Anatomy

The boundaries of the cardiac chambers in mammals are easily defined by the great veins (i.e., cranial and caudal venae cavae) that return blood to the right atrium, the smaller pulmonary veins that return oxygenated blood from the lung to the left atrium, the coronary sulcus (i.e., groove) that demarcates the atria from the ventricles, and the anterior (i.e., ventral) and posterior (i.e., dorsal) interventricular sulci that contain branches of the left circumflex coronary artery that separate the right and left ventricles (Fig. 33.3). All four chambers of the heart are easily visualized (Fig. 33.3A). The ventral interventricular branch of the left main coronary artery, occasionally referred to as the “left anterior descending coronary artery” in humans, provides blood supply to the ventricular septum and left ventricular free wall. The dorsal interventricular artery, generally an extension of the left circumflex coronary artery (the other major branch of the left main coronary artery), provides blood supply to most of the left ventricle. The right coronary artery provides blood supply to the right ventricular free wall and occasionally a large portion of the left ventricle (Fig. 33.3B). Anatomical differences in the anatomy of the coronary circulation among species account for dissimilarities in the source and distribution of myocardial blood flow. The left interventricular (i.e., anterior descending) coronary artery and its diagonal branches supply a larger mass of myocardium than the circumflex in humans, swine, rats, and nonhuman primates. The circumflex artery supplies the largest mass of cardiac muscle in dogs, cats, horses, and cattle although there is considerable species variation. Dogs have an extensive collateral coronary circulation (i.e., a network of tiny blood vessels that are not open under normal conditions but open during reduced blood flow), while pigs, monkeys, and humans do not. Cardiac veins empty into the great cardiac vein, which empties into the right atrium via the coronary sinus and accounts for over 90% of the venous return from the heart. Small capillary‐like vessels (Thebesian veins) are present throughout the endocardium and drain directly into the cardiac chambers accounting for approximately 4% of the heart’s venous return.

Blood returning from the systemic circulation (i.e., venous return) and pulmonary veins empties into the right and left atrium, respectively. The ventricles are the major pumping chambers of the heart and are separated from the atria by a fibrous skeleton of dense connective tissue (i.e., fibrous trigone) that anchors the atrioventricular (AV) (i.e., tricuspid and mitral) and semilunar (i.e., pulmonic and aortic) heart valves. The tricuspid valve is located between the right atrium and right ventricle and the mitral valve between the left atrium and left ventricle. The pulmonic valve is located between the right ventricle and pulmonary artery and the aortic valve between the left ventricle and aorta. Once the process of cardiac contraction is initiated, almost simultaneous contraction of the atria is followed by nearly synchronous and simultaneous contraction of the ventricles. Cardiac contraction produces pressure changes that are responsible for AV and semilunar valve opening and closing and the production of audible heart sounds. Fibrous bands (i.e., chordae tendineae) originating from papillary muscles located on the inner wall of the ventricular chambers are attached to the free edges of the AV valve leaflets and limit valve prolapse into the atria during ventricular contraction thereby preventing the regurgitation of blood into the atrium (Fig. 33.3A). Alterations in heart chamber geometry (e.g., stretch, dilation, or hypertrophy) produced by changes in blood volume, ventricular deformation (pericardial tamponade), incompetent heart valves, or disease (e.g., tumors and scarring) can have profound effects on ventricular pressures, blood flow, and myocardial function.

Metabolism

The maintenance of normal cardiac electrical and mechanical activity is dependent upon the energy (i.e., adenosine triphosphate [ATP]) derived from multiple metabolic pathways. Mitochondria generate more than 95% of the ATP used by the heart, in addition to regulating intracellular calcium concentrations, cell signaling, and coordinated cell death. A detailed description of these pathways is beyond the scope of this chapter and is more appropriately described in reviews and texts specifically dedicated to this subject [10,11]. The heart produces ATP when mitochondrial oxidative phosphorylation is fueled by electrons generated by dehydrogenation of carbon fuels (i.e., fats and carbohydrates) and the oxidation (i.e., electron transfer) of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂). NADH and FADH₂ are primarily produced by fatty acid oxidation, the citric acid cycle, and to a minor extent, by the pyruvate dehydrogenase reaction and glycolysis (Fig. 33.4). Oxidative phosphorylation is responsible for approximately 60–90% of the ATP formation in the heart during normal non‐ischemic conditions with the remainder derived from the citric acid cycle. The citric acid cycle is dependent upon acetyl‐CoA formed by the decarboxylation of pyruvate and the oxidation of fatty acids (Fig. 33.4) [10]. Approximately 60–70% of ATP hydrolysis is consumed by cardiac contraction, while the remaining 30–40% is used to maintain the ion pumps and sarcoplasmic reticulum Ca²⁺ ATPase. The rate of oxidative phosphorylation is directly linked to the rate of ATP hydrolysis so that ATP concentrations remain constant during intense exercise or changes in neurohumoral activity (e.g., variations in catecholamine concentrations) [11].

Electrophysiology and electrocardiogram

A highly integrated series of electrical, metabolic, and mechanical events are required to produce normal cardiac contractile function (i.e., excitation–contraction coupling). Notably, myocardial contraction is preceded by, and will not occur without, electrical activation although normal or near‐normal electrical activity is possible without myocardial contraction (e.g., electrical–mechanical uncoupling, electrical–mechanical dissociation, and pulseless electrical activity [PEA]). PEA is the presence of organized cardiac electrical activity, other than ventricular fibrillation or ventricular tachycardia, that should produce a pulse, but does not. The cardiac cell membrane (sarcolemma) is a highly specialized lipid bilayer that contains protein‐associated channels, pumps, enzymes, and exchangers in an architecturally organized, yet fluid (i.e., reorganizable and movable) medium [12]. The molecular composition and fluidity (i.e., freely movable membrane protein and lipid constituents) of cardiac membranes determine their ion transport/exchange and membrane‐associated electrical properties, as well as the ability to generate and propagate electrical impulses [12,13]. The unequal distribution (i.e., concentrations) of various ions (i.e., sodium, potassium, chloride, and calcium) across the sarcolemma and its permeability to these ions are responsible for the development of the resting membrane potential. Resting membrane potential can be estimated by the Nernst equation or more accurately determined by the Goldman–Hodgkin–Katz constant‐field equation [12] as shown below.

Nernst equation for potassium ions:

where E is electromotive force; 2.303 is the conversion of ln to log₁₀; C_i and C_o are ion concentrations inside (i) and outside (o) the cell membrane; R is the gas constant; T is absolute temperature in Kelvin; z is valence of the ion (in this case, 1); F is the Faraday constant; and mV is millivolts at 37 °C.

Goldman–Hodgkin–Katz equation:

where E_m is the resting membrane potential and P_Na (0.04), P_K (1.0)_, and P_Cl (0.45) are the relative permeabilities of the membrane at rest, and other terms are defined above.

Transmembrane changes in the electric potential (i.e., action potential) generated by cardiac cells are the result of transmembrane ion fluxes (active properties) that generate currents through voltage‐ and ligand‐gated membrane channels (Fig. 33.5; Table 33.3) [12,14,15]. The term “gated” refers to the opening (activation) or closing (deactivation or inactivation) of ion channels. Ion channels are characterized by their ionic selectivity, conductance, gating characteristics, and density. The channel gating mechanisms control ion passage and are composed of both activation and inactivation gates, which are voltage‐ and frequently time‐dependent (e.g., sodium channels). The functional configuration of the gates determines channel state: activated or open, inactivated or closed, and resting (i.e., capable of being activated) [13]. The directional movement (inward or outward) of the various ions ultimately depends on channel state and the electrochemical driving force (i.e., equilibrium potential minus membrane potential) for each ion. The electrochemical driving force, as illustrated by the Nernst equation, is composed of an electric force and the transmembrane ion concentration gradient. It should be noted that most local anesthetics (e.g., lidocaine, bupivacaine, etc.) demonstrate use‐ (i.e., frequency‐) dependent block [16,17]. Use‐dependent block is the phenomenon exhibited by cardiac cells when, in the presence of a drug, increases in stimulation rate (i.e., chronotropy) produce a more pronounced drug effect because more drug molecules are able to enter the channel and cause more inactivation than during slower rates of stimulation [16].

Excitability (i.e., bathmotropy), or the ability of the cardiac cell membrane to be activated, generate, and propagate an electric potential (action potential), is a fundamental intrinsic property of cardiac cells [12,13]. The cardiac action potential (AP) morphology and duration vary considerably from that of nerves and skeletal muscle (Fig. 33.6A) [15]. The cardiac muscle AP arises from a more negative membrane potential (–90 versus –70 mV), may be of similar magnitude, but is much longer in duration (150–300 versus 1 ms) than APs recorded from nerve or skeletal muscle (Fig. 33.6A). Cardiac AP magnitude and duration also vary depending on the type of cardiac cell that generates them (Fig. 33.6B). Five characteristic phases of the cardiac AP are discernible in most cardiac cells: phase 0, or the phase of rapid depolarization, is caused by the rapid and relatively large influx of sodium ions (i.e., fast inward current) into the cell; phase 1, the early repolarization phase, is caused by the transient outward movement of potassium ions; phase 2, the plateau phase, is attributed to the continued, but decreased, entry of sodium ions and a large, but slower, influx of calcium ions (i.e., slow inward current) into the cell; phase 3 is the phase of membrane repolarization during which the membrane potential returns to its resting value primarily due to potassium efflux (i.e., outward current) from the cell; and phase 4 is a resting phase in atrial and ventricular muscle cells during which membrane pumps (i.e., Na⁺–K⁺ ATPase, Ca²⁺ pumps), and exchange mechanisms maintain the negative membrane potential and keep intracellular ion concentrations more or less constant prior to initiation of the next AP. For example, the Na⁺–Ca²⁺ exchanger (NCX) or antiporter membrane protein removes calcium from cells helping to restore normal transmembrane electrolyte concentrations (Fig. 33.5; Table 33.3) but is reversible, moving Ca²⁺ out or into the cell depending on the prevailing electrochemical driving forces for Ca²⁺ and Na⁺. Notably, a great deal of interest has been focused upon repolarization currents (I_K) due to their importance in determining membrane resting potential, AP duration, and their involvement in repolarization abnormalities (i.e., inhomogeneities or dispersion of the QT interval) including long QT syndrome [18,19]. Long QT syndrome is an uncommon hereditary or drug‐induced condition (e.g., select antiarrhythmics, antidepressants, antipsychotics, antimicrobials, and opioids), in which AP duration becomes longer and may become highly variable among ventricular myocytes leading to electrical instability and the risk of reentrant induced torsades de pointes and ventricular fibrillation [20–22].

The speed of conduction of the cardiac electrical impulse (i.e., dromotropy) is determined by the magnitude and rate of sodium influx into the cardiac muscle cells and is directly related to the rate of voltage change (dV/dt) during phase 0 (Fig. 33.5; Table 33.4) [23]. A large dV/dt indicates more rapid depolarization of the cell membrane and more rapid conduction of the cardiac impulse through cardiac tissue [12]. The change (d) in transmembrane potential (V) is determined by the transmembrane ionic current (I_ion) and the membrane capacitance (C_m; 1 μF/cm²) provided by the charge separation across the lipid bilayer:

Ion movement occurs due to the activity of voltage‐gated ion channels, pumps, and exchangers [13]. A negative I_ion indicates the inward flow of positive ions into the cell and produces a positive dV/dt, which depolarizes (i.e., makes the inside of the cells more positive) the membrane potential. A positive I_ion indicates an outward flow of positive ions, which repolarizes the membrane potential by generating a negative dV/dt. The generation of the cardiac AP results from the time‐, voltage‐, and concentration‐dependent evolution of I_ion and represents the contribution of multiple ion‐selective mechanisms for ion movement across the cardiac cell membrane (Fig. 33.5) [23]. Current flows from a depolarized cell to its neighboring less depolarized cells via intercellular resistive pathways known as “gap junctions.” Gap junctions are hydrophilic intercellular protein channels (i.e., connexons) composed of six connexin proteins that allow ions and electrical impulses to pass between cells through regulated hydrophilic channels [23]. Voltage‐gated ionic channels and gap junctions are depressed (i.e., resistance is increased) by anesthetic drugs through direct interaction with their protein subunits, thereby interfering with cardiac excitability, transmission, and propagation of electrical impulses [24–26].

Calcium enters cardiac cells through L‐type calcium channels during phase 2 of the AP triggering intracellular calcium release from the sarcoplasmic reticulum, which is important for normal cellular contraction. Since calcium enters the cell more slowly than sodium (i.e., slow inward calcium current) and from a less negative membrane potential, cardiac cells with a reduced resting membrane potential (e.g., the sinoatrial [SA] and atrioventricular [AV] nodes) demonstrate a considerably smaller phase 0 dV/dt and slower conduction velocity compared to those with a more negative resting membrane potential (e.g., atrial and ventricular muscle and Purkinje cells) [11–13]. Potassium efflux from cardiac cells is controlled by a variety of mechanisms, including the concentration difference of potassium across the membrane and changes in membrane permeability to potassium as the membrane potential changes (Table 33.3). The channels responsible for repolarization (phase 3) are major determinants of cardiac AP duration and cardiac cell refractoriness (Fig. 33.7). The duration of the cardiac AP and refractoriness have important clinical implications relative to the amount of calcium that enters the cell during depolarization (i.e., longer AP duration permits more calcium entry) and the potential for arrhythmia development, respectively [12,27]. Arrhythmias develop if there are large differences (i.e., inhomogeneities) in myocyte AP duration (e.g., > 20–40 ms) among groups of adjacent cardiac cells because of the potential for electrical impulses to re‐enter cells that have rapidly repolarized and regained excitability and conduction capabilities (i.e., reentry). Cardiac cells with particularly long AP durations are thought to predispose to dispersion of refractoriness and afterdepolarizations (i.e., afterpotentials) that leads to electrical instability and cardiac arrhythmias [27–29].

Phase 4, diastolic depolarization, endows the heart with the unique property of automaticity (i.e., self‐excitation). SA automaticity is produced by depolarizing membrane currents and is influenced by local factors, including temperature, pH, and blood gases (PO₂ and PCO₂), extracellular potassium concentration, catecholamines, and various hormones (Fig. 33.8). Cells in the SA and AV nodes and specialized atrial and ventricular muscle cells (i.e., Purkinje) cells are automatic (Table 33.4) [30]. The resting membrane potential of these cells depolarizes toward a threshold potential, which when reached triggers the development of an AP. The ionic processes responsible for phase 4 diastolic depolarization vary among the various specialized tissues of the heart primarily because of differences in their resting membrane potential and cell type (e.g., SA node, AV node, and Purkinje cell), but all are dependent upon the funny current (I_f), a mixed sodium–potassium current that activates upon hyperpolarization [31]. The funny current, first described in SA node myocytes as an inward current activated during hyperpolarization, determines the end of an AP, the steepness of phase 4 depolarization, and the frequency of AP firing [31]. Cells in the SA and AV nodes have comparatively less negative maximum diastolic potentials (–65 mV) compared to cardiac muscle and Purkinje cells (≥ –90 mV) and depend upon I_f, the entry of calcium ions (i.e., inward calcium current), and a progressive decrease in membrane permeability to potassium efflux for their automaticity [12,13,31,32]. Automatic cells in atrial specialized pathways and the ventricular Purkinje network have a more negative maximum diastolic potential (≥ –90 mV) and depend more upon I_f [32]. The principal mechanisms responsible for altering automaticity are changes in the threshold potential, the rate of phase 4 depolarization, and the maximum diastolic potential following repolarization. The cardiac tissue with the most rapid rate of phase 4 depolarization (normally the SA node) is termed the “pacemaker” and determines the heart rate (HR). The cardiac pacemaker normally activates (i.e., overdrives) and, therefore, resets the automaticity of slower or subsidiary pacemakers, thereby preventing other potential pacemakers from controlling HR (i.e., overdrive suppression; Fig. 33.9A) [32]. Overdrive suppression of subsidiary pacemakers is caused by activation of the sodium–potassium (Na⁺–K⁺) pump, leading to membrane hyperpolarization and a longer time required to reach threshold (Fig. 33.9B) [13]. Subsidiary pacemakers are depressed by fast HRs because the Na⁺–K⁺ pump is more active at faster rates, resulting in a more negative maximum diastolic potential. Clinically, the administration of anticholinergic drugs (e.g., atropine and glycopyrrolate) can produce increases in sinus rate that eliminate (i.e., overdrive suppress) infrequent or slower automatic ventricular arrhythmias. Alternatively, ivabradine, a drug that selectively and specifically inhibits the cardiac pacemaker current I_f, slows HR [33].

The average of the voltage vectors produced by all the APs produced by activation of each cardiac cell is responsible for the body surface electrocardiogram (ECG; a graphical representation of the electrical depolarization and repolarization of the heart) (Fig. 33.10). Initiation of an electric impulse in the SA node is followed by rapid transmission of a wave of depolarization throughout the atria, giving rise to the P wave. Repolarization of the atria gives rise to the T_a wave, which is small and difficult to identify in smaller animals (e.g., rats, rabbits, dogs, cats, etc.) but becomes obvious in larger animals (e.g., horses and cattle) because the total atrial tissue mass is substantial enough to generate an electromotive force that can be detected electrocardiographically from the body surface. Similarly, depolarization of the SA and AV nodes does not normally generate a large enough electromotive force to be recorded at the body surface. Once the wave of depolarization reaches the AV node, conduction is slowed because of its less negative resting membrane potential (i.e., –40 to –60 mV) and reduced slope (dV/dt) of phase 0 (Fig. 33.6B). This is especially evident when the AV node is stimulated at higher rates due to a phenomenon called “decremental conduction,” which is characterized by poor propagation of the electrical impulse due to progressive decreases in membrane potential and AP dV/dt. Increased parasympathetic tone also produces marked slowing of AV nodal conduction, leading to first‐degree, second‐degree, and, occasionally, third‐degree AV block. Many drugs used for anesthesia, including opioids, α₂‐adrenergic receptor agonists, and occasionally acepromazine, can increase parasympathetic tone, causing sinus slowing and bradyarrhythmias. The use of anticholinergic drugs (e.g., atropine and glycopyrrolate) is generally effective therapy in these situations but not when AV block is caused by inflammation or structural disease (e.g., fibrosis and calcification). Caution is indicated when atropine or glycopyrrolate are co‐administered with α₂‐adrenergic receptor agonists due to their potential to produce or exacerbate ventricular arrhythmias. α₂‐Adrenergic receptor agonist–anticholinergic drug combinations that produce cardiac arrhythmias are likely due to increases in the rate–pressure product and myocardial oxygen consumption, or myocardial ischemia in conjunction with functional impairment of autonomic tone (i.e., dysautonomia) [34,35].

The conduction of the electrical impulse through the AV node provides time for the atria to contract (i.e., atrial priming or kick) prior to activation and contraction of the ventricles. The delay in ventricular depolarization is responsible for the PR or PQ interval of the ECG (Fig. 33.10). This delay is functionally important, particularly at faster HRs, because it enables atrial contraction to contribute to ventricular filling. It is worth remembering that cells of the AV node depend upon both sodium and calcium ions for the generation and conduction of their AP. Thus, cells of the AV node are extremely sensitive to drugs that block transmembrane calcium flux, including excessive doses of anesthetic drugs and calcium channel antagonists (e.g., verapamil and diltiazem). Excessive doses of injectable or inhalant anesthetic drugs can produce post‐repolarization refractoriness, a phenomenon wherein cardiac cells remain refractory to electric activation after complete repolarization. This phenomenon is likely to produce AV block as HR increases. In addition, increases in parasympathetic tone in the presence of drugs or diseases (e.g., inflammation and ischemia) that interfere with conduction of the electric impulse through the AV node can lead to ECG sinus bradycardia and first‐degree (prolonged PR interval), second‐degree (blocked P wave), or third‐degree (dissociation of P from the QRS complex) AV block.

Once the electrical impulse has traversed the AV node, it is rapidly transmitted via specialized pathways to ventricular muscle cells. Bundles of Purkinje cells (the right and left bundle branches) transmit the electrical impulse to the ventricular septum and the right and left ventricular wall papillary muscles, respectively, via the moderator band in the right ventricle and the left anterior and posterior divisions of the left bundle branch, in the left ventricle (Fig. 33.11A). Purkinje fibers conduct the electric impulse at relatively rapid speeds (3–4 m/s) throughout the ventricles. Purkinje cells and midmyocardial (M) cells located at the terminal ends of the Purkinje bundle branches and in the middle of the ventricular walls, respectively, have the longest AP durations and, therefore, serve as physiological “gates” preventing reentry or recycling of electric impulses into the ventricular myocardium [36,37]. The comparatively long duration of Purkinje and M cell APs is also considered to be one cause for the development of U waves in the ECG (Fig. 33.10). It is important to remember that the electrical transmission of the cardiac AP ultimately depends on spatial variation in myocardial cell refractoriness and the maintenance of uniform (isotropic) cell‐to‐cell resistive and capacitive (passive force) membrane properties that are largely determined by low‐resistance gap or nexus junctions between cells [38,39].

The interval beginning immediately after the terminal S wave of the QRS complex (J point) and the ventricular repolarization T wave is referred to as the “ST segment.” Elevation or depression of the ST segment (±0.2 mV or greater) from the isoelectric line is indicative of myocardial hypoxia or ischemia caused by low cardiac output (CO), hypotension, anemia, pericarditis, or cardiac contusion, and suggests the potential for arrhythmias to develop. The ST segment is followed by, and may slur into, the T wave [40]. The configuration and magnitude of the T wave vary considerably among species and are particularly influenced by changes in HR, blood temperature, and the extracellular potassium concentration. Hyperkalemia, for example, produces an increase in membrane conductance to potassium and shortens repolarization producing large magnitude, spiked, or pointed T waves and a shortened QT interval. U waves, when present, can be distinguished immediately following the T wave (Fig. 33.10) [36,41]. Like T_a waves, U waves are more frequently observed in larger species of animals (horses and cattle).

As described previously, the ECG is produced by recording the electrically synchronized depolarization and repolarization of the atria and ventricles. The morphology of the various waveforms (i.e., P, QRS, and T waves) that characterize atrial and ventricular depolarization and repolarization is dependent upon the different patterns of depolarization, electrode placement, the size of the cardiac chambers (e.g., hypertrophy increases the electromotive force generated), the orthogonal direction of the dominant electromotive force, resistance to electrical signal transmission (i.e., fat, fluid, and air), and a host of electrode, equipment, and environmental factors (e.g., electrical noise). P wave morphology will vary depending on where within the crescent‐shaped SA node electrical activation originates and spreads into the right atrium. The electrical signal is then transmitted via intra‐atrial and interatrial specialized pathways that depolarize the right and left atrial (e.g., Bachmann’s bundle) muscle fibers, respectively (Fig. 33.11A). The right atrium is normally activated before the left atrium since the electrical signal normally originates in the SA node. This sequence of activation (i.e., right atrium then left atrium) may be hard to appreciate in smaller animals (e.g., rats, rabbits, cats, and small dogs) since their atrial muscle mass is relatively small and the electrical activation process is completed in a shorter time compared to larger animals (e.g., pigs, horses, goats, and cattle). The larger atrial muscle mass in large animals or in larger smaller species (e.g., dogs) with an enlarged left atrium can often be identified by a bifid P wave. Once the atrial electrical signal traverses the AV node, it activates the rapidly conducting Purkinje fiber network. Bundles of Purkinje fibers form the right and left bundle branches, which distribute the wave of depolarization to the respective papillary muscles and ventricular muscle cells of the right and left ventricles generating the QRS wave that represents ventricular depolarization (Figs. 33.10 and 33.11B). Purkinje fibers penetrate a short distance from the subendocardium in smaller animal species (Category I: rats, rabbits, cats, and dogs) while larger animal species have evolved a more diffuse Purkinje fiber distribution that extends close to the subepicardium (Category II: sheep, goats, cattle, pigs, and horses). This difference in Purkinje fiber anatomical distribution ensures the synchrony of ventricular activation and contraction. Fiber‐to‐fiber spread of the ventricular myocardial electrical signal occurs from the endpoints of the Purkinje fibers in the subendocardium of Category I (i.e., smaller) species (Fig. 33.12A) or wherever Purkinje fibers terminate in Category II (i.e., larger) species (Fig. 33.12B). Orthogonal (i.e., X, Y, Z; ECG leads: I, aVf, V10) ECG lead placement illustrates differences in the dominant ventricular electrical activation forces, spatial orientation, and pattern of ventricular depolarization generated by animals in Category I (e.g., cats, dogs, and humans) and Category II (Category IIA: sheep, goats, and cattle; Category IIB: pigs and horses) (Fig. 33.13).

Several inhalant (e.g., halothane, isoflurane, and enflurane) and injectable (e.g., thiopental, propofol, and opioids) anesthetic drugs are known to sensitize the myocardium to catecholamines or facilitate torsadogenicity resulting in the development of cardiac arrhythmias [42–45]. Cardiac sensitization to anesthetic drugs has been linked to cardiac α₁‐adrenerigc receptor stimulation and is likely produced by drug‐related alterations in intracellular calcium cycling, alterations in electrical impulse propagation, and muscle cell excitability [46,47]. Anesthetic drugs, particularly volatile anesthetics, are also known to interact with multiple cardiac ion channels. Halothane, isoflurane, and sevoflurane depress ion channels at different minimum alveolar anesthetic concentration (MAC) multiples: sodium (> 2 MAC), calcium (~30% at > 2 MAC), potassium (~20% at > 1 MAC), and chloride (> 2 MAC) [48]. Inhibition of these channels may alter AP shape (i.e., triangulation) and conduction velocity and these are the two most common proarrhythmic changes in the cardiac AP associated with volatile anesthetics [48–51]. Triangulation allows more time for Na⁺–Ca²⁺ exchange, reactivation of the sodium current, reduced synchronization of APs, and facilitation of re‐excitation predisposing to the development of early afterdepolarizations [50,51]. Slowed conduction and tissue refractoriness are key factors for determining whether reentrant arrhythmias occur. In addition to these mechanisms, autonomic nervous system imbalances lead to events that predispose to cardiac repolarization and conduction abnormalities, coronary vasospasm, and unifocal or multifocal ventricular tachycardias. Autonomic imbalance may be responsible for the cardiac arrhythmias attributed to the concurrent administration of anticholinergic (e.g., atropine) and α₂‐adrenerigc receptor agonist (e.g., medetomidine and dexmedetomidine) drugs [34]. γ‐Aminobutyric acid type A (GABA_A) anesthetics (i.e., propofol, etomidate, and alfaxalone) acting on various GABA_A subunits (α, β, γ) may also inhibit postganglionic vagal input (i.e., reduce M₂ receptor activity) to the heart provoking sinus tachycardia while several opioids, particularly methadone, are known to lengthen the QT interval predisposing to ventricular arrhythmias [52,53].

In summary, the active (i.e., ion movement) and passive (resistive and capacitive) properties of cardiac cell membranes determine the heart’s excitability (i.e., bathmotropy), automaticity (i.e., chronotropy), conduction (i.e., dromotropy), rhythmicity, and refractoriness. Injectable and inhalant anesthetic drugs produce alterations in cardiac ion channels and transmembrane ion flux that may impair mechanical contraction or induce cardiac arrhythmias [42,46,47,54,55].