Download Cardiovascular toxicity Cardiac Structure The cardiovascular system

General Toxicology
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Cardiovascular toxicity
Cardiac Structure
The cardiovascular system consists of the myocardium and vascular
vessels which supply the tissues and cells of the body with appropriate
nutrients, respiratory gases, hormones, and metabolites and remove the
waste products of tissue. In addition to the maintaining of the optimal
internal homeostasis of the body as well as for critical regulation of body
temperature and maintenance of tissue and cellular pH.
Cardiac myocytes are composed of contractile elements known as
myofibrils, which consist of a number of thick and thin myofilaments.
The thick filaments consist of the protein myosin, whereas the thin
filaments primarily consist of the protein actin. Cardiac myocytes are
joined end to end by intercalated disks. Within those disks, there are tight
gap junctions that facilitate action potential propagation and intercellular
communication.
Cardiac Electrophysiology
Action Potential
The ionic movement of action potential can be classified into 4 phases:
Phase 0: a phase of rapid depolarization due to a fast inflow of Na + into
the cells.
Phase 1: a short initial period of rapid repolarization caused mainly by
outflow of K+ from the cells.
Phase 2: a period of delay in repolarization caused by inflow of Ca +2 into
the cells.
Phase 3: a second period of rapid repolarization caused mainly by
outflow of K+ from the cell .
Phase 4: It’s a fully repolarized state during which Na+ and Ca+2 move
out of the cell while K+ move back into the cell
Electrical Conduction in the Heart
Spontaneous depolarization can be found in the sinoatrial (SA) node,
the atrioventricular (AV) node, the bundle of His (atrioventricular
bundle), and Purkinje fibers. SA nodal cells set the pace of the heart. If
the SA node is damaged or inhibited, the next fastest depolarizing cells
(AV node) assume the pacemaking activity. The dense fibrous tissue of
the AV node causes the electrical impulse to slow down. This delayed
transfer of current between the atria and the ventricles allows the atria to
complete contraction before depolarization of the ventricles.
Electrical cardiac activity is regulated by the autonomic nervous
system (ANS). Norepinephrine and similar sympathomimetics stimulate
an increase in cardiac rate and the contractility of the myocardium. The
major effect of parasympathomimetics is to decrease the rate of
depolarization with only a slight decrease in ventricular contractility.
Excitation-Contraction Coupling
For contraction to occur, both ATP and Ca2 + must be available.
Mechanical contraction of cardiac myocytes occurs when Ca2 + binds to
the protein troponin C with tropomysin. After a Ca2 +-induced
conformational change in troponin C and tropomysin, ATP is hydrolyzed,
and subsequently allowing myosin to bind actin, thus producing
contraction.
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Electrocardiogram:
The P wave is generated by atrial depolarization, the QRS by
ventricular muscle depolarization, and the T wave by ventricular
repolarization. The PR interval is a measure of conduction time from
atrium to ventricle through AV node, and the QRS duration indicates the
time required for all ventricular cells to be activated ( i.e the
intraventricular conduction time). The QT interval reflects the duration of
the ventricular action potential.
Cardiac Output
Normal cardiac output at rest is approximately 5 L/min in an average
adult human, and that value may increase three- to fourfold during
exercise. Toxicants may alter cardiac output
Abnormal Heart Rhythm
The normal human heart rate at rest is approximately 70 beats per
minute. A rapid resting heart rate (i.e., above 100 beats per minute) is
known as tachycardia, whereas a slow heart rate (i.e., below 60 beats per
minute) is known as bradycardia. Any variation from normal rhythm is
termed an arrhythmia, and arrhythmias are often complications secondary
to other ongoing disturbances in cardiac function. Supraventricular
arrhythmias may be based on defects in AV nodal reentry circuits.
Ventricular arrhythmias may arise from muscle injury secondary to
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ischemia, infarction, or from ventricular hypertrophy. Heart block is due
to impairments in the cardiac conducting system.
Ischemic Heart Disease
Ischemic heart disease (IHD) may be produced by various pathologic
conditions and/or xenobiotics that disturb the balance of myocardial
perfusion and myocardial oxygen and nutrient demand. A major cause of
IHD is coronary artery atherosclerosis and the resulting arterial
obstruction. Prolonged ischemia may lead to myocardial infarction, or
death of myocardial cells because of lack of blood flow. Areas of the
heart that are permanently damaged by myocardial infarction are replaced
with scar tissue. The cardiac remodeling process thus includes
hypertrophy of remaining myocytes, , and microcirculatory changes
within the heart.
Cardiac Hypertrophy and Heart Failure
Cardiac hypertrophy is an important component of cardiac
remodeling after IHD. However, cardiac hypertrophy is often a
compensatory response of the heart to an increased workload. For
example, prolonged hypertension contributes to load-induced left
ventricular hypertrophy. hypertrophy of the surviving myocytes may be
necessary to sustain cardiac output for life support. At some point in the
progression of IHD, however, the hypertrophic myocardium may
"decompensate" by unknown mechanisms, resulting in failure.
During failure, ventricular contractility and/or compliance are reduced
such that cardiac output is diminished. Failure may present as left-or
right-sided failure or both. When left-sided failure is the primary
pathology, blood pools in the lungs and pulmonary edema develops.
When right-sided failure is the primary pathology, blood pools in the
extremities and pitting edema is found in the lower legs.
Cardiomyopathies
The term cardiomyopathy essentially refers to any disease state that
alters myocardial function. Therefore, causes of cardiomyopathy include
IHD (ischemic cardiomyopathy), cardiac hypertrophy, infectious diseases
(e.g., viral cardiomyopathy), drug- or chemical-induced cardiomyopathy,
and unknown causes (idiopathic cardiomyopathy).
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General Mechanisms of Cardiotoxicity
1-Interference with Ion Homeostasis
any xenobiotic that disrupts ion movement or homeostasis may induce
a cardiotoxic reaction that consists principally of disturbances in heart
rhythm. This disruption include:
Inhibition of Na+,K+-ATPase
Na+,K+-ATPase reduces intracellular Na+ in exchange for extracellular
K+. Inhibition of cardiac Na+,K+-ATPase increases resting intracellular
Na+ concentrations. This in turn increases intracellular Ca2 +
concentrations through Na+/Ca2 + exchange, and the elevated
intracellular Ca2 + and Ca2 + stores thus contribute to the inotropic
actions of these inhibitors.
Na+ Channel Blockade
Agents that inhibit Na+ channels in cardiac cells alter cardiac excitability,
results in reduction of conduction velocity, prolonged QRS duration,
decreased automaticity
K+ Channel Blockade
Many different K+ channels are expressed in the human heart. Blockade
of K+ channels increases the duration of the action potential and
increases refractoriness (the cell undergoing repolarization is refractory to
depolarization).
Ca2+ Channel Blockade
The L-type Ca2 + channel contributes to excitation-contraction coupling,
whereas the T-type Ca2 + channels contribute to pacemaker potential in
the SA node. Blockade of Ca2 + channels in the heart produces a
negative inotropic effect.
2-Altered coronary blood flow
1-Coronary Vasoconstriction
Xenobiotic-induced constriction of the coronary vasculature induces
symptoms consistent with IHD. Epinephrine stimulation of β-adrenergic
receptors increases heart rate, contractility, and myocardial oxygen
consumption. The direct effect of sympathomimetics on the coronary
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vasculature includes coronary vasospasm through activation of αadrenergic receptors. When β-adrenergic receptors are blocked or during
underlying pathophysiologic conditions of the heart, the direct actions of
sympathomimetics
may
predominate,
leading
to
coronary
vasoconstriction.
2-Ischemia-Reperfusion Injury
Relief of the cause of ischemia provides reperfusion of the
myocardium. Reperfusion of the myocardium leads to subsequent tissue
damage that may be reversible or permanent, a phenomenon is known as
ischemia-reperfusion (I/R) injury. Mechanisms proposed to account for
the reperfusion injury include the generation of toxic oxygen radicals,
Ca2+ overload, changes in cellular pH, uncoupling of mitochondrial
oxidative phosphorylation, and physical damage to the sarcolemma
(the cell membrane of a striated muscle fiber cell).
3-Oxidative Stress
Reactive oxygen species are generated during myocardial ischemia
and at the time of reperfusion. In patients with atherosclerosis, oxidative
alteration of low-density lipoprotein is thought to be involved in the
formation of atherosclerotic plaques. Xenobiotics such as doxorubicin
and ethanol may induce cardiotoxicity through the generation of reactive
oxygen species.
3-Organellar Dysfunction
1- Sarcolemmal Injury, sarcoplasmic reticulum (SR)
Dysfunction, and Ca2+ Overload: All cells contain systems for the
regulation of intracellular Ca2 +. Because extracellular Ca2 + concentrations are
typically higher than resting intracellular free Ca2 +, the sarcolemmal
membrane must prevent a rapid influx of Ca2 + and subsequent Ca2 + overload.
The principal Ca2 + regulatory organelle in cardiac myocytes is the
sarcoplasmic reticulum (SR). Alterations of cardiac Ca2 + homeostasis by
toxicants may perturb the regulation of cellular functions.
2- Mitochondrial Injury: ATP is the immediate energy source required for
work in most biological systems and is obtained mainly through the oxidative
phosphorylation of adenine diphosphate (ADP) in the mitochondria. Oxidative
phosphorylation can be affected at various sites along the respiratory chain
through the use of different chemical inhibitors, such as rotenone, cyanide, and
antimycin A. Conversely, uncouplers such as 2,4-dinitrophenol prevent the
formation of ATP.
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3- Apoptosis (programmed cell death) In the early periods after
myocardial infarction, ishemic injury, I/R injury, or toxicant-induced
injury, cardiac myocyte death probably occurs through apoptotic
pathways. Xenobiotics that are associated with the induction of cardiac
myocyte apoptosis in vitro include cocaine, daunorubicin, doxorubicin,
isoproterenol, and norepinephrine.
Cardiotoxicants:
Pharmaceutical Agents
The cardiotoxicity of a cardiovascular drug often represents an overexpression of its
principal pharmacologic effect on the heart. For example, digitalis, quinidine, and
procainamide may induce cardiac arrhythmias as an exaggerated pharmacologic
action of those drugs. In contrast, drugs may produce cardiotoxicity by actions that
are not necessarily related to their intended therapeutic use.
1-Alcohol
The acute toxicity of ethanol includes reduced conductivity. Chronic
consumption of ethanol by humans has been associated with myocardial
abnormalities, arrhythmias, and a condition known as alcoholic
cardiomyopathy. Metabolites from the metabolism of ethanol eg.
acetaldehyde may lead to lipid peroxidation of cardiac myocytes and
inhibition of protein synthesis.
2-Antiarrhythmic and Inotropic Agents
-Cardiac Glycosides
Cardiac glycosides (digoxin and digitoxin) used for the treatment of
congestive heart failure inhibit Na+,K+-ATPase, elevate intracellular Na+,
activate Na+/Ca2 + exchange, and increase the availability of intracellular
Ca2 + for contraction. Cardiotoxicity may result from Ca2 + overload, and
arrhythmias may occur.
-Catecholamines and Sympathomimetics
Catecholamine-induced cardiotoxicity includes increased heart rate,
enhanced myocardial oxygen demand, and an overall increase in systolic
arterial blood pressure.
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-Anthracyclines and Other Antineoplastic Agents
Doxorubicin and daunorubicin are antineoplastic agents whose clinical
usefulness is limited because of cardiotoxicity. The acute effects mimic
anaphylactic-type responses such as tachycardia and various arrhythmias.
These effects are usually manageable and most likely are due to the
potent release of histamine from mast cells that sometimes is observed in
acute dosing. Long-term exposure to anthracyclines often results in the
development of cardiomyopathies and, in severe stages, congestive heart
failure.
3- Centrally Acting Drugs
-Tricyclic Antidepressants:
Standard tricyclic antidepressants have significant cardiotoxic actions,
particularly in cases of overdose, that include ECG abnormalities and
sudden cardiac death. As a result of peripheral α-adrenergic blockade,
postural hypotension is a prevalent cardiovascular effect. The tricyclics
also may have direct cardiotoxic actions on cardiac myocytes and
Purkinje fibers, depressing inward Na+ and Ca2 + and outward K+
currents.
-Antipsychotic Agents
The adverse cardiovascular effect of antipsychotic agents is orthostatic
hypotension. Direct effects on the myocardium include negative inotropic
actions.
4- General Anesthetics
Inhalational general anesthetics may reduce cardiac output by 20 to 50
percent, depress contractility, and produce arrhythmias. Halothane, as a
prototype, may block Ca2 + channels, disrupt Ca2 + homeostasis
associated with the SR, and modify the responsiveness of contractile
proteins to activation by Ca2 +.
5- Local Anesthetics Local anesthetics interfere with the transmission
of nerve impulses in other excitable organs, including the heart and the
circulatory system.
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6- Cocaine
The cardiotoxicity of cocaine includes its ability to act as a local
anesthetic and block nerve conduction by reversibly inhibiting Na +
channels. In the heart, cocaine decreases the rate of depolarization and the
amplitude of the action potential, slows conduction speed, and increases
the effective refractory period.
7- Androgens
Anabolic steroids increase low-density lipoprotein (LDL) and decrease
high-density lipoprotein (HDL) cholesterol. high-dose has been
associated with cardiac hypertrophy and myocardial infarction.
8- Glucocorticoids
Chronic glucocorticoid therapy often results in elevated total, LDL, and
HDL cholesterols. Furthermore, glucocorticoids are known to cause Na+
and water retention which could produce hypertension during chronic
therapy. Glucocorticoids may induce hypertrophic growth and alter the
expression of several ion transporters.
9- Thyroid Hormones
Hypothyroid states are associated with decreased heart rate,
contractility, and cardiac output, whereas hyperthyroid states are
associated with increased heart rate, contractility, cardiac output, ejection
fraction.
Vascular system toxicity
The vascular system delivers oxygen and nutrients to tissues
throughout the body and removes the waste products of cellular
metabolism.
Disturbances of Vascular Structure and Function:
Atherosclerosis involves focal intimal thickenings formed after the
migration of smooth muscle cells to the intima and uncontrolled
proliferation with collagen and elastin, intra- and extracellular lipids,
complex carbohydrates, blood products, and calcium accumulate to
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varying degrees as the lesion advances. The plaque also contains
inflammatory cells, such as monocytes and leukocytes, that leads to a
restricted blood supply to distal sites.
Oxidative metabolism of plasma lipoproteins is critical in the initiation
and progression of atherosclerosis. LDLs are oxidized by oxygen free
radicals that are released by arterial cells. Modified LDLs attract
macrophages and prevent their migration from the tissues. Oxidation of
LDLs generates activated oxygen species, which can directly injure
endothelial cells and increase adherence and the migration of monocytes
and T lymphocytes into the subendothelial space. Subsequent release of
growth modulators from endothelial cells and/or macrophages can
promote smooth muscle cell proliferation and the secretion of
extracellular matrix proteins.
Hypotension, a sustained reduction in systemic arterial pressure, is
common in poisonings with CNS depressants or antihypertensive agents.
Postural hypotension, can be induced by agents such as drugs that lower
cardiac output or decrease blood volume.
Hypertension may result from an increased concentration of circulating
vasoconstrictors such as angiotensin II and catecholamines. Sustained
hypertension is the most important risk factor that predisposes a person to
coronary and cerebral atherosclerosis.
Thrombosis, is the formation of a semisolid mass from blood
constituents in the circulation, can occur in both arteries and veins as a
result of exposure to toxicants. thrombosis occurs by means of induction
of platelet aggregation, an increase in their adhesiveness, or the creation
of a state of hypercoagulability through an increase in or activation of
clotting factors. Portions of a thrombus may be released and travel in the
vascular system until they are arrested as an embolus in a vessel with a
caliber even smaller than that of its origin. The consequence depends on
the site of arrest, but a thrombus can result in death.
General Biochemical Mechanisms of Vascular Toxicity
Chemicals absorbed through the gastrointestinal, respiratory, cutaneous,
and intravenous routes contact vascular cells before reaching other sites
in the body. This property alone puts the vascular system at increased risk
of toxic insult. Many target organ toxicities have a significant
microvascular component. Chemicals can produce degenerative or
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inflammatory changes in blood vessels as a direct consequence of an
excessive pharmacologic effect or secondary to the interaction of
chemicals or their metabolites with components of the vessel wall.
Common mechanisms of vascular toxicity include
membrane structure and function.
(1) alterations in
(2) redox stress leading to disruption of gene regulatory mechanisms,
compromised antioxidant defenses, and generalized loss of homeostasis,
(3) vessel-specific bioactivation of protoxicants.
(4) Accumulation of the active toxin in vascular cells.
(5) deficiencies in the capacity of target cells to detoxify the active toxin.
Agents:
Nicotine
Nicotine at pharmacologic doses increases heart rate and blood pressure
as a result of stimulation of sympathetic ganglia and the adrenal medulla.
Cocaine
It causes increase in circulating levels of catecholamines and a
generalized state of vasoconstriction. Hypertension and cerebral strokes
are notable vascular complications.
Oral Contraceptives
can produce thromboembolic disorders such as deep vein phlebitis and
pulmonary embolism. Intracranial venous thrombosis and secondary
increases in the risk of stroke.
Natural Products
Bacterial Endotoxins
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Bacterial Endotoxins produce various toxic effects to the liver causes
endothelial swelling. In the lung, endotoxins increase vascular
permeability and pulmonary hypertension.
Vitamin D
Vitamin D hypervitaminosis causes degeneration, calcification of the
coronary arteries.
Industrial Agents
Heavy Metals: lead, has direct vasoconstrictor effect. Inorganic mercury
produces vasoconstriction of preglomerular vessels and disrupts the
integrity of the blood-brain barrier. Acute arsenic poisoning causes
capillary dilation, which contributes to transudation of plasma and
decreased intravascular volume.
Gases
-Carbon Monoxide
The toxic effects of carbon monoxide have been attributed to the
formation of carboxyhemoglobin because carboxyhemoglobin decreases
the oxygen-carrying capacity of blood, causing functional anemia.
-Oxygen
The administration of oxygen to a premature newborn can cause
irreversible vasoconstriction and blindness.
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