances (eg. ventricular tachycardia)
The primary signs and symptoms of all types of CHF include:
• tachycardia
• decreased exercise tolerance
• shortness of breath
• peripheral and pulmonary edema
• cardiomegaly
Cardinal feature: cardiac output (CO falls short of what is required for normal tissue
perfusion
Reason: decrease in cardiac contractility
Low output failure: responds to positive inotropic drugs
High output failure: the demands of the body are so great that even increased CO is
insufficient (eg. hyperthyreodism, beri-beri, anaemia, arteriovenous shunt). Respond
poorly to positive inotropic drugs.
Haemodynamics of heart failure
Forward or inotropic failure - reduced ejection into the aorta and pulmonary artery
Backward or lusitropic failure - inadequate emptying of the venous reservoirs
Flow=8 l/min
PRESSURES
VENOUS
SYSTEM
5
Flow=8 l/min
30
RIGHT VENTRICLE
8
LUNGS
100
LEFT VENTRICLE
5
SYSTEMIC
CIRCULATION
SITE OF FAILURE
BACKWARD FAILURE
FORWARD FAILURE
Right heart failure
Increased systemic
Reduced ejection into
venous pressure
pulmonary artery
Left heart failure
Increased pulmonary
Reduced ejection into the a
venous pressure
aorta
Because blood flows in a circle, none of these occurs in pure form.
In "Forward failure" - when the ventricle empties poorly, the filling is reduced
In "Backward failure" - when filling is reduced, the stroke volume is reduced
In right ventricular failure: the increase in systemic venous pressure and decreased ejection of
blood into the pulmonary artery reduce the output of the left ventricle
Flow=6 l/min
10
PRESSURES
VENOUS
SYSTEM
Flow=6 l/min
30
RIGHT VENTRICLE
RVEDP 
8
LUNGS
100
LEFT VENTRICLE
10
SYSTEMIC
CIRCULATION
Circulatory reflexes
maintain mean arterial
pulmonary pressure
In left ventricular failure: increased pulmonary venous pressure  impedes the blood out of the
lungs  increases pulmonary capillary pressure. This is transmitted across the pulmonary
circulation and results in increased pulmonary arterial pressure which can impair right ventricular
ejection.
Flow=6 l/min
Flow=6 l/min
PRESSURES
VENOUS
SYSTEM
5
40
RIGHTVENTRICLE
18
LUNGS
100
LEFT VENTRICLE
LVEDP 
5
SYSTEMIC
CIRCULATION
Signs and symptoms of heart failure
The clinical picture in heart failure consists of:
• signs (the objective manifestations of depressed cardiac performance),
• symptoms (abnormalities perceived by the patient).
Left heart failure: is a "forward failure" - reduced ejection,
"backward failure" - rise in pulmonary capillary pressure.
Systemic reflex activation: vasoconstriction  increased blood pressure (to maintain
perfusion of vital organs; ie. heart, brain)
Despite the increased sympathetic tone perfusion decreases
• to the skeletal muscle: fatigue and skeletal muscle myopathy
• to the kidneys: oliguria, sodium and water retention
• to the tissues: cyanosis
Because of the backward failure  pulmonary congestion  impaired respiration
• Dyspnea (difficulty breathing) due to arterial hypoxia, and decreased lung
compliance (excess fluid transudates from the pulmonary capillaries) depth and rate of
breathing increase). Typical in supine position.
Mild HF: dyspnea occurs only during heavy exercise
Severe HF: dyspnea is present at rest (bubbling noises during respiration)
End-stage HF: fluid fills the bronchial system; pulmonary edema
Right heart failure: is a backward failure rather than a forward failure.
• The central venous pressure is over the maximum.
• Edema (liver, kidneys, spleen, GIT, skin, genitalies)
• Cyanosis
Cardiomegaly - one of the major signs of heart failure.
• Initially due to the operation of the Frank-Starling relationship
• Remodelling of the ventricular wall is a complex process
Pressure overload (hypertension, aortic stenosis  `inward' hypertrophy,
reduced ventricular cavity (concentric hypertropy)
Volume overload (aortic regurgitation)  the ventricle dilates (eccentric
hypertrophy)
Grading of severity of heart failure according to the New York Heart Association
(NYHA)
NYHA I. Signs of heart failure appears only heavy exertion and disappear after its
discontinuation
NYHA II. On normal workload signs of CHF appears in the evening but disappear
after night rest
NYHA III. At rest minimal signs of CHF causing no complains but marked signs of
CHF on walking, which are not fully relieved by night rest.
NYHA IV. Signs of CHF even at bed rest.
Compensatory mechanisms in heart failure
Extrinsic reflex mechanisms for compensation:
Sympathetic nervous system (SNS)
Renin-angiotensin-aldosterone hormonal response.
Increased sympathetic outflow:
• tachycardia,
• increased contractility,
• increased vascular tone (venous tone)
• increased ventricular filling pressure
• dilatation of the heart
• increased fiber stretch
Increased aldosterone secretion:
• sodium and water retention
• increased blood volume
• edema.
Intrinsic compensatory mechanism: myocardial hypertrophy
• Increased muscle mass (to maintain cardiac performance)
• Hypoxic myocardium
• Decreased oxygen supply to the myocardium
1
Developed
tension
2
normal
Velocity of
contraction
normal
failing
failing
0
5
10
15
PCWP (Hgmm)
20
25
0
5
10
15
20
25
LOAD
Depressed contractility in heart failure reflected either as a reduced peak tension
development (1) or depressed force-velocity curve (2)
Pathophysiology of cardiac performance
Cardiac performance depends on at least 4 primary function:
A: PRELOAD (LVEDP, LVEDV, reflected as central venous pressure)
Preload refers to the diatolic loading conditions of the heart;
- Left ventricle: left atrial pressure (or pulmonary capillary wedge pressure = PCWP)
- Right ventricle: right atrial pressure for the right ventricle.
These are the "filling pressures"
Left ventricular function curve: (SV or SW against the filling pressure)
Stroke volume
or
work
plató phase
Frank - Starling
relation
0
5
10
15
20
25 PCWP (Hgmm)
The ascending limb (bellow 15 mmHg) represents the classic Frank-Starling relation. Beyond
approximately 15 mmHg, there is a plateau of performance. Preload greater than 20-25 mmHg
result in pulmonary congestion.
The Frank-Starling low of the heart describes the property of cardiac muscle to increase
its contractility as the length of the myocardial fiber (stretch) is increased.
To accomplish this increase in stretch, more blood must be returned to the heart by:
a.) Increased sympathetic tone causing  vasoconstriction  decreased venous blood
storage (pooling)  increased end-diastolic volume (or filling pressure) and CO.
b.) Redistribution of blood from viscera to heart
c.) Fluid or sodium retention due to decreased renal perfusion, and renin-angiotensinaldosterone activation. This increases volume of blood returned to the heart and also
may cause edema.
REDUCTION OF PRELOAD: DIURETICS
B: AFTERLOAD: is the resistance against which the heart must pump blood. Systemic
vascular resistance is frequently increased in CHF (increased sympathetic outflow
and circulating catecholamines). This may speed failure.
REDUCTION OF AFTERLOAD: ARTERIAL VASODILATORS
C: CONTRACTILITY: is the vigor of contraction of heart muscle. In CHF the
primarily defect: reduction in the intrinsic contractility (dP/dt)
INCREASE IN CONTRACTILITY: POSITIVE INOTROPIC DRUGS.
D: HEART RATE: is the major determinant of cardiac output (CO)
- When CO decreases HR increases (beta-adrenoreceptor activation)
- Consequences: - diastole shortens
- myocardial perfusion worsens
- hypoxia
CARDIAC HYPERTROPHY
The most important intrinsic compensatory mechanisms. Complex biochemnical
biophysical mechanisms in the background.
a.) Energetics in the failing heart
Imbalance betwen energy production and energy utilization.
Cause: is the overload itself
Result: "state of energy starvation" (increased energy utilization and decreased high
energy phosphate production).
b.) Structural changes in the chronically overloaded heart
Failing heart is not equal with a normal enlarged heart (sportmen’s heart)
Architectural changes: Pressure overload - the walls of the heart thicken
Volume overload - dilated heart
Chronic heart failure: hyperthrophied heart:
• myocyte necrosis (fibroblast poliferation)
• muscle is replaced by connective tissue
• the heart begins to dilate
• wall tension incerases
• propensity for arrhythmias
c.) Altered blood supply
• Imbalance between the capillary density and muscle mass (increased
intercapillary distance)
• Decreased coronary reserve (underperfused subendocardium)
• Subendocardial necrosis
d.) Altered proportion of mitochondria and myofibrils
• Imbalance between myofibrils and mitochondria (more energy-consuming
myofibrils must be supplied with ATP by relatively fewer mitochondria)
• Exacerbated energy starvation
NOTE:
a.) Many of these sings and symptoms of CHF are a direct result of these compensatory
mechanisms.
b.) Despite all attempts to compensate, the cardiac function deteriorate
VITIOUS CYCLE
occur, and CO cannot be maintained without medical intervention
Arrhythmogenic mechanisms in the hyperthropied heart
• Enlargement and fibrosis of the atria and ventricles: increased susceptibility to
arrhythmias (slow conduction  reentrant arrhyhtmias)
• Increased calcium accumulation in the cells  initiate triggered activity.
• Lowered resting potential (sodium pump inhibition)  slow conduction.
• Acidosis  slowing of conduction
SUDDEN CARDIAC DEATH
Altered gene expression in the chronically overloaded, failing heart
Gives the answer; Why the prognosis is so poor in this patients?
• Appearance of abnormal proteins (accelerated potein synthesis)
• Abnormalities in gene expression (accelerate the deterioration)
The detrimental consequences of hypertrophy seems to represent a `price' that the
overload heart must pay in order to accelerate protein sysnthesis.
The heart's response to overload can be divided in three phases that have different
functional and prognostic implications.
a.) First short-term stage of acute heart failure
Clinical: left heart failure, pulmonary congestion
Pathological: dilatation of the left ventricle
Histological: swelling and separation of myofibrils
Biochemical: glicogene and ATP levels decreased, lactate slightly increased
b.) Second long-term stage of compensatory hyperfunction
Clinical: relief of symptoms
Pathological: hypertrophy
Histological: increased size of cardiac fibers, minimal fibrosis
Biochemical: glycogen, ATP normal, lactate increased. Miofibrillar mass
increased relative to that of the mitochondrial mass.
3.) Third long-term stage of progressive exhaustion, cell death and fibrosis
Clinical: reappearance of heart failure
Pathological: fibrous replacement of muscular tissue
Histological: connective tissue, fatty dystrophy
Biochemical: as in second stage, exept decline in protein systhesis and marked
decline in DNA levels.
NEUROHUMORAL AND RENAL MECHANISMS IN HEART FAILURE
Neurohumoral systems may play both a detrimental and protective role in the
pathogenesis of CHF.
Compensatory mechanisms activated in CHF: vasoconstrictive and antinatriuretic
vasodilatory and natriuretic
The biologic activities of these systems are antagonistic.
Vasoconstrictive-antinatriuretic
Vasodilatory-natriuretic
Renin-angiotensin-aldosterone system
Atrial natriuretic factor (ANF)
Sympathetic nervous system (SNS)
Prostaglandins
Vasopressin
Dopamine
Thromboxane
Kallikrein, kinins
Endothelin
EDRF
1. Vasoconstrictive-antinatriuretic system
a.) Sympathetic nervous system (SNS)
Increased activity of SNS occurs early in the course of CHF and contributes to
clinical deterioration and mortality in HF
(1) Adrenergic receptor function
Increased sympathetic activity  receptor down-regulation
ACE inhibitors (eg. Captopril)  resensitization (reduced NA release)
Evidence for: decreased level of Gs and increased level of Gi
Future tool?
(2) Baroreceptor or baroreflex abnormalities in heart failure
Baroreflex control of the heart is impaired (structural changes in
baroreceptors or arterial wall).
(3) Sympathetic stimulation is involved in:
• LV remodelling
• loss of myocardial cells
• gene expression
Increased sympathetic drive induces:
a.) myocardial hypertrophy and fibroblast hyperplasia through stimulation of 1
and  receptors
b.) accelerated myocardial cell lost - apoptosis
c.) NA may induce apoptosis through  receptor activation
d.) changes in myocardial gene expression which results in progressive
worsening in contractility (downregulation of the adult type, high ATP-ase activity
-myosin heavy chain isoform and upregulation of the fetal type, low ATP-ase
activity -myosin heavy chain isoform)
b.) Renin-angiotensin system
Angiotensin II (AGII) is the key element with multiple biologic activity
AG II influences cardiac metabolism, involved in the development of
ventricular hypertrophy through its growth promoting effects.
Interaction with other neurohumoral systems (enhances NA synthesis,
reduces NA reuptake, facilitates NA release from nerve endings). Antagonistic
with the ANF system
Plasma RAS maintains circulatory homeostasis during acute and subacute alterations
in cardiac output
Tissue RAS contributes to maintain homeostasis during impairment of CO
1. Activation of the RAS
Occurs in response to reduction in cardiac output.
Arterial constriction   SABP and DABP
Catecholamine release 
Angiotensin II.
 aldosteron secretion  (adrenal cortex)
• sodium retention
• water retention
• potassium excretion
Increased blood pressure
• water intake 
• vasopressin secretion 
• adrenocorticotropic hormon 
AGII binding to AT1 receptor leads to cardiac remodelling which includes:
• upregulation of many early active cardiac myocyte genes
• induction of late markers of cardiac hypertrophy (a-actin) and
growth factors such as TGF
• shift to fetal type myocardium
AGII binding to AT2 receptor may oppose the effect of AGII on AT1 receptors
c.) Vasopressin
Crutial role in hyponatremia in CHF (V2 linked hydro-osmotic effect)
In small concentrations  vasodilator (EDRF release?)
2. Vasodilatory-natriuretic systems
a.) Atrial natriuretic factor (ANF)
Maintains renal haemodynamic function, attenuates the RAS system
ANF levels are elevated in CHF (indicator of developing dysfunction)
In CHF relative ANF deficiency
Therapeutical value: ANF replacement ?
b.) Prostaglandins
Endogenous vasodilator PGs (PGI2) opposing the effect of the
vasoconstrictive endogenous agents
c.) Dopamine
Therapeutic agent in CHF
d.) Endothelium derived vasoactive agents
Both vasodilator (EDRF -- NO ?) and vasoconstrictor (endothelin)
Endothelin - renal and systemic vasoconstrictor, activates RES
CELLULAR MECHANISMS IN HEART FAILURE
1. Role of calcium levels
• Calcium regulates - contraction/and relaxation.
• Intracellular calcium is modulated by: cAMP and IP3 "second messenger"
systems
• Extrusion of calcium is regulated by: calcium pump (CaATP-ase) and calciumsodium exchange
• In CHF abnormal calcium handling is apparent
2. cAMP
It is an important "second messenger" modulates calcium handling
• activates protein kinases (Ca2+ entry)
• regulates calcium sequestration into the SR
• regulates myofilament responsiveness to calcium
In CHF reduced cAMP levels are apparent.
3. Sarcolemmal receptors and mechanisms
• Homologous  receptor downregulation  cAMP dependent protein kinase
phosphorilates the  receptors  desensitization
• In CHF the SR cacium uptake function is altered
4. Altered myocardial responsiveness to calcium
• In CHF altered responsiveness to Ca2+ (reduced Ca2+ affinity to troponin C)
• Altered gene expression  abnormal protein synthesis  fatal myosin isoforms
Factors stimulate cell growth
Cell deformation
Stretch activated ion channels
Cytoskeletal rearrangements (microtubules, desmin)
Extracellular growth factors
FGF (fibroblast growth factor)
TGF (type  transforming factor)
Extracellular neurohormonal pharmacological modulators
-adrenoceptor stimulants
-adrenoceptor stimulants
angiotensin II and endothelin
thyroxin, insulin
growth hormone (GS/TGF-I ratio)
glucocorticoids
cytokines
TNF 
Intracellular energy deficit
decreased high energy phosphates (ATP, CP)
increased products of excessive energy utilisation (ADP, AMP, ceratine)
Intracellular second messengers
cAMP, cAMP-dependent kinases
calcium and IP3/DG/PKC pathway
Cellular protooncogens
c-fos, c-myc, c-jun
Cellular signalling factors
citochrome-c and apoptotic protein activting factor-1
caspases
protoapoptotic proteins (bax)
Death receptors
Fas
TNF receptors
Genetic factors in the development of heart failure
1. Non-familial hypertrophic cardiomyopathy (NF-HCM)
LV mass is partially determined by familial influence and 60 % of the variability can
be explained by heritable factors.
Local RAS gene polimorphism  predisposition to hypertrophy.
Genetic polimorphism in intron 16 of ACE gene, characterised by an insertion (I) or
a deletion (D) of a 287-bp sequence. This ACE I/D polimorphism is strongly related
to ACE plasma level and myocardial concentration.
2. Familial hypertrophic cardiomyopathy (FHC)
Genetically heterogenous - 7 genes have been identified as responsible for the
disease:
14q11-12
- b myosin heavy chain
1q3
- cardiac troponine T
15q2
- a-tropomyosin
11p11.2
- cardiac myosin binding protein c
12q
- regulatory light chain of myosin
3p
- essential light chain of myosin
19p13-q13
- cardiac troponine I
Catabolic/anabolic imbalance
The general feature of neuroendocrine abnormalities:
A catabolic/anabolic imbalance exists in HF. TNF is a key factor regulating energy
metabolism, immune status, neuroendocrine and hormonal function.
• Catabolic/anabolic status in CHF can be estimated by the cortisol/DHEA
(dehydroepiandosterone) ratio. This ratio is highest in cachectic patients and
correlates strongly with the degree of immune activation, represented by circulating
TNF and soluble TNF receptor 1 and 2.
• Cytokines induce programmed cell death (apoptosis) which is present in the skeletal
musculature especially in cachectic patients.
• Growth hormone (GH) - insulin like growth factor-I (IGF-I) axis is abnormal in severe
CHF. In cachectic CHF patients GH is elevated and IGF-I is normal or low.
• Insulin resistance is frequently observed in CHF. (Insulin is the strongest endogenous
anabolic hormone which regulates the metabolic status of peripheral musculature.
(Fasting insulin levels are only increased in non-cachectic patients. This might be due
to a compensatory metabolic mechanism to overcome the insulin resistance). Use of
insulin sensitizers might be useful!
• Immune activation is present in CHF. TNF could be casual for the metabolic
disturbances:
• elevated metabolic rate
• impaired tissue flow
• altered fat and protein metabolism
TNF is mainly elevated in cachectic CHF patients and it is the strongest predictor of
the degree of weight loss.
Apoptosis in heart failure
Apoptosis is an important mode of cell death (progressive loss of cardiac myocytes) in heart
failure. AGII promotes apoptosis
Apoptotic pathways:
1. Cytochrome c- is released in response to an apoptotic stimulus from the mitochondria.
Cytochrome c, in the presence of dATP, forms an activation complex with apoptotic proteinactivating factor-1 and caspase-9. This complex activates downstream caspases which leads to
the final morphological and biochemical changes. This pathway is tightly regulated by a group
of antiapoptotic proteins, such as Bcl-2 and proapoptotic proteins, such as Bax. Further
regulation occurs downstream by various inhibitors of caspases. Bcl-2 is upregulated soon
after coronary artery occlusion, espcially in the salvagable myocardium but is decreased in
chronic HF induced by pressure overload. Apoptosis occurs in a high rate during reperfusion .
The overexpression of BCL-2 effectively reduces reperfusion injury by reducing myocyte
apoptosis. Bcl-2/Bax balance is important in the increased rate of apoptosis in cardiac
myocytes..
2. Death receptors (e.g. Fas, and TNF receptors) and caspase 8 also activate downstream
caspases. Expression of Fas is upregulated in cardiac myocytes during ischaemia and heart
failure.
Antiapoptotic therapy includes:
Beta adrenoceptor blockers: e.g. Carvedilol
ACE inhibitors
Caspase inhibitors
Some hypertrophic signalling factors, such as cardiotrophin-1 via gp 130, insulin-like growth
factor-1 via phosphoinositide-3-kinase, and calcineurin via the nuclear factor of activated T-cells
seem to be protective.
Apoptotic stimulus
Pproteinactivating
factor
caspase 9
Proapoptotic
protein Bax
citochrom c release
from the mitochondrium
Antiapoptotic
protein Bcl-2
activation complex
caspase-cascade activation
morphological and biochemical alterations
„death receptors”
Fas és TNF
GOALS OF DRUG THERAPY FOR CHF
The major goal of therapy is: to increase cardiac contractility (positive inotropic action)
improve cardiac output
to stop progression
1.) Improving the ability of the heart to meet the demands placed upon it (eg. by
increasing contractility), or
2.) By reducing the demands being placed on the heart (eg. by reducing afterload with
vasodilators)
A: Drugs which enhance contractility of the failing myocardium
a.) Cardiac glycosides
b.) dopamine and dobutamine
c.) PDE III inhibitors (amrinone, milrinone)
B: Vasodilators
To reduce preload and afterload
a.) Venodilators (nitrites and nitrates)
b.) Direct acting arterial dilators (hydralazine and minoxidil)
c.) Alpha-adrenoreceptor blocking agents (prazosin)
d.) Calcium antagonists (nifedipine)
C: ACE inhibitors
To reduce afterload and inhibit the progression of hypertrophy (gene expression ?)
Captopril, Enalapril, Ramipril
D: Antiarrhythmic agents
To reduce irregular ventricular arrhythmias and prevent sudden death
E: Diuretics
Use to decrease edema, reduce blood volume. However, vigorous diuresis can be
harmful (excessive reduction in preload which leads to a further decrease in CO).
Role of positive inotropic drugs in the treatment of CHF
Positive inotropic agents are able to
1. Increase the extent and the speed of myocardial shortening (when preload, afterload,
heart rate are kept constant). Act in normal myocardium, some play a physiologic
role: NE, E.
2. Improve contractility of the failing heart during polonged administration
Goals for use of positive inotropic drugs
1. Immediate lie-saving situations (after cardiac surgery, intensive care) i.v.
DOPAMINE, DOBUTAMINE, DOPEXAMINE, ENOXIMONE,
LEVOSIMENDAN, are useful if depression of myocardial function is thought to be
reversible and is primarily related to abnormal excitation-contraction coupling
2. Chronic heart failre from NYHA II to NYHA IV they remain the part of the therapy
despite full therapy with diuretics, vasodilators and ACE inhibitors. Aim to improve
the symptoms and quality of life; if possible to improve survival. CARDIAC
GLYCOSIDES, PDE INHIBITORS.
CARDIAC GLYCOSIDES
Egyptans 3000 years ago. In the 18th century William Withering described the clinical
effects of an extract of the foxglove plant (Digitalis purpurea).
Chemistry
All of the used cardiac steroids, or cardenolides combine a steroid nucleus with an
unsaturated lactone ring at the 17 position and a series of sugars linked to carbon 3 of
O
the nucleus.
O
23
21
lacton
20
22
CH3
12
11
CH3
O
glucose
3 digitoxose
16
HH
14
15
9
1
2
10
8
5
3
17
13
4
OH
7
6
H
oid
s er
mi
o
lik
ge
n(
n)
ag
The lactone ring and the steroid nucleus are essential for activity.
The pharmacological active principle is the genin or aglicone. Three aspects of this general
structure are required for optimal activity:
a.) the hydroxyl at position of 14
b.) the unsaturated (5 or 6 numbered) lactone ring at position of 17
c.) the cis relationship between rings C and D (all other natural steroids are trans)
The sugars are not necessary for activity but greatly affect water solubility, the speed of onset,
potency and duration of action of the drug.
Sources of these drugs: white and purple foxglove (D lanata and D purpurea), Mediterranean sea
onion (squill), Strophantus gratus, Oleander, lilly of the valley etc.
Certain toads skin glands: bufadielonides (6 membered lactone ring)
PHARMACOLOGICAL ACTIONS
1.) POSITIVE INOTROPIC ACTION (force of myocardial contractility)
They increase the force and velocity of cardiac contractions (dP/dt).
Mechanism of action
T-tubulus
Na
Ca2+
+
Ca2+
ATPáz
1
C a 2+
Exch.
K
+
Na
+
2
1/a
3
2+
SR
Ca
ACTIN
MIOZIN
Inhibition of K+-Na+ATP-ase (membrane bound enzyme, associated with the "sodium pump")
The therapeutic direct action: increase the intensity of the "activate state" of the contractile apparatus by
increasing free Ca2+ concentration in the vicinity of the contractile proteins during systole)
The facilitation of excitation-contraction coupling may be as a result of:
1.) Inhibition of Na+-K+ATP-ase  reduced Na+ transport out  increased [Na+]i (1) 
reduced normal transport of Ca2+ out (via Na+/Ca2+ exchange)  increased [Ca2+]i (1/a)
2.) Facilitation of Ca2+ entry, through the voltage-gated Ca-channels, during the plateau
phase
of action potential (2).
3.) Increased release of stored Ca2+ from the SR (3).
NOTE: Toxic effects are well correlated to inhibition of ATP-ase and to ‘calcium overload’.
Loss of intracellular K+ (increase in [Na+], and increase in [Ca++]i) favours the induction of
Haemodynamic effects of cardiac glycosides
a.) Effects in patients with heart failure
• Cardiac glycosides increases CO.
• All of the other observed changes are secondary to this one effect.
b.) Relationship of ventricular function
NORMAL
CO (ml)
FAILING + DIGITALIS
C
N
Low output
syndrome
Fatigue
FAILING
I
B
A
Congestive symptoms
LVEDP (Hgmm)
DYSPNOE
N to A = reduction in myocardial contractility
A to B = compensation (ie. increase in preload to increase output of failing heart)
B to C = digitalis action (ie. increased myocardial contractility)
C to D = reduction in heart size (ie. decreased preload) secondary to improved
performance (CO) during digitalis treatment
D to E = reduction in filling pressure with no positive inotropic intervention
(eg. diuretics)
c.) Effect of digitalis in normal patients
(1) Myocardial contractility increases
(2) Vascular tone increases
(3) CO does not change or may even decrease
2. Indirect (vagal) electrophysiolcical effects
a.) BRADYCARDIA: both direct and vagal effects
Vagus effect is due to:
• stimulation of the vagal nucleus
• greater sensitivity of the heart to Ach
This can be abolished by atropine or by vagotomy
• In lower doses, cardioselective parasympathomimetic effects predominate
• Cholinergic innervation: in the atria and AV node
• Less indirect effect on Purkinje or ventricular function.
In hear failure tachycardia can abolish automatically when CO is increased
b.) SHORTENING OF THE REFRACTORY PERIOD (RP) OF ATRIAL MUSCLE
• Speeding of atrial rate  atrial flutter transfers to fibrillation
c.) SLOWING CONDUCTION THROUGH THE AV NODE
• Prolonged P-R interval (1o heart block)
• Dropped beats (2o heart block)
• Complete AV dissociation (3o heart block)
• Slowing of ventricular rate during atrial flutter or fibrillation
Since ventricular rate depens primarily on the activity of the AV node, prolongation
of the RP of the AV node  protects the ventricle from the rapid atrial impulses 
ventricular rate will be slowed
3. Direct electrophysiological effects
(1) Atrial muscle
• Early, brief prolongation of AP (increased membrane resistance), followed by
• shortening of the AP (decreased membrane resistance; due to increased [Ca2+]i
 increased [K+]out). This results in AP shortening of atrial and ventricular
refractoriness.
(2) AV node
• Slowed conduction, prolongation of RP (direct effect is synergistic with vagal
effects).
(3) Automaticity
• Digitalis increases the automaticity in the latent pacemakers
• It generates ”afterdepolarizations, afterpotentials"  arrhythmias.
• Slowing of intracardiac conduction (toxic doses) and increased automaticity
leads to:
- ES formation
- AV junctional rhythm
- bigeminy
- VT, VF
- asystole (cardiac standstill)
Digitalis can cause virtually every variety of arrhythmia.
Conduction disturbance (AV block): due to Na+ pump inhibition
Arrhythmias: due to oscillatory afterdepolarizations (caused by overload of
intracellular Ca2+).
Electrocardiographic effects
ECG changes: ST-segment depression, inversion of T wave, PR prolongation, QT
shortening. Induction or increase of U waves. These precede signs of
toxicity such as bigeminal rhythm, ES, AV dissociation and ventricular
arrhythmias.
Ventricular arrhythmias
(1) Cardiac glycosides are utilized as antiarrhythmic drugs:
• supraventricular tachyarrhythmias (increase the RP of the AV node; flutter 2 :1;
fibrillation 3 : 1)  slower ventricular rate  increase in CO (diastolic filling
time increases)
(2) Cardiac glycosides may cause virtually any type of arrhythmias (ventricular or
supraventricular).
• Inhibition of Na+-K+ATP-ase  [Na]+i increases  resting MP reduces
• Increased rate of diatolic depolarization of the Purkinje cells
• Decreased AV conduction (direct and indirect effects)
• Abnormal automaticity (delayed afterdepolarizations)  arrhythmias
Vascular system
• Direct constriction on arterial and venous smooth muscle  increased TPR and
BP (best seen after iv injection in normals)
• Venoconstriction seen in CHF patients decreases after cardiac glycosides
(cardiac function, compensatory sympathetic tone)
Gastrointestinal effects
• GIT is the main extracardiac site of digitalis effect (unwanted side effects)
anorexia, nausea, vomiting, diarrhea
• These effects are partially due to the direct effects on the GIT or indirect; ie.
stimulation of CNS, including chemoreceptor trigger zone
CNS effects
• Stimulates the vagal nucleus in the medulla slowing HR and increase in GIT
motility.
• Stimulates chemoreceptor emetic zone in the area postrema  nausea and vomiting
• Visual changes - changes in color vision
• Neurological symptoms- headache, fatigue, disorientation, digitalis delirium seen
particularly in elderly, rare convulsions, facial pain, similar to trigeminal neuralgia
Other effects
• Diuresis • due to increased cardiac function and circulation (renal blood flow)
• inhibition of K+Na+ATP-ase in the kidneys
• Interactions with K+, Ca2+ and Mg2+
• K+ and Ca2+ are antagonistic
• K+ and digitalis (i) inhibit each-other's binding to Na+-K+ATP-ase, therefore,
hyperkalemia reduces, hypokalemia faciltates the effects of
cardiac glycosides
• Ca2+ facilitates the toxic actions of digitalis
• Mg2+ opposes the effect of Ca2+
Indications
a.) Heart failure with atrial or supraventricular tachyarrhythmias (flutter or fibrillation)
b.) Atrial flutter or fibrillation with rapid ventricular rate
c.) Acute supraventricular tachycardia and decompensated heart
d.) Prevention of atrial fibrillation and junctional tachycardia
Contraindications
a.) Hypertrophic cardiomyopathy (hypertrophic subaortic stenosis); cardiac glycosides
increase the obrtruction against ejection, and inhibit relaxation
b.) WPW syndrome (they enhance the redtrograde pulse conduction, provoke VT)
c.) AV block
Relative contraindications
a.) If the decompensation is caused by: pericarditis, valvular stenosis, cor pulmonale
b.) Hyperthyreosis (high CO syndrome)
c.) Acute myocarditis
d.) Acute myocardial infarction, ischaemia
e.) Hypokalemia, renal insufficiency
f.) Together with calcium antagonists, beta blockers, quinidine (reduce clearence of
digitalis)
Toxic effects of digitalis
Reason: calcium overload, N+K+ATP-ase inhibition.
Toxicity is exacerbated by:
• sympathomimetics
• increase in calcium
• decrease in magnesium
• hypoxia
• increased heart rate
• potassium depletion
Symptoms: extreme bradycardia, arrhythmias, anorexia, fatigue, headache, nausea,
neuralgic pain and altered color vision (yellow hues)
Treatment of toxicity
• Discontinue cardiac glycosides
• Correct precipitating factors (eg. electrolite disturbance)
• Treat serious arrhythmias
• K+ salts with normal renal function and constant monitoring
• Antiarrhythmic drugs (Phenytoin, Lidocain)
• Asystole may result in presence of complete heart block and abolition of
ventricular arrhythmia
• Steroid binding resins (primarily for digitoxin) and digoxin specific
antibodies may be useful to aid drug removal
OTHER POSITIVE INOTROPIC DRUGS
A: BETA ADRENERGIC RECEPTOR AGONISTS
DOPAMINE, DOBUTAMINE, DOPEXAMINE
• The positive inotropic action is accompanied only with little chronotropic activity
or incerase in TPR
• Use in acute heart failure (iv) due to AMI
ISOPROTERENOL is NOT used in CHF (HR)
ARAMINE (METARAMINOL), XAMOTEROL and METOPROLOL
• Partial  agonists, stimulate  receptors  positive inotropic action during longterm administration
•  receptor antagonists when sympathetic drive incerases (stress, exercise)
• Improves LV diastolic function
• They could be detrimental in NYHA IV
• Indication: mild or moderate HF
B: PDE INHIBITORS
AMRINONE (INOCOR), MILRINONE (PRIMACOR), ENOXIMONE
Mechanism of action
• PDE inhibition  cAMP   Ca2+ influx through calcium channels 
• Increased release of Ca2+ from SR
Result: positive inotropic action, balanced veno and arterial dilation
Efficacy: • Negative during prolonged therapy in mild and severe HF
• Proarrhythmic
• No functional benefit, incerased mortality compared to digoxin
Since in end-stage failure cAMP production is reduced (downregulation of  receptors)
PDE inhibitors and  agonists are not adequately effective.
Preparations
Narrow therapeutic range, small therapeutic index.
LANOXICAPS (LANOXIN) - DIGOXIN
LANATOZID C - duration is similar to digoxin, but poor oral absorpt
OUABAIN (Strophantin) - short acting, only used experimentally
ACETYLSTROPHANTIDIN - ultra short acting, only used experimentally
ACIGOXIN (ACETYLDIGITOXIN) - lanatoside A glycoside; inj. tabl.
CARDITOXIN (DIGITOXIN) - tabl.
DIGOXIN - inj, solutio, tabl.
ISOLANID (DESLANATOSID) - Lanatoside C glycoside, inj, tabl.
TALUSIN (PROSCILLARIDIN) - tabl.
DIGITALIS LEAF (whole leaf preparation) - duration is similar to digitalis but less
potential
Administration
• Individual dosing ("titration”) to achieve adequate therapeutic effects and minimize
undesirable side effects or toxicity.
• Digitalizing dose and maintenance dose:
Tradicional: large starting doses to achieve high plasma levels and tissue
concentration, followed by smaller doses to maintain plasma levels.
Modern: slower dosage is recommended (large starting doses only in emergency
situation)
C: CALCIUM SENSITIZERS
SULMAZOL, PIMOBENDAN, SIMENDAN, LEVOSIMENDAN
Mechanism of action
• Sensitisation of contractile proteins (troponin C) for calcium  positive inotropic
action
• Inhibits PDEIII enzyme  cAMP
 vasodilatation
 unwanted tachycardia
 arrhythmia generation
D: VASODILATORS
NITRATES (NITROGLYCERIN, NITROPRUSSID)
CALCIUM ANTAGONISTS (NIFEDIPINE = CORINFAR = ADALAT)
DIRECTLY ACTING VASODILATORS (HYDRELAYINE = DEPRESSAN,
MINOXIDIL)
ALFA-ADRENOCEPTOR BLOCKERS (PRASOZIN = MINIPRESS)
Vasodilators therapy is advocated:
• systemic resistance is increased in CHF
• vasodilators (e.g. Nitrates) reduce LV filling pressure and increase CO
However, most vasodilators are not selective  the initial enthusiasm has waned
• The immediate haemodynamic effects are not sustained in the long-term
• They do not relate to long-term clinical improvement
• They do not increase excersise capacity
• There is no evidence that they alter mortality
• Nitrates could be used to delay progression of myocardial damage
E: ACE INHIBITORS
CAPTOPRIL (TENSIOMIN), ENALAPRIL (RENITEC)
Plasma RAS maintains circulatory homeostasis during acute and subacute alterations in
cardiac output
Tissue RAS contributes to maintain homeostasis during impairment of CO
1. Activation of the RAS
Occurs in response to reduction in cardiac output.
Arterial constriction   SABP and DABP
Catecholamine release 
Angiotensin II.
 aldosteron secretion  (adrenal cortex)
• sodium retention
• water retention
• potassium excretion
Increased blood pressure
• water intake 
• vasopressin secretion 
• adrenocorticotropic hormon 
AGII binding to AT1 receptor leads to cardiac remodelling which includes:
• upregulation of many early active cardiac myocyte genes
• induction of late markers of cardiac hypertrophy (a-actin) and
growth factors such as TGF
• shift to fetal type myocardium
AGII binding to AT2 receptor may oppose the effect of AGII on AT1 receptors
2. Hyperaldosteronemia
AGII activates aldosterone secretion (+ decreases hepatic aldosterone clearance)
Incerased aldosterone levels are indicators of HF (like the increased level of ANP)
Elevated aldosterone leads to
• myocardial fibrosis
• sympathetic activation
• BRS activation
• magnesium loss
• arrhythmias
Angiotensin receptor blockade
ACE inhibition fails to produce complete blockade of the RAS; ie. in response to the
decrease in plasma AGII levels following ACE inhibition, the compensatory renin
secretion rapidly restores AGII levels and this attenuates the effects of ACE inhibition.
Similarly, cardiac ACE and chymase are specific AGII forming enzymes which are not
abolished after chronic ACE inhibition.
AT1 receptor antagonists: LOSARTAN, IBESARTAN, VALSARTAN, LISINOPRIL,
CANDESARTAN
Combined ACE inhibitor and AT1 receptor therapy:
AT1 receptors are inhibited + the ACE inhibition leads to reduced sympathetic tone and
generation of vasodilator kinins. In addition in this case, AGII acts on AT2 receptors
which effect, together with the increase in kinin production, might be beneficial.
Efficacy:
• reduction in symptoms of HF
• increased exercise capacity
• delay in progression of damage
• reduction in mortality
• act in all patients with mild to severe HF
• reduction in preload (venodilatation)
• reduction in afterload (arterial dilatation)
• improvement in regional blood flow (renal vasodilatation)
• improvement in coronary blood flow (due to reduced NE release)
• reduction in sympathetic tone and arrhythmias
• prevention of cardiac hypertrophy and dilatation
• prevention of cardiac remodelling
F: BETA RECEPTOR ANTAGONISTS
Sympathetic stimulation is involved in:
• LV remodelling
• loss of myocardial cells
• gene expression
Increased sympathetic drive induces:
1. myocardial hypertrophy and fibroblast hyperplasia through stimulation of 1 and 
receptors
2. accelerated myocardial cell lost - apoptosis
3. NA may induce apoptosis through  receptor activation (this can be blocked by
CARVEDILOL)
4. changes in myocardial gene expression which results in progressive worsening in
contractility
(downregulation of the adult type, high ATP-ase activity -myosin heavy chain
isoform and upregulation of the fetal type, low ATP-ase activity -myosin heavy
chain isoform)
Beta-adrenoceptor blockers
PROPRANOLOL, METOPROLOL, BUCINDOLOL, CARVEDILOL
First generation: PROPRANOLOL (non selective) blocks all myocardial  receptors
and increases systemic vascular resistance
Second generation: METOPROLOL and BISOPROLOL (1selective) produce lower
reduction in cardiac index because they do not block cardiac 2 receptors and they
have no effect on the 2-mediated vasodilatation. Metoprolol selectively upregulate
1 receptors and slightly improve maximal functional capacity
Third generation: CARVEDILOL and BUCINDOLOL are non-selective or mildly
selective agents. Their vasodilator (1 adrenoceptor blockade) activity may
counteract their negative inotropic and 2 adrenoceptor blocking effects thus they do
not worsen haemodynamics.
They might yield a greater protection against the increased sympathetic drive.
(i) They do not upregulate 1 receptors, a mechanism that may further reduce
the sensitivity of the heart to sympathetic drive.
(ii) They also block 2 receptors which because of 1 downregulation represents
40% of the total adrenergic receptors in patients with heart failure (dilated
cardiomyopathy) and may mediate the cAMP-dependent effects of
sympathetic stimulation even a greater extent than 1 receptors.
(iii) Presynaptic 2 receptors facilitate NA release. Thus, only non-selective
agents may decrease cardiac NA release.
(iv) Cardiac 2 receptors may favour malignant tachyarrhythmias through cAMP.
CRITICAL EVALUATION OF DRUGS USED IN THE TREATMENT OF CHF
Positive inotropic drugs
1. CARDIAC GLYCOSIDES (particularly digoxin)
• Improvement in exercise tolerance (controlled trials: captopril-digoxin, milrinonedigoxin, xamoterol-digoxin)
• In patients with sinus rhythm it’s efficacy is questionable
• No improvement in NYHA IV.
• Effect on cardiac mortality is controversial
USEFUL BUT WEAK POSITIVE INOTROPIC DRUGS WITH LOW
THERAPEUTIC INDEX
2. PDEIII INHIBITORS (AMRINONE, MILRINONE)
• Efficacy during prolonged therapy in mild to severe HF is negative
• Danger in arrhythmogenesis
• Lack in functional benefit
• Increased mortality (cp. to digoxin)
• In end-stage failure (cAMP production is reduced) they are not effective
3. BETA-ADRENOCEPTOR PARTIAL AGONISTS (XAMOTEROL)
• In normal subjects positive inotropic action
• If sympahetic drive is increased (exercise or severe HF) acts as -blocker
• Improves LV diastolic function
• Improves symptoms and quality of life in mild and moderate HF
4. VASODILATORS
• Most vasodilators are not selective
• The immediate beneficial haemodynamic effects are not sustained in the long-term
• Exercise capacity is not improved
• There is no evidence that they alter mortality
Nitrates could be used to delay progression of myocardial damage