Download Cardiovascular toxicity Cardiac Structure The cardiovascular system

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 .
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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,
inducing a conformational change in myosin and subsequently allowing
myosin to bind actin, thus producing "cross-bridge cycling" and
contraction.
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
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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
ischemia, infarction, or from ventricular hypertrophy.
Ischemic Heart Disease
is adisturbance of 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.
Cardiac Hypertrophy and Heart Failure
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.
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
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(e.g., viral cardiomyopathy), drug- or chemical-induced cardiomyopathy,
and unknown causes (idiopathic cardiomyopathy).
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+ Channel Blockade, K+ Channel
Blockade, Ca2+ Channel Blockade
2-Altered coronary blood flow
1-Coronary Vasoconstriction
Epinephrine stimulation of β-adrenergic receptors increases heart rate,
contractility, and myocardial oxygen consumption. In contrast, the direct
effect of sympathomimetics on the coronary vasculature includes
coronary vasospasm through activation of α-adrenergic 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 (e.g., thrombolytic therapy after acute
myocardial infarction) 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 ischemiareperfusion (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.
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
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and ethanol may induce cardiotoxicity through the generation of reactive
oxygen species.
3-Organellar Dysfunction
1- Sarcolemmal Injury, sacroplasmic reticulum (SR) Dysfunction, and
Ca2+ Overload.
2- Mitochondrial Injury
3- Apoptosis and Oncosis
Cardiotoxicants:
1-Alcohol
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.
-Anthracyclines and Other Antineoplastic Agents
Doxorubicin and daunorubicin cause tachycardia and various
arrhythmias due to the potent release of histamine Long-term exposure
causes cardiomyopathies.
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3- Centrally Acting Drugs
-Tricyclic Antidepressants:
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 and quinidine-like effects.
4- General Anesthetics
Inhalational general anesthetics may reduce cardiac output by 20 to 50
percent, depress contractility, and produce arrhythmias.
5- Local Anesthetics
Local anesthetics interfere with the transmission of nerve impulses in
other excitable organs, including the heart and the circulatory system.
6- Cocaine
Cocaine inhibits Na+ channels, inhibits norepinephrine and dopamine
reuptake into sympathetic nerve terminals, The net effect is ventricular
fibrillation.
7- Antihistamines
The second-generation antihistamines terfenadine and astemizole have
been associated with life-threatening torsades de pointes arrhythmias.
8- 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.
9- Thyroid Hormones
Hypothyroid states are associated with decreased heart rate,
contractility, and cardiac output, whereas hyperthyroid states are
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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
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.
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 as an embolus.
Common mechanisms of vascular toxicity include:
(1) alterations in membrane structure and function.
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(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
The plant alkaloid 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.
Oral Contraceptives
can produce thromboembolic disorders such as deep vein phlebitis and
pulmonary embolism.
Bacterial Endotoxins
Bacterial Endotoxins produce various toxic effects to the liver causes
endothelial swelling. In the lung, endotoxins increase vascular
permeability and pulmonary hypertension.
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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