The fibrous skeleton of the heart is a framework of 4 dense collagen rings around the atrioventricular (AV) and semilunar valves, as well as the left and right fibrous trigones (also known as the central fibrous body), and the membranous portion of the interatrial and interventricular septum. Its main component is the central fibrous body, where the leaflets of all 4 cardiac valves converge. The fibrous skeleton reinforces the ostia of the valves and prevents the annuli from overdistension by resisting forces of pressure developing through the cardiac cycle. It provides attachment for the valvular leaflets and cusps, as well as for some of the musculature of the atrial and ventricular wall. It is electrically impermeable, only allowing electrical propagation from the atrioventricular node across the right fibrous trigone to the bundle of His. Chronic degenerative changes and calcium deposition into the collagen skeleton results in delayed conduction and depolarization, arrhythmias, rigidity of the valvular ostia, restricted leaflet opening and/or leaflet malcoaptation.

Excessive apoptosis within the septum primum, or incomplete development of the septum secundum results in an atrial septal defect (ASD), the most common congenital heart defect to manifest in adulthood:

ASDs often remain clinically silent with preserved normal left atrial size, however, longstanding left-to-right shunting and resultant dilatation of the right-sided chambers along with persistent pulmonary hypertension may reverse the direction of the shunt, resulting in hypoxemia and Eisenmenger physiology.

The interventricular septum (IVS) separates the left and right ventricles from one another. Under physiological pressure and filling conditions its convexity is bowing into the right ventricle. Its margins are marked externally by the anterior and posterior interventricular grooves. The upper, posterior part of the interventricular septum is thin, and constitutes the membranous interventricular septum. The greater, anterior portion is the muscular interventricular septum.

During cardiogenesis, along with the atrial septation a concurrent ventricular septation is also taking place. With the development of the endocardial cushions and the atrioventricular separation, there is tissue growth between the left and the right sides of the developing atrioventricular canal. This is the muscular portion of the interventricular septum, growing from the inferior portion of the ventricle toward the endocardial cushion. As the muscular IVS reaches the endocardial cushion, a small interventricular foramen remains. This is closed by tissue growth from the endocardial cushion, connective tissue from the muscular IVS, as well as tissue from the septation of the truncus pulmonalis and the conus arteriosus. Inadequate contribution from either component results in different types of ventricular septal defects.

The right atrium is the cardiac chamber receiving the systemic and cardiac venous return via the superior and inferior venae cavae (SVC and IVC) and the coronary sinus. It is divided into 3 components.

The venous component receives deoxygenated blood from the SVC and the IVC. At the inferior cavoatrial junction lies the Eustachian valve, important before birth in directing blood from the IVC to the left atrium across the foramen ovale. A network of fine filamentous strands, the Chiari network, may be seen in this region. The variably sized Eustachian valve and Chiari network are normal variants within the right atrium.

The second component is the vestibule, which converges into the leaflets of the tricuspid valve, and the third is the appendage (also known as auricle). The right atrial appendage has a wide junction with both the vestibule and the venous component. The vestibuloauricular junction is identified by the terminal groove, the external marking of the prominent terminal crest on the internal surface. A consistent feature of the right atrial anatomy is the extension of the auricular pectinate muscles beyond the appendage to the atrioventricular junction.

The sinus node, a cluster of specialized myocardial cells capable of spontaneous electrical impulse generation, lies at the superior cavoatrial junction at the terminal groove. It is supplied by the nodal artery, arising from the right coronary artery in 55% of cases, or the proximal left circumflex artery in the remaining 45%. The atrioventricular node is located in the floor of the right atrium, near the opening of the coronary sinus. Preserving blood flow to the sinus node and other conductive tissues is key to avoiding arrhythmias and other conduction abnormalities.

The tricuspid valve is located nearly vertically behind the aortic valve. With a valve area of 4–6 cm², it is the largest of the 4 valves in the heart. Its annular plane is saddle-shaped and is apically displaced relative to that of the mitral valve. A displacement index greater than 8 mm/m² (body surface area) suggests the presence of Ebstein’s anomaly. Its 3 leaflets are the septal, anterior, and posterior tricuspid valve leaflets, attached by their chordae tendineae to the right ventricular papillary muscles (true chords), or, not uncommonly, directly to the septum (false chords). The subvalvular apparatus of the tricuspid valve is variable. Most commonly, the chordae tendineae originate from 2 or 3 papillary muscles, the anterior being the most prominent; the posterior, which is usually less prominent and may have several subdivisions; and the septal, which is the least prominent or may be entirely absent.

The right ventricle is the most anterior of the 4 chambers of the heart, located immediately behind the sternum. Its geometry is complex: The right ventricle is crescent shaped when viewed in the short axis, and triangular when viewed longitudinally. Current guidelines identify its walls as anterior, inferior, and lateral free wall. Medially, the right ventricle shares the septum with its left-sided counterpart. For purposes of functional quantification, these walls are further divided into basal, mid, and apical segments.

Anatomically and functionally, the right ventricle is composed of 3 portions: the smooth muscular right ventricular inflow tract, the apical trabecular, and the right ventricular outflow tract. The inlet portion encircles the tricuspid valve. The trabecular portion of the right ventricle extends into the apical region. The wall of the ventricle is thin here, making it vulnerable to perforation by catheters and electrodes.

The most prominent of the trabeculae is the septomarginal trabecula. It carries part of the right bundle branch of the conduction system. It was once wrongly thought to prevent the right ventricle from overdistending, hence the name “moderator band.” The septomarginal trabecula originates from the base of the septum, it divides into an anterior limb that supports the pulmonic valve cusps, and a posterior limb, from which the medial papillary muscle arises. Its main mass extends from the base of the septum to the apex and divides into smaller muscle ridges. Two of these are particularly prominent, one giving rise to the anterior papillary muscle, and the other crossing the right ventricular cavity as the moderator band.

The outlet portion consists of the circumferential muscular infundibulum that supports the pulmonic valve, which is the only one of the cardiac valves with no single ringlike annulus. It is supplied by the conus branch of the right coronary artery.

The pulmonic valve separates the right ventricular outflow tract from the pulmonary artery. It is located anteriorly and to the left of the aortic valve. It is a semilunar valve formed by 3 cusps, labeled as anterior (nonseptal), left, and right, each with a fibrous nodule at the midpoint of their free edges. The leaflets coapt via their crescent-shaped surfaces. The cusps of the pulmonic valve are formed by endocardial folds that are supported by internal dense collagenous plates as well as elastic connective tissue, continuous with the fibrous skeleton of the heart. They are thinner than the cusps of the aortic valve, and, lacking fibrous continuity with the septal leaflet of the tricuspid valve, are supported only by a prominent ridge of the posterior subpulmonary infundibular musculature. This is the supraventricular crest that separates the pulmonic and tricuspid valves from one another, and supports the semilunar attachments of the pulmonic valve. Surgical incisions made through this crest may run toward the interventricular septum, and jeopardize the right coronary artery.

Oxygen-rich blood returning from the lungs via the 4 pulmonary veins is received first by the left atrium. The left atrium has 3 basic components: first, the largest, smooth-walled pulmonary venous component; second, the vestibule; and third, the left atrial appendage. The wall of the vestibule is continuous with both the venous component and the posterior (mural) leaflet of the mitral valve, and may affect normal valvular function when left atrial dilation is present. Pectinate muscles are confined almost exclusively to the appendage in the left atrium. The flap valve of the fossa ovalis is found on the left atrial side of the interatrial septum.

Recurrent, symptomatic, drug-refractory atrial fibrillation most often originates from the pulmonary veins or their pulmonary venous ostia. Circumferential or segmental ablation of potential triggers is considered effective means to control refractory atrial fibrillation, as scar forming is thought to prevent propagation of abnormal signals to the rest of the atrial musculature. The ablation and mapping catheters are inserted via the femoral or jugular veins, and are placed through separate transseptal punctures. Most often, radiofrequency energy is used to make ablation lesions around the pulmonary vein ostia. In the presence of a left atrial appendage thrombus, or inability to anticoagulate in the 30-day peri- and post-procedural period, pulmonary vein isolation for atrial fibrillation ablation is contraindicated. A rare, frequently disabling, sometimes fatal complication of the procedure is an atrio-esophageal fistula resulting from thermal damage. Other potential complications are cardiac tamponade, arrhythmias or atrioventricular block, embolic events, valvular complications, or peripheral vascular damage.

The bileaflet mitral valve is located between the left atrium and left ventricle, embedded into the saddle-shaped mitral valve annulus. It serves as a unidirectional valve directing blood from the atrium toward the ventricle by passively opening during diastole and closing in systole, as determined by the pressure gradient between the chambers.

The mitral valve apparatus consists of the left atrial wall, the annulus, the anterior leaflet attached to the aortic root, the posterior leaflet attached to the left atrial myocardium, the chordae tendineae attached to the ventricular side of the mitral valve leaflets, and the anteromedial and posterolateral papillary muscles.

The anterior leaflet of the mitral valve is wide. It occupies about one-third of the annular circumference, and forms the anterior portion of the left ventricular outflow tract. In contrast with the posterior leaflet, its free edge has no indentations. The posterior (mural) leaflet is narrower, it occupies about two-thirds of the annular circumference, and it is further divided into 3 scallops by 2 clefts. Because the posterior aspect of the mitral valve annulus contains little fibrous tissue, the posterior leaflet, especially the middle scallop, is more prone to prolapse than the anterior. The circumflex artery courses near the left half of the posterior leaflet, whereas the right half is in close proximity to the coronary sinus and the arterial branch supplying the AV node.

The mitral valve leaflets are supported by a dense collagen annulus. The most vulnerable portion of the mitral valve annulus is its aspect continuous with the right fibrous trigone, due to the proximity of the atrioventricular node and the penetrating bundle of His.

The muscular components of the mitral valve apparatus are the anteromedial and posterolateral papillary muscles. The anteromedial papillary muscle is more prominent and is supplied by the left coronary system. The posteromedial papillary muscle is smaller, and is supplied by the right coronary artery. The mitral valve closes with the contraction of the papillary muscles, and open when they relax. Papillary rupture, as a result of ischemia, will result in acute mitral regurgitation. Because the anterolateral papillary muscle is supplied by both the left anterior descending (LAD) artery and the left circumflex artery, its ischemic dysfunction is relatively uncommon. In about 60–65% of individuals, the posteromedial papillary muscle was found to be perfused by a single vessel, most commonly by the right coronary artery.

The left ventricle (LV) is the largest and thickest chamber of the heart. It receives oxygenated blood from the left atrium during diastole, to transfer it to the body during across the aortic valve during systole. Relative to the right ventricle, it is located laterally and posteriorly. Its superior, widest aspect is termed the base, leaning upward and toward the right shoulder, opposing its apex, pointing down and to the left. By consensus, its 4 walls are termed septal, and the free anterior, inferior, and lateral walls. For purposes of functional quantification, these are further divided into basal, mid, and apical segments.

Morphologically, the left ventricle also has an inlet, a fine trabecular and an outlet component. The inlet portion extends from the mitral valve annulus to the origins of the papillary muscles, and contains the mitral valve apparatus. In contrast to the coarsely trabeculated right ventricle, the left ventricular free wall is finely trabeculated. The trabeculation extends to the apex, where, due to the progressively decreasing number of myocardial fibers, the wall thickness is thin. Its outflow tract differs from that of the right ventricle in that it is anatomically and functionally contiguous with the inlet via the aortic-mitral continuity. The left ventricular outflow tract supports the aortic valve, and its septal portion, in contrast with the primarily muscular right ventricular infundibulum, includes the membranous interventricular septum. The left bundle branch of the conduction system courses posteriorly to the membranous septum between the right and noncoronary cusps of the aortic valve.

The interventricular septum is formed by subendocardial myocardial fibers of both the left and the right ventricle, intermingled with circumferentially arranged fibers derived from the left ventricle. For this reason, in a normally functioning heart, the septum thickens toward the left ventricle during systole. During contraction, the high left ventricular pressure along with the septum provides a “splint” against which the right ventricle is able to shorten, hereby contributing to the emptying of the right ventricle (systolic ventricular interdependence). Under pathologic conditions, for example, during acute right ventricular volume or pressure overload, or due to conduction abnormalities or pacemaker activation, the septum may appear flat, or move paradoxically toward the right ventricle during systole. Blood flow to the anterior 2/3 of the septum is supplied by the septal perforators of the left anterior descending artery. The posterior 1/3 is supplied by the distal branches of the right coronary artery.

The 2 papillary muscles of the left ventricle arise from the anterolateral and posteromedial portions of the left ventricular free wall. Their arrangement ensures parallel alignment of the chordae tendineae with the LV axis during systole, allowing for complete leaflet coaptation and closure of the mitral valve in the normally functioning heart.

All 3 coronary branches contribute to the blood supply of the left ventricle, acute ischemic events therefore predictably manifest as regional wall motion abnormalities based on the coronary distribution. The left anterior descending artery and its branches, the septal perforators and the diagonals perfuse the anterior wall, the anterior two-thirds of the septum, and the apex. The obtuse marginal branches of the left circumflex artery supply the lateral wall. The right coronary artery perfuses the medial portions of the inferior wall, as well as the posterior one-third of the interventricular septum. Anastomotic connections between the left and the right coronary system allows for preserved myocardial perfusion distal to a significant obstruction or total coronary occlusion.

The aortic valve is part of the aortic root consisting of the annulus, the aortic valve cusps, the sinuses of Valsalva, the junction between the sinuses and the proximal ascending aorta (the sinotubular junction), and the proximal ascending aorta. It is located at the left ventricular outlet, separating the aorta and the ventricle. Owing to its central location, it is the only valve in the heart that is related to all 4 chambers and each of the valves. As a trileaflet semilunar valve, it consists of 3 cusps: the left and right coronary cusps giving rise to their respective coronary arteries, as well as the non-coronary cusp, which faces the interatrial septum. The right coronary cusp is the most anterior and is adjacent to the right ventricular outflow tract. The left coronary cusp is located posteriorly relative to the other 2. Histologically, its cusps are composed of dense collagenous plates, which are in continuity with the fibrous skeleton of the heart, covered by endocardium. Each cusp has its attachment to the aorta and the left ventricle. Immediately behind the cusps, the wall of the proximal ascending aorta bulges outward to form the aortic sinuses of Valsalva. The function of these sinuses is to prevent coronary ostial occlusion by creating eddy currents of blood flow during rapid ejection. As with the pulmonic valve, each cusp has a fibrous nodule at the midpoint of their free edges, forming the nodule of Arantius. The leaflets coapt via their crescent-shaped surfaces. Incomplete coaptation of the valve leaflets during diastole results in aortic regurgitation, whereas limited systolic leaflet excursion due to excessive leaflet thickening resulting from degenerative or rheumatic disease process suggests the presence of aortic stenosis. The severity of aortic stenosis can be assessed by various methods. A peak transaortic velocity of greater than 4 m/second, a peak transaortic gradient of at least 70 mm Hg and a mean gradient of at least 40–50 mm Hg, as well as an aortic valve area of less than 1 cm² is consistent with severe aortic stenosis.

The left coronary artery arises from the left coronary sinus as the left main stem, which then bifurcates into 2 segments: the left anterior descending (LAD) and the circumflex (LCx) artery. The relatively short left main stem courses between the left atrial appendage and the pulmonary trunk before giving off the LAD and the LCx, and, in 15–30% of cases the variant coronary ramus intermedius, the branch supplying the anterior aspect of the heart.

The left anterior descending artery traverses the anterior interventricular groove and perfuses the anterior wall via the diagonal branches, as well as the anterior two-third of the interventricular septum via its septal perforators coursing along the anterolateral wall, and a small portion of the anterior wall of the right ventricle, adjacent to the interventricular groove, via the right ventricular branches.

The circumflex artery courses in the left atrioventricular groove. Its primary branches are the obtuse marginals, supplying the lateral aspect of the left ventricle, including the posteromedial papillary muscle. In 10% to 15% of individuals, it gives off the posterior descending artery (left dominance). Further branches of the left circumflex artery supply the left atrium, and, in 45% of the cases, the sinus node. A left dominant coronary system also supplies the atrioventricular node.

The right coronary artery emerges from the right sinus of Valsalva and is carried by the right atrioventricular groove. In about half of the cases it gives off the conus branch that supplies the right ventricular outflow tract. The RCA perfuses the anterior free wall of the right ventricle via its acute marginal branches, the sinus node via the nodal artery in 55% of individuals, and the atrioventricular node in patients with right-dominant coronary circulation. It bifurcates into the posterior descending artery and the posterolateral branch at the posterior interventricular groove. The posterior descending artery gives off the posterior septal perforators that supply the posterior one-third of the interventricular septum. The posterolateral branch supplies the inferoposterior wall of the left ventricle along with the acute marginal branches of the RCA and/or the circumflex artery. The Kugel’s artery is an anastomotic branch between the RCA and the LCx that may give off a branch that supplies collateral circulation to the atrioventricular node.

Of the cardiac veins, the great cardiac vein courses in the anterior interventricular groove upward from the apex, alongside the LAD. It drains into the coronary sinus. The middle cardiac vein courses in the inferior interventricular groove, upward from the apex, accompanying the PDA.

The coronary sinus courses in the posterior atrioventricular groove, alongside the left circumflex artery. It receives the great cardiac vein proximally and the middle cardiac vein distally, and drains into the right atrium. Its orifice is guarded by the Thebesian valve.

The anterior right ventricular veins course on the anterior surface of the right ventricle, where they may drain directly into the right atrium, or coalesce to form the small cardiac vein. The small coronary vein runs posteriorly through the right AV groove.

The Thebesian veins are small veins draining directly into the cardiac chambers, primarily into the right atrium and the right ventricle.

In the normal resting myocardium, transmembrane potential is determined primarily by potassium conductance, and is maintained by the Na⁺/K⁺ ATPase. The resting transmembrane potential is stable around −90 mV (the intracellular compartment being more negative relative to the outside of the cell), approaching the potassium equilibrium potential.

An action potential is triggered by either the cardiac pacemaker cells, or by the surrounding cardiomyocytes. This results in a transient increase in Na⁺ conductance, which in turn initiates an increase in Na⁺-influx through fast sodium channels. When the threshold potential is reached at around −70 mV, a large enough number of sodium channels have been opened to generate a self-sustaining sodium influx. Above −40 mV, long-opening (L-type) Ca²⁺-channels open with resultant Ca²⁺-influx down its concentration gradient. At around 0 mV, fast Na⁺-channels start to close. This is Phase 0 (early rapid depolarization), peaking at +20 mV (Na⁺-equilibrium potential).

The increase in Na⁺-conductance is inactivated. This, with the outward movement of K⁺ via transient K⁺-channels results in a brief period of initial repolarization. The transmembrane potential returns from slightly positive to approximately 0 mV. This is Phase 1.

Following the initial repolarization, a constant Ca²⁺-influx via slow (L-type, “long-opening”) Ca²⁺-channels, and an increase in K⁺ conductance via delayed rectifiers maintains the membrane potential just below 0 mV. The electrical countercurrents are balanced. This is Phase 2, the plateau. The phase between the initiation of the upstroke and the end of the plateau is the absolute refractory period, during which the cell is unable to be depolarized regardless of the strength of the stimulus, and corresponds with phase between the beginning of the QRS complex and the beginning of the T wave on the electrocardiogram (ECG).

The next phase of the cardiac action potential is the rapid repolarization. Ca²⁺-conductance via the L-channels is inactivated, but the K⁺-channels remain open. Potassium is rapidly shifted out of the cell, and the transmembrane potential rapidly approaches the K⁺-equilibrium. This is Phase 3. The phase between the initiation of the upstroke and the transition between Phase 2 and 3 is the relative refractory period, during which the cell may be able to be depolarized to allow for a non-propagated stimulus. This corresponds with the early upstroke of the T wave. During phase 3, the cell is able to be depolarized by supranormal stimuli (relative refractory period), resulting in an action potential. This corresponds with the dome of the T wave on the ECG. Membrane hyperpolarization at the end of this phase results in a hyperexcitable period, during which even weak stimuli can trigger an action potential. This brief phase corresponds with the downward slope of the T wave.

During Phase 4, Na⁺ and Ca²⁺ channels are closed. There is a constant outflow of potassium ions through inward rectifier channels. This is the resting phase in the contractile cells, or spontaneous diastolic depolarization in the cardiac pacemaker cells.

Pacemaker cells are found primarily in the dominant and subsidiary rhythm generators (SA node, AV node, His-Purkinje system) of the heart. However, impulses may originate from other sites; for example, cells at the coronary sinus, atrioventricular valves, or cells at the crista terminalis. Abnormally, impulses may originate from around the pulmonary veins. These cells are different from contractile cardiomyocytes in that they share the characteristic to generate spontaneous cardiac action potentials. They exhibit automaticity, have an unstable membrane potential, and have no rapid depolarization phase.

Automaticity means that pacemaker cells are capable of initiating their own action potential without external stimulus. These cells undergo a spontaneous diastolic depolarization and action potential is triggered when threshold potential is reached.

Pacemaker cells undergo spontaneous diastolic depolarization during phase 4 (as opposed to the resting phase during phase 4 in contractile cells), and have no rapid depolarization phase. These cells have fewer inward K rectifier channels than contractile myocytes do, and their transmembrane potential is never lower than −60 mV. Therefore, the fast Na⁺-channels that need −90 mV to get activated are permanently inactivated in these cells.

Multiple ion currents are responsible for the generation of spontaneous action potentials. The synergy of 3 different currents—(1) the decay of the K⁺-efflux; (2) an inward depolarizing “funny” mixed Na⁺-K⁺ inward current, activated by membrane hyperpolarization, and playing a major role in the spontaneous depolarization of the sinoatrial node; and (3) an inward Ca²⁺-current in the late phase of the spontaneous diastolic depolarization—determines the rate and shape of action potentials in cardiac pacemaker cells. Physiologically, the dominant pacemaker is the sinoatrial node. When its rate drops below the intrinsic rate of a latent, non-dominant pacemaker—for example, as a result of parasympathetic stimulation or SA nodal disease—the removal of the sinus overdrive leads to “escape-activation” of these non-dominant centers. Junctional rhythm may also occur when the AV junctional pacemaker rate exceeds and suppresses the sinoatrial rate.

Nitroglycerin (NTG) is an endothelium-independent smooth muscle relaxant that acts predominantly on venous capacitance vessels and large epicardial coronary arteries, maximizing blood flow to the subendocardial areas. Peripheral venodilatory effects are prominent even at low doses and are not dose-dependent, whereas dilation of peripheral conductance and resistance vessels occur at higher doses, and further increases in dose result in more pronounced vasodilation. Nitroglycerin reduces myocardial O₂ demand and increases oxygen supply by reducing preload and decreasing ventricular dimension and wall tension, dilating normal and atherosclerotic coronary arteries, and enhancing collateral circulation. The degree to which coronaries are able to dilate is dependent on their baseline vascular tone. Nitroglycerin produces a dose-dependent systemic and pulmonary arterial vasodilatory effect, and predictably decreases cardiac filling pressures. Its use is indicated for initial treatment of nearly all types of myocardial ischemia, as well as for managing hypertension and heart failure. Elimination half-life of nitroglycerin is approximately 1.5 min.

As discussed in the previous section, beta-blockers are class II antiarrhythmics with a multitude of favorable properties utilized in the treatment of cardiac ischemia. Their negative inotropic, negative chronotropic, and antihypertensive properties allow for reduction in O₂ consumption and an increase in blood supply during diastole. Beta blockers slow spontaneous diastolic depolarization and shorten the duration of cardiac action potentials. Ventricular fibrillation threshold is increased. Beta blockers reduce myocardial infarct size. In the absence of contraindications (cardiogenic shock, decompensated heart failure, severe sinus bradycardia, second- or third-degree atrioventricular block, or active bronchospasm), beta blockers should be administered early in the treatment of myocardial ischemia. While early administration has not been shown to improve short-term survival, beta blockers decrease reinfarction and the frequency of ventricular dysrhythmias, and their use has been associated with mortality benefit after myocardial infarction. Perioperative beta blockers should be continued in patients already receiving beta blockers, according to class 1 indications for perioperative beta blockade from the 2014 ACC/AHA recommendations; patients at high perioperative risk for adverse cardiac events should be started on beta blockers preoperatively, and continued up to 30 days postoperatively. In these patients, it is reasonable to titrate beta blockers to heart rate and blood pressure.

Calcium channel blockers (CCBs) comprise a diverse group of agents that selectively inhibit calcium influx into myocardial and vascular smooth muscle cells. Dihydropyridines (such as nifedipine, nicardipine, nimodipine, amlodipine, felodipine, isradipine) exert their effect on the peripheral arteriolar beds (nimodipine favors cerebral vessels), and produce marked peripheral vasodilation with little direct effect on heart rate, AV conduction, and inotropy. They may elicit reflex sympathetic activation via the baroreceptor reflex. Non-dihydropyridines (phenylalkylamines, for example, verapamil; and benzothiazepines, for example, diltiazem), on the other hand, block AV nodal calcium channels, and have significant negative inotropic, chronotropic, and dromotropic effects. Their main anti-ischemic effects are due to their ability to reduce myocardial O₂ consumption by depressing contractility, decreasing heart rate and systemic afterload, and increasing O₂ supply by coronary and collateral vasodilation. Calcium channel blockers are preferred in vasospastic (variant) angina, as beta-blockers may provoke or aggravate ischemia in some patients. All calcium channel blockers are effective in the treatment and prevention of coronary vasospasm. They may reduce reinfarctions and long-term events in hypertensive patients with acute myocardial infarction.

Phenylalkilamines bind to the intracellular portion of the L-type calcium channel when it is in the open state, and occlude the channel.