Cardiology: Cellular physiology
Membrane potential, ion channels and pumps
The cell membrane is a lipid bilayer with an intrinsically low permeability to charged ions. However, a variety of structures span the membrane through which ions can enter or leave the cell. These include ion channels through which ions passively diffuse and ion pumps which actively transport ions across the membrane. Pumps regulate ionic gradients, and channels determine membrane potential and underlie action potentials.
Resting membrane potential
The resting membrane is more permeable to K+ and Cl− than other ions and is therefore semipermeable. The cell contains negatively charged molecules (e.g. proteins) which cannot cross the membrane.
This fixed negative charge attracts K+ but repels Cl−, leading to accumulation of K+ within the cell and loss of Cl−. However, the consequent increase in K+ concentration gradient drives K+ back out of the cell. An equilibrium is reached when the electrical forces exactly balance those due to concentration differences (Gibbs–Donnan equilibrium); the net force or electrochemical gradient for K+ is then zero. The opposing effect of the concentration gradient means fewer K+ ions move into the cell than are required by the fixed negative charges. The inside of the cell is therefore negatively charged compared to the outside (charge separation), and a potential develops across the membrane. Only a small charge separation (e.g. 1 in ~100,000 K+ ions) is required to cause a potential of ~−100 mV. If the membrane was only permeable to K+ and no other cations, the potential at equilibrium (K+ equilibrium potential, EK) would be defined by the K+ concentration gradient and calculated from the Nernst equation. As cardiac muscle intracellular [K+] is ~120 mmol/L and extracellular [K+] ~4 mmol/L EK = ~−90 mV (Figure 10.1).
In real membranes K+ permeability (PK) at rest is indeed greater than for other ions, so the resting membrane potential (RMP) is close to EK (~−85 mV). RMP does not equal EK because there is some permeability to other ions; most notably Na+ permeability (PNa) is ~1% of PK. The Na+ concentration gradient is also opposite to that for K+ (intracellular [Na+] ~10 mmol/L, extracellular ~140 mmol/L), because the Na+ pump actively removes Na+ from the cell. As a result, the theoretical equilibrium potential for Na+ (ENa) is ~+65 mV, far from the actual RMP. Both concentration and electrical gradients are therefore in the same direction, and this inward electrochemical gradient drives Na+ into the cell. As PNa at rest is relatively low, the amount of Na+ leaking into the cell is small but is still sufficient to cause an inward current that slightly depolarizes the membrane. RMP is thus less negative than EK. RMP can be calculated using the Goldman equation, a derivation of the Nernst equation taking into account other ions and their permeabilities.
A consequence of the above is that if PNa was increased to more than PK, then the membrane potential would shift towards ENa.
This is exactly what happens during an action potential, when Na+ channels open so that PNa becomes 10‐fold greater than PK, and the membrane depolarizes. An equivalent situation arises for Ca2+, as intracellular [Ca2+] is ~100 nmol/L at rest, much smaller than the extracellular [Ca2+] of ~1 mmol/L.
Ion channels and gating
Channels differ in ion selectivity and activation mechanisms. They are either open or closed; transition between these states is called gating. When channels open ions move passively down their electrochemical gradient. As ions are charged, this causes an electrical current (ionic current); positive ions entering the cell cause inward currents and depolarization. Phosphorylation of channel proteins – by protein kinase A/cAMP for example – can modify function, for example Ca2+ channels. There are several types of gating; two are described.
Voltage‐gated channels (VGCs) are regulated by membrane potential. Some (e.g. certain K+ channels) simply switch between open and shut states according to the potential across them (Figure 10.2).
Others, such as the fast inward Na+ channel responsible for the upstroke of the action potential in nerves, skeletal and cardiac muscle (Figure 10b), have three states: open, shut and inactive. When a cell depolarizes sufficiently to activate these Na+ channels (i.e. reaches their threshold potential), they open and the cell depolarizes towards ENa. After a short period (<ms) the channels spontaneously inactivate, as though another gate had closed. Inactivated channels can only be reactivated once the membrane potential becomes negative again. This is essential for generation of action potentials.
Receptor‐gated channels (RGCs; important in smooth muscle) are commonly non‐selective cation channels (NSCCs; permeable to Na+ and Ca2+). They open when a hormone or neurotransmitter (e.g. noradrenaline) binds to a receptor and initiates production of a second messenger, such as diacylglycerol (DAG, Figure 10.2).
Ion pumps and exchangers
Ion pumps use energy to transfer ions against their electrochemical gradient. Primary active transport consumes ATP for energy, the prime example being the Na+ pump (Na+–K+‐ATPase), which pumps three Na+ out of the cell in exchange for two K+. Another is the Ca2+‐ATPase that pumps Ca2+ into intracellular stores (SERCA). Secondary active transport uses the Na+ electrochemical gradient generated by the Na+ pump to drive the transfer of other ions or molecules across the membrane. An example is the Na+–Ca2+ exchanger, which exchanges three Na+ ions for a Ca2+ ion. Na+ pump inhibitors (e.g. digoxin) reduce the Na+ gradient and thus indirectly inhibit secondary transport. Pumps are regulated by ion concentrations and modulated by second messengers.
Ion pumps and membrane potential
The Na+ pump and Na+–Ca2+ exchanger are electrogenic as unequal amounts of charge are transported, and thus a small ionic current is generated. They can therefore both affect, and be affected by, membrane potential. An example is Na+–Ca2+ exchange during the cardiac muscle action potential.
Electrophysiology of cardiac muscle and origin of the heartbeat
An action potential (AP) is the transient depolarization of a cell as a result of activity of ion channels. The cardiac AP is considerably longer than those of nerve or skeletal muscle (∼300 vs ∼2 ms). This is due to a plateau phase in cardiac muscle, lasting for 200–300 ms.
Ventricular muscle action potential
Initiation of the action potential
At rest, the ventricular cell membrane is most permeable to K+ and the resting membrane potential (RMP) is therefore close to the K+ equilibrium potential (EK), ∼–90 mV. An AP is initiated when the membrane is depolarized to the threshold potential (∼−65 mV). This occurs due to transmission of a depolarizing current from an adjacent activated cell through gap junctions. At threshold, sufficient voltage‐gated Na+ channels are activated to initiate a self‐regenerating process – the inward current caused by entry of Na+ (INa) through these channels causes further depolarization, which activates more Na+ channels, and so on. The outcome is a very large and fast INa, and therefore a very rapid AP upstroke (phase 0; ∼500 V/s).
Activation of Na+ channels during phase 0 means that the Na+ permeability is now much greater than that for K+, and so the membrane potential moves towards the Na+ equilibrium potential (ENa, ∼+65 mV). It does not reach ENa because the Na+ channels rapidly inactivate as the potential nears +40 mV; this, and activation of a transient outward K+ current, can lead to a rapid decline in potential, leaving a spike (phase 1), best seen in Purkinje fibres (Figure 11.2). The inactivated Na+ channels cannot be reactivated until the potential returns to less than −60 mV, so another AP cannot be initiated until the cell repolarizes (refractory period). The refractory period therefore lasts as long as the plateau and contraction (Figure 11.1), so unlike skeletal muscle, cardiac muscle cannot be tetanized.
The plateau (phase 2)
By the end of the upstroke all Na+ channels are inactivated, and in skeletal muscle the cell would now repolarize. In cardiac muscle, however, the potential remains close to 0 mV for ∼250 ms. This plateau phase is due to opening of voltage‐gated (L‐type) Ca2+ channels, which activate relatively slowly when the membrane potential becomes more positive than ∼−35 mV. The resultant Ca2+ current (slow inward or ISI) is sufficient to slow repolarization until the potential falls to ∼−20 mV. The length of the plateau is related to slow inactivation of Ca2+ channels and the additional Na+ inward current provided by the Na+–Ca2+ exchanger. Ca2+ entry during the plateau is vital for cardiac muscle contraction.
Repolarization (phase 3)
By the end of the plateau the membrane potential is sufficiently negative to activate delayed rectifier K+ channels, and the associated outward K+ current (IK) therefore promotes rapid repolarization.
As the membrane potential returns to resting levels (phase 4), IK slowly inactivates again. Factors that influence IK will affect the rate of repolarization, and hence the AP length, and mutations in the underlying channels cause long QT syndrome.
Role of Na+–Ca2+ exchange
The Na+–Ca2+ exchanger (NCX) exchanges three Na+ for one Ca2+ and is thus electrogenic. In the early plateau, when
membrane potential is most positive, the NCX may reverse and contribute to inward current and movement of Ca2+. As the plateau decays and becomes more negative NCX returns to its usual function of expelling Ca2+ from the cell in exchange for Na+, which is potentiated by the high cytosolic [Ca2+]. This influx of Na+ ions causes an inward current (INCX) that slows repolarization and lengthens the plateau.
Sinoatrial node
The sinoatrial node (SAN) is the origin of the heartbeat, and its AP differs from that of the ventricle (Figure 11.3). The resting potential (phase 4) exhibits a slow depolarization, and the upstroke (phase 0) is much slower. The latter is because there are no functional Na+ channels, and the upstroke is due instead to activation of slow l‐type Ca2+ channels. The slow upstroke leads to slower conduction between cells. This is of particular importance in the atrioventricular node (AVN), which has a similar AP to the SAN.
The SAN resting potential slowly depolarizes from ∼−60 mV to a threshold of ∼−40 mV, at which point l‐type channels activate and an AP is initiated; the threshold is more positive because of substitution of l‐type for Na+ channels. The rate of decay determines how long it takes for threshold to be reached and therefore the heart rate. The resting potential is therefore commonly called the pacemaker potential. As for ventricular cells, repolarization of the AP in SAN involves activation of IK, which then slowly inactivates. In addition, there are two inward currents, Ib and If (‘funny’), mostly due to inward movement of Na+. Ib is stable, and present in other cardiac cells, but If is specific to nodal cells and activated at the end of repolarization by negative potentials (Figure 11.2). The combination of inward current from If plus Ib and decay in IK causes the slow depolarization of the pacemaker potential. As this approaches threshold, another type of voltage gated Ca2+ channel (transient, t‐type) is activated, which contributes to the depolarization and the early part of the upstroke.
Factors influencing IK, Ib, or If thus alter the slope of the pacemaker and so heart rate and are called chronotropic agents. The sympathetic neurotransmitter noradrenaline increases heart rate by increasing the size of If. It also reduces AP length by increasing the rate of Ca2+ entry and hence the slope of the upstroke. The parasympathetic transmitter acetylcholine reduces the slope of the pacemaker potential and causes a small hyperpolarization, both of which increase the time required to reach threshold and reduce heart rate (Figure 11.4).
Other regions of the heart
Atrial muscle has a similar AP to ventricular muscle, although the shape is more triangular. Purkinje fibres in the conduction system have a prominent phase 1, reflecting a greater INa (due to their large size); the latter causes a more rapid upstroke and faster conduction. APs in the AVN are similar to those of the SAN, although the rate of decay of the resting potential is slower. The resting potential of the bundle of His and Purkinje system may also exhibit an even slower rate of decay (due to decay of IK). All of these could therefore act as pacemakers, but the SAN is normally faster and predominates.
This is called dominance or overdrive suppression.
Cardiac muscle excitation–contraction coupling
Cardiac muscle contracts when cytosolic [Ca2+] rises above about 100 nmol/L. This rise in [Ca2+] couples the action potential (AP) to contraction, and the mechanisms involved are referred to as excitation–contraction coupling.
The ability of cardiac muscle to generate force for any given fibre length is described as its contractility. This depends on cytosolic [Ca2+], and to a lesser extent on factors that affect Ca2+ sensitivity of the contractile apparatus. The contractility of cardiac muscle is primarily dependent on the way that the cell handles Ca2+.
Initiation of contraction
During the plateau phase of the AP, Ca2+ enters the cell through l‐type voltage‐gated Ca2+ channels (Figure 12.1). L‐type channels are specifically blocked by dihydropyridines (e.g. nifedipine) and verapamil. However, the amount of Ca2+ that enters the cell is less than 20% of that required for the observed rise in cytosolic [Ca2+] ([Ca2+]i). The rest is released from the sarcoplasmic reticulum (SR), where Ca2+ is stored in high concentrations by the Ca2+ binding protein calsequestrin. AP travels down the T tubules which are close to, but do not touch, the terminal cisternae of the SR (Figure 12.1). During the first 1–2 ms of the plateau Ca2+ enters and causes a rise in [Ca2+] in the gap between the T tubule sarcolemma and SR. This rise in [Ca2+] activates Ca2+‐sensitive Ca2+ release channels in the SR, through which stored Ca2+ floods into the cytoplasm. This is called calcium‐induced calcium release (CICR) (Figure 12.1). The amount of Ca2+ released depends both on the content of the SR and size of the activating Ca2+ entry, and modulation of the latter is the major way by which cardiac function is regulated (see Regulation of contractility below). Ca2+ release and entry combine to cause a rapid increase in [Ca2+]i, which initiates contraction. Peak [Ca2+]i normally rises to ~2 μmol/L, although maximum contraction occurs when [Ca2+]i rises above 10 μmol/L.
Generation of tension
Force is generated when myosin heads protruding from thick filaments bind to actin thin filaments to form crossbridges and drag the actin past in a ratchet fashion using ATP bound to myosin as an energy source. This is the sliding filament or crossbridge mechanism of muscle contraction. In cardiac muscle [Ca2+]i controls crossbridge formation via the regulatory proteins tropomyosin and troponin. Tropomyosin is a coiled strand which, at rest, lies in the cleft between the two actin chains that form the thin filament helix and covers the myosin binding sites. Myosin therefore cannot bind, and there is no tension. Troponin is a complex of three globular proteins (troponin C, I and T), bound to tropomyosin by troponin T at intervals of 40 nm. When [Ca2+]i rises above 100 nmol/L, Ca2+ binds to troponin C causing a conformational change which allows tropomyosin to shift out of the actin cleft. Myosin binding sites are uncovered, crossbridges form and tension develops. Tension is related to the number of active crossbridges and will increase until all troponin C is bound to Ca2+ ([Ca2+]i >10 μmol/L).
Relaxation mechanisms
When [Ca2+]i rises above resting levels (∼100 nmol/L), ATP-dependent Ca2+ pumps in the SR (sarcoendoplasmic reticulum Ca2+‐ATPase; SERCA) are activated, and start to pump (sequester) Ca2+ from the cytosol back into the SR (Figure 12.2). As the AP repolarizes and L‐type Ca2+ channels inactivate, this mechanism reduces [Ca2+]i towards resting levels, so Ca2+ dissociates from troponin C and the muscle relaxes. However, the Ca2+ originally entering the cell must now be expelled. Ca2+ is transported out of the cell by the membrane Na+–Ca2+ exchanger (NCX). This uses the inward Na+ electrochemical gradient as an energy source to pump Ca2+ out, and three Na+ enter the cell for each Ca2+ removed (Figure 12.2). Sarcolemmal Ca2+‐ATPase pumps are present but less important. At the end of the AP about 80% of the Ca2+ will have been resequestered into the SR, and most of the rest ejected from the cell. The remainder is slowly pumped out between beats.
Regulation of contractility
Inotropic agents alter the contractility of cardiac muscle; a positive inotrope increases contractility, while a negative decreases it. Most inotropes act by modulating cell Ca2+ handling, although some may alter Ca2+ binding to troponin C. A high plasma [Ca2+] increases contractility by increasing Ca2+ entry during the AP.
Noradrenaline (norepinephrine) from sympathetic nerve endings, and to a lesser extent circulating adrenaline (epinephrine), are the most important physiological inotropic agents. They also increase heart rate (positive chronotropes).
Noradrenaline binds to β1‐adrenoceptors on the sarcolemma and activates adenylate cyclase (AC), causing production of the second messenger cAMP. This activates protein kinase A (PKA), which phosphorylates L‐type Ca2+ channels so that they allow more Ca2+ to enter during the AP (Figure 12.3). The elevation of [Ca2+]i is thus potentiated and more force develops. Any agent that increases cAMP will act as a positive inotrope, for example milrinone, an inhibitor of the phosphodiesterase that breaks down cAMP. Noradrenaline (and cAMP) also increase the rate of Ca2+ reuptake into the SR, mediated by PKA and phosphorylation of phospholamban, a SERCA regulatory protein. While not affecting contractility, this assists removal of the additional Ca2+ and shortens contraction, which is useful for high heart rates.
The classic positive inotropic drug is digoxin, a cardiac glycoside.
Digoxin inhibits the Na+ pump (Na+‐K+ ATPase) which removes [Na+] from cells. Intracellular [Na+] therefore increases, so reducing the Na+ gradient that drives NCX. Consequently, less Ca2+ is removed from the cell by the NCX (Figure 12.3) and peak [Ca2+]i and force increase.
Overstimulation by positive inotropes can lead to Ca2+ overload, and damage due to excessive uptake of Ca2+ by the SR and mitochondria. This can contribute to the progressive decline in myocardial function in chronic heart failure, when sympathetic stimulation is high.
Acidosis is negatively inotropic, largely by interfering with the actions of Ca2+. This is important in myocardial ischaemia and heart failure, where poor perfusion can lead to lactic acidosis and so depress cardiac function.
Influence of heart rate
When heart rate increases there is a proportional rise in cardiac muscle force. This phenomenon is known as the staircase, Treppe or Bowditch effect. It can be attributed both to an increase in cytosolic [Na+] due to the greater frequency of APs, with a consequent inhibition of NCX, and to a decreased diastolic interval, which limits the time between beats for Ca2+ to be extruded from the cell.
Electrical conduction system in the heart
Electrical conduction in cardiac muscle
Cardiac muscle cells are connected via intercalated discs.
These incorporate regions where the membranes of adjacent cells are very close, called gap junctions. Gap junctions consist of proteins known as connexons, which form low‐resistance junctions between cells. They allow the transfer of small ions and thus electrical current. As all cells are therefore electrically connected, cardiac muscle is said to be a functional (or electrical) syncytium.
If an action potential (AP) is initiated in one cell, local currents via gap junctions will cause adjacent cells to depolarize, initiating their own AP. A wave of depolarization will therefore be conducted from cell to cell throughout the myocardium. The rate of conduction is partly dependent on gap junction resistance and the size of the depolarizing current. This is related to the upstroke velocity of the AP (phase 0). Drugs that slow phase 0 therefore slow conduction (e.g. lidocaine, class I antiarrhythmics). Pathological conditions such as ischaemia may increase gap junction resistance and slow or abolish conduction. Retrograde conduction does not normally occur because the original cell is refractory. Transfer of the pacemaker signal from the sinoatrial node (SAN) and synchronous contraction of the ventricles is facilitated by conduction pathways formed from specialized muscle cells.
Conduction pathways in the heart
Sinoatrial node
The heartbeat is normally initiated in the SAN, located at the junction of the superior vena cava and right atrium. The SAN is a ∼2‐mm‐wide group of small elongated muscle cells that extends for ∼2 cm down the sulcus terminalis. It has a rich capillary supply and sympathetic and parasympathetic (right vagal) nerve endings.
The SAN generates an AP about once a second (sinus rhythm, Figure 13.3.1).
Atrial conduction
The impulse spreads from the SAN across the atria at ∼1 m/s.
Conduction to the atrioventricular node (AVN) is facilitated by larger cells in the three internodal tracts of Bachmann (anterior), Wenckebach (middle) and Thorel (posterior).
The atrioventricular node
The atria and ventricles are separated by the non‐conducting annulus fibrosus. The AVN marks the upper region of the only conducting route through this band. It is similar in structure to the SAN, situated near the interatrial septum and mouth of the coronary sinus, and innervated by sympathetic and left vagal nerves. The complex arrangement of small cells and slow AP upstroke result in a very slow conduction velocity (∼0.05 m/s). This provides a functionally significant delay of ∼0.1 s between contraction of the atria and ventricles, reflected by the PR interval of the electrocardiogram (ECG).
Sympathetic stimulation increases conduction velocity and reduces the delay, whereas vagal stimulation slows conduction and increases the delay.
Bundle of His and Purkinje system
The bundle of His transfers the impulse from the AVN to the top of the interventricular septum. Close to the attachment of the tricuspid septal cusp it branches to form the left and right bundle branches. The left bundle divides into the posterior and anterior fascicles. The bundles travel under the endocardium down the walls of the septum and at the base divide into the multiple fibres of the Purkinje system. This distributes the impulse over the inner walls of the ventricles. Cells in the bundle of His and Purkinje system have large diameters (~40 μm) and rapid AP upstroke and consequently fast conduction (~4 m/s). The impulse spreads from the Purkinje cells through the endocardium towards the epicardium at 0.3–1 m/s, thereby initiating contraction.
Abnormalities of impulse generation or conduction
Sinus tachycardia (100–200 beats/min) is normal in exercise or excitement, but also occurs when pathological stimuli (e.g. phaeochromocytoma, heart failure, thyrotoxicosis) elevate sympathetic tone and accelerate SAN firing. Sinus tachycardia generally starts and stops gradually. Treatment, if required, involves removing the underlying cause. The ECG is otherwise normal. Conversely, sick sinus syndrome, generally caused by SAN fibrosis, causes slowed impulse generation and bradycardia (slow heart rate), or a sustained or intermittent failure of the impulse to reach the AVN, termed sinoatrial block (Figure 13.3.2). Because other parts of the conduction system also exhibit pacemaking activity,
sick sinus syndrome can result in the emergence of escape beats or rhythms in which impulses arising elsewhere (usually the AVN) can activate ventricular depolarization. Sick sinus syndrome can be treated by implantation of a pacemaker.
Heart block Abnormally slow conduction in the AVN can result in incomplete (first‐degree) heart block (AV block; Figure 13.3.3), where the delay is greater than normal, resulting in an extended PR interval. Second‐degree heart block occurs when only a fraction of impulses from the atria are conducted; for example, ventricular contraction is only initiated every second or third atrial contraction (2:1 or 3:1 block; Mobitz II; Figure 13.3.4). Mobitz I block (Wenckebach) is another type of second‐degree block, in which the PR interval progressively lengthens until there is no transmission from atria to ventricles and a QRS complex is missed; the cycle then begins again (Figure 13.3.5). Patients with first‐ or second‐degree block are often asymptomatic. Complete (third‐degree) heart block occurs when conduction between atria and ventricles is abolished (Figure 13.3.6, 13.3.7). This can result from ischaemic damage to nodal tissue or the bundle of His. In the absence of a signal from the SAN, the AVN and bundle of His can generate a heart rate of ∼40 beats/min. Some ventricular cells spontaneously generate APs, but at a rate less than 20/min.
Bundle branch block When one branch of the bundle of His does not conduct (left or right bundle branch block), the part of the ventricle that it serves is stimulated by conduction through the myocardium from unaffected areas. As this form of conduction is slower, activation is delayed.
The electrocardiogram
The electrocardiogram (ECG) is the surface recording of electrical activity of the heart as the cardiac muscle depolarizes and repolarizes. The recorded voltage (1–2 mV) is much smaller than that of the action potential and reflects the vector sum of currents between depolarized and resting cells, thus providing both amplitude and directional information. Identification of intermittent events such as paroxysmal arrhythmias may require ambulatory ECG recording over 24 hours (Holter test), or an exercise tolerance test where workload is progressively increased to elicit events related to coronary artery disease for example.
Recording the ECG
The ECG is based around the concept of an equilateral triangle (Einthoven’s triangle; Figure 14.1). The points of the triangle are approximated by placing electrodes on the right arm (RA), left arm (LA) and left leg (LL). The right leg is commonly used as an earth to minimize interference. The voltage between any two electrodes will depend on the amplitude of the current, which is related to muscle mass, and the mean direction of current; it is thus a vector quantity (Figure 14.2). The greatest voltage and thus deflection are therefore seen when the wave of depolarization is directly towards or away from the respective electrodes. By convention, the ECG is connected such that a wave of depolarization towards the positive electrode causes an upward deflection, and the paper speed of the recorder is normally 25 or 50 mm/s.
The various combinations of electrodes are called leads (not to be confused with the cables connecting the electrodes). The three bipolar limb leads each approximate the potential difference (PD) between two corners of Einthoven’s triangle and are essentially looking at electrical activity in the heart from three different directions, separated by 60°. Lead I measures the PD between RA (positive electrode) and LA (negative electrode); lead II, RA (negative) and LL (positive); and lead III, LA (negative) and LL (positive).
The unipolar leads use a single sensing electrode and measure the PD between this and an indifferent electrode representing the average potential of the whole body (i.e. zero). Practically, this is obtained by connecting RA, LA and LL together, which approximates the centre of Einthoven’s triangle (i.e. the heart). The six precordial (chest) leads use a separate sensing (positive) electrode placed on the chest so as to accentuate activity in particular regions of the heart (Figure 14.3): V1 and V2, right ventricle; V3 and V4, interventricular septum; V5 and V6, left ventricle. However, the augmented limb leads use one limb connection as the sensing electrode (aVR, RA; aVL, LA; aVF, LL), with the remaining two connected together as the indifferent electrode. As they therefore measure from each corner of Einthoven’s triangle towards the centre, they ‘see’ the heart at angles rotated by 30° compared with the bipolar leads. The six limb leads therefore give a view of the electrical activity of the heart every 30° (hexaxial reference system; Figure 14.4). Lead II and AVR normally shows the tallest QRS, as they lie closest to the mean direction of ventricular depolarization; as the ventricles have the greatest muscle mass, they generate the largest current. Together, the limb and precordial leads provide the standard 12 lead ECG (Figure 14.5).
General features of the ECG
The P wave (≤0.12 s duration) is a small deflection due to depolarization of the atria (atrial systole). The QRS complex is normally <0.08 s in duration and reflects ventricular depolarization; it is largest because of the large ventricular mass. The relative size of the individual components varies between leads. In lead II the Q wave is a small downward deflection, reflecting left to right depolarization of the interventricular septum. The R wave is a strong upwards deflection, reflecting depolarization of the main ventricular mass. The S wave is a small downward deflection in lead II and reflects depolarization of the last part of the ventricle close to the base of the heart. The T wave reflects ventricular repolarization and is normally in the same direction as the R wave (e.g. upwards deflection in lead II). This is because although it is opposite in polarity, its direction is the opposite of that for depolarization (Figure 14.2), as the length of action potential in the epicardium is shorter than that in the endocardium, so although the epicardium depolarizes last it repolarizes first. The reversal in direction therefore cancels out the reversal in polarity. Note that atrial repolarization is too small and diffuse to be seen, and the conducting system has too small a mass to generate any significant voltage.
The PR interval represents the delay between atrial and ventricular depolarization, mostly in the atrioventricular node (AVN), and is measured from the start of P to the start of QRS. Normal duration is 0.12–0.20 s. The ST segment (∼0.25 s) is normally isoelectric (i.e. at zero potential), because all ventricular muscle is depolarized and so there can be no current flow between cells. The QT interval, from the start of QRS to the end of T, represents the duration of ventricular activation. It is strongly dependent on heart rate and is generally corrected by the Bazett formula (QTC = QT/square root of R–R interval). QTC is normally <0.44 s, slightly longer in females.
Basic interpretation of the ECG
Rate and rhythm Heart rate in beats/min is 1/RR interval × 60. At a paper speed of 25 mm/s one large square = 0.2 s, one small square = 0.04 s. A heart rate above 100 beats/min is tachycardia, and below 60 beats/min bradycardia. A regular rhythm with a constant normal PR interval is sinus rhythm. A prolonged PR interval or disassociation of P and QRS waves suggests impaired conduction in the AVN or bundle of His.
QRS A broad and negative Q wave (sometimes normal in AVR and V1) or broad and misshapen QRS can be caused by a number of defects, including bundle branch block or a ventricular origin of the heartbeat (e.g. ectopic beats). A slowly developing Q wave may indicate a full wall‐thickness myocardial infarction (MI; Figure 14.6).
Cardiac axis The direction of maximum ECG amplitude (mean vector) and thus of the sum of currents generated by the ventricles. It is calculated from the relative size of the QRS for each limb lead, and ranges from +90° to −30° (Figure 14.4). It depends on the orientation of the heart and so varies during breathing. Left axis deviation (−30° to −90°) may reflect left ventricular hypertrophy, and right axis deviation (+90° to +120°) right ventricular hypertrophy.
ST segment elevation Due to injury currents between damaged and undamaged cells, normally transient and indicative of recent MI (Figure 14.6). Subendocardial MI may cause ST segment depression.
T wave inversion Often normal in lead III and V1, but in other leads may reflect MI and slowed conduction, such that repolarization of the epicardium occurs before repolarization of the endocardium. A tall peaked T wave can be caused by hyperkalaemia.
Prolonged QTC Reflects delayed repolarisation and can be caused by class IA and III antiarrhythmic drugs, heart failure and inherited long QT syndrome.
Vascular smooth muscle excitation–contraction coupling
Vascular smooth muscle (VSM) contraction is, like that of cardiac muscle, controlled by the intracellular Ca2+ concentration [Ca2+]i.
Unlike cardiac muscle cells, however, VSM cells lack troponin and utilize a myosin‐based system to regulate contraction.