The rhythm of the heart is normally generated and regulated by pacemaker cells within the sinoatrial (SA) node, which is located within the wall of the right atrium. SA nodal pacemaker activity normally governs the rhythm of the atria and ventricles. Normal rhythm is very regular, with minimal cyclical fluctuation.
How common are arrhythmias?
About 14 million people in the USA have arrhythmias (5% of the population). The most common disorders are atrial fibrillation and flutter. The incidence is highly related to age and the presence of underlying heart disease; the incidence approaches 30% following open heart surgery.
What are the clinical symptoms?
Patients may describe an arrhythmia as a palpitation or fluttering sensation in the chest. For some types of arrhythmias, a skipped beat might be sensed because the subsequent beat produces a more forceful contraction and a thumping sensation in the chest. A "racing" heart is another description. Proper diagnosis of arrhythmias requires an electrocardiogram , which is used to evaluate the electrical activity of the heart.
Depending on the severity of the arrhythmia, patients may experience dyspnea (shortness of breath), syncope (fainting), fatigue, heart failure symptoms, chest pain or cardiac arrest.
A frequent cause of arrhythmia is coronary artery disease because this condition results in myocardial ischemia or infarction . When cardiac cells lack oxygen, they become depolarized, which leads to altered impulse formation and/or altered impulse conduction. The former concerns changes in rhythm that are caused by changes in the automaticity (spontaneous activity) of pacemaker cells or by abnormal generation of action potentials at sites other than the SA node (termed
ectopic foci ). Altered impulse conduction is usually associated with complete or partial block of electrical conduction within the heart. Altered impulse conduction commonly results in reentry , which can lead to
tachyarrhythmias. Changes in cardiac structure that accompany heart failure (e.g., dilated or hypertrophied cardiac chambers), can also precipitate arrhythmias. Finally, many different types of drugs (including
antiarrhythmic drugs ) as well as electrolyte disturbances (primarily K + and Ca ++ ) can precipitate arrhythmias.
What are the consequences of arrhythmias?
Arrhythmias can be either benign or more serious in nature depending on the
hemodynamic consequence of the arrhythmia and the possibility of evolving into a lethal arrhythmia. Occasional premature ventricular complexes (PVCs), while annoying to a patient, are generally considered benign because they have little hemodynamic effect. Consequently, PVCs if not too frequent, are generally not treated. In contrast, ventricular tachycardia is a serious condition that can lead to heart failure, or evolve into ventricular fibrillation and cause death.
How are arrhythmias treated?
When arrhythmias require treatment, they are are treated with drugs that suppress the arrhythmia. These drugs are called
antiarrhythmic drugs . There are many different types of antiarrhythmic drugs and many different mechanisms of action. Most of the drugs affect ion channels that are involved in the movement of sodium, calcium and potassium ions in and out of the cell. These drugs include mechanistic classes such as sodium-channel blockers, calcium-channel blockers and potassium-channel blockers. By altering the movement of these important ions, the electrical activity of the cardiac cells (both pacemaker and non-pacemaker cells ) is altered, hopefully in a manner that suppresses arrhythmias. Other drugs affect autonomic influences on the the heart, which may be stimulating or aggravating arrhythmias. Among these drugs are beta-blockers.
Membrane Potential
If a voltmeter is attached to the two terminals of a battery, a voltage difference will be measured across the two terminals. Likewise, if a voltmeter is used to measure voltage across the cell membrane (inside versus outside) of a cardiomyocyte, it will be found that the inside of the cell has a negative voltage (measured in millivolts; mV) with respect to the outside of the cell (which is referenced as 0 mV). Under resting conditions, this is called the resting membrane potential . With appropriate stimulation of the cell, this negative voltage inside the cell (negative membrane potential) may transiently become positive owing to the generation of an action potential . Membrane potentials result from a separation of positive and negative charges (ions) across the membrane, similar to the plates within a battery that separate positive and negative charges.
Membrane potentials in cells are determined primarily by three factors: 1) the concentration of ions on the inside and outside of the cell; 2) the permeability of the cell membrane to those ions (i.e., ion conductance ) through specific ion channels ; and 3) by the activity of electrogenic pumps (e.g., Na + /K + -ATPase and Ca ++ transport pumps) that maintain the ion concentrations across the membrane.
Potassium ion
To understand how a membrane potential is generated, first consider a hypothetical cell in which K + is the only ion across the membrane other than the large negatively charged proteins inside of the cell. Because the cell has potassium channels through which K + can move in and out of the cell, K + diffuses down its chemical gradient (out of the cell) because its concentration is much higher inside the cell than outside. As K + (a positively charged ion) diffuses out of the cell, it leaves behind negatively charged proteins. This leads to a separation of charges across the membrane and therefore a potential difference across the membrane. Experimentally it is possible to prevent the K
+ from diffusing out of the cell. This can be achieved by applying a negative charge to the inside of the cell that prevents the positively charged K + from leaving the cell. The negative charge across the membrane that would be necessary to oppose the movement of K + down its concentration gradient is termed the equilibrium potential for K + (E K ; Nernst potential ). The Nernst potential for K + can be calculated as follows
The E K represents the electrical potential necessary to keep K + from diffusing out of the cell, down its chemical gradient. If the outside K + concentration were increased from 4 to 40 mM, then the chemical gradient driving K + out of the cell would be reduced, and therefore the membrane potential required to maintain electrochemical equilibrium (E K ) would be less negative according to the Nernst relationship. In this example, the E K becomes -35 mV when the outside K + concentration is 40 mM. In other words, when K + is elevated 10-fold outside of the cell, the chemical gradient driving K + out of the cell is reduced and therefore a less negative voltage is required to keep K + from diffusing out of the cell.
The resting potential for a ventricular myocyte is about -90 mV, which is near the equilibrium potential for K + when extracellular K + concentration is 4 mM. Since the equilibrium potential for K + is -96 mV and the resting membrane potential is -90 mV, there is a net electrochemical driving force (difference between membrane potential and equilibrium potential) of 6 mV acting on the K + . The membrane potential is more positive than the equilibrium potential, therefore the net driving force is outward due to K + having a positive charge. Because the resting cell has a finite permeability to K + and the presence of a small net outward driving force acting upon K + , there is a slow outward leak of K + from the cell. If K + continued to leak out of the cell, its chemical gradient would be lost over time; however, a Na + /K + -ATPase pump brings the K + back into the cell and thereby maintains the K + chemical gradient.
Sodium and calcium ions
Because the Na + concentration is higher outside the cell, this ion diffuses down its chemical gradient into the cell. Experimentally, this inward diffusion of Na + can be prevented by applying a positive charge to the inside of the cell. When this positive change counterbalances the chemical diffusion force driving Na + into the cell, there will be no net movement of Na + into the cell, and Na + will therefore be in electrochemical equilibrium. The membrane potential required to produce this electrochemical equilibrium is called the
equilibrium potential for Na +(E Na ) and is calculated by:
(where [Na + ]i = 20 mM and [Na + ]o = 145 mM; and z=1 because Na + is monvalent)
The positive E Na means that in order to balance the inward directed chemical gradient for Na+ , the cell interior needs to be +52 mV to prevent Na + from diffusing into the cell. At a resting membrane potential of -90 mV, there is not only a large chemical driving force, but also a large electrical driving force acting upon external Na + to cause it to diffuse into the cell. The difference between the membrane potential and the equilibrium potential (-142 mV) represents the net electrochemical force driving Na + into the cell at resting membrane potential. At rest, however, the permeability of the membrane to Na + is very low so that only a small amount Na + leaks into the cell. During an action potential, the cell membrane become more permeable to Na + , which increases sodium entry into the cell through
sodium channels . At the peak of the action potential in a cardiac cell (e.g., ventricular myocyte), the membrane potential is approximately +20 mV. Therefore, while the resting potential is far removed from the E Na, the peak of the action potential approaches E Na. Because a small amount of Na + enters the cell at rest, and a relatively large amount of Na + enters during action potentials, a Na + /K + -ATPase pump is required to transport Na + out of the cell (in exchange for K + ) in order to maintain the chemical gradient for Na + .
Similar to Na + , there is a large Ca ++ concentration difference across the cell membrane. Therefore, Ca ++ diffuses into the cell through calcium channels . Applying the Nernst equation to external and internal calcium concentrations of 2.5 mM and 0.0001 mM, respectively, results in an equilibrium potential of +134 mV as shown below.
This value also includes that the fact that Ca
++ is a divalent instead of a monovalent cation; therefore, the -61 constant in the above equation is divided by 2 because z = 2 (z = number of charges). Because the equilibrium potential is much more positive than the resting membrane potential, there is a net electrochemical force trying to drive Ca
++ into the cell, which occurs when the calcium channels are open.
The above discussion shows how changes in the concentration of individual ions across the membrane can alter the membrane potential. However, to fully understand how multiple ions affect the membrane potential, and ultimately how the membrane potential changes during action potentials, it is necessary to learn how changes in membrane ion permeability, that is, changes in ion conductance , affect the membrane potential. Furthermore, electrogenic ion pumps such as the Na + /K + -ATPase pump contribute to the membrane potential as they transport ions across the membrane to maintain the ion concentrations across the membrane.
TO BE CONTINUED....
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