Sarah Miter and Ramesh Singh
This chapter is a revision and update of that included in the previous edition of the TSRA Review written by Hampton Gray (2nd edition).
Overview of the myocyte
The myocyte is composed of various protein filaments that comprise the contractile apparatus of the cardiac cell. Myofibrils, a collection of individual sarcomeres, enable contraction and relaxation of the myocyte. The sarcomere is the chief contractile unit of the cell. It is made up of two main proteins, myosin (thick filament) and actin (thin filament), as well as two regulatory proteins, tropomyosin and troponin. In order for the myocyte to contract and shorten it must receive a stimulus allowing myosin and actin to interact. This stimulus comes from the depolarization of the cardiac cell membrane (sarcolemma) at the cell surface. The sarcolemma is composed of a hydrophobic phospholipid membrane that prevents the passive diffusion of water-soluble molecules enabling the cell to compartmentalize and determine the ion composition of the intra and extracellular space. The difference in ion concentration created by the cell membrane is fundamental to the action potential and cell depolarization.
A unique characteristic of the myocyte is the presence of intercalated disks (gap junctions) in the cell membrane. Gap junctions provide continuity between myocytes enabling an electrical impulse to propagate from one cell throughout the entire myocardium. The sarcoplasmic reticulum (SR) and t-tubules are also unique features of the myocyte. The SR is an organelle responsible for Ca++ storage, uptake and release during contraction. T-tubules are extensions of the cell membrane into the cell interior, increasing surface area of the membrane and allowing for close proximity of the depolarized membrane, SR and intracellular contractile proteins. This spatial relationship is important for calcium induced calcium release and excitation-contraction coupling leading to synchronous contraction and relaxation of the myocardium.
Electrophysiology and conduction
The resting potential of the cardiac cell (i.e., ventricles, atria) is approximately -90 mV (negative inside with respect to outside). This resting voltage is created and maintained by the Na/K ATPase (3Na+ out / 2K+ in). The myocyte also has K+ channels that are open at rest allowing K+ to flow down its concentration gradient outside of the cell contributing to the negative resting membrane potential of the cell.
The electrical impulse propagates through normal myocardium as follows: Sinoatrial (SA) node (spontaneous depolarization) > atria > AV node (delay) > Bundle of His > Purkinje fibers > ventricles leading to synchronous contraction. There are three main types of electrical tissue in the myocardium: ventricle & atria, SA & AV node (pacemaker cells), and Purkinje fibers. Each type of cell differs in the composition of ion channels in the membrane, which influences the action potential and transmission of electrical stimulus.
There are 4 phases of the action potential. During phase 0, activation of voltage-gated fast sodium channels cause a rapid increase in the intracellular [Na+] and change in membrane potential. This leads to opening of L-type Ca++ channels releasing Ca++ into the cell (phase 1). Next, K+ channels open and K+ exits the cell balancing the influx of Ca++ leading to a plateau of the action potential (phase 2). As more K+ channels open (phase 3), L-Type Ca++ channels begin to close and the membrane potential returns to its resting state (phase 4). The number of fast sodium channels differs in each cell type: Purkinje fibers > atria/ventricles > SA/AV nodal cells. This helps explain the difference in the speed of depolarization and conduction in each of these cells.
Pacemaker cells (SA and AV node) have a slightly less negative resting membrane potential of around -60 / -70 mV compared with the rest of the myocardium. They have a special intrinsic property known as automaticity, enabling them to spontaneously depolarize. The ion channel responsible for this is known as the pacemaker current (slow Na+ current) causing gradual spontaneous depolarization and leading to a slow onset action potential. The SA node and AV node in particular have certain K+ channel’s that respond to molecules such as acetylcholine and adenosine leading to hyperpolarization (efflux of K+) of the cell, blocking transmission through the AV node and slowing conduction from the atria to the ventricle.
Excitation-contraction coupling
Myosin, actin, tropomyosin and troponin (TnC, TnT, TnI) are the main contractile elements of the myocyte. They work in conjunction with the cell membrane, T-Tubules and Ca++ in coupling excitation into muscle contraction. When the cell membrane is depolarized, Ca++ enters the cell by L-Type Ca++ channels. Roughly 20-25% of the Ca++ necessary for cellular contraction is contributed by the influx from these L-Type Ca++ channels. The increase in localized Ca++ stimulates specialized Ca++ channels in the SR to open. Ca++ binds to ryanodine receptors on the SR membrane leading to a release of Ca++ from the SR and a dramatic increase in cytosolic Ca++ concentration. The release of Ca++ from the SR accounts for the remainder of the 75-80% of Ca++ needed for contraction. Ca++ then binds to TnC causing a conformational change in the troponin complex and reorientation of tropomyosin on the actin filament. This exposes the myosin-binding site allowing actin and myosin interaction and contraction of the cell. Contraction ceases as Ca++ is pumped back into the SR. This causes a significant drop in cytosolic Ca++ leading to the dissociation of Ca++ and TnC producing relaxation. Signaling from ß-adrenergic and cholinergic pathways help regulate excitation-contraction coupling through G-protein coupling and phosphorylation of substrates influencing the level of cytosolic Ca++ concentration in the myocyte.
Pump function and mechanics of the myocardium
Frank-Starling mechanism
Cardiac output (CO) is a measure of ventricular function and is determined by heart rate (HR) and stroke volume (SV). SV is the difference in ventricular end-diastolic volume (EDV) and end-systolic volume (ESV). Factors that influence SV and thus CO include contractility, preload and afterload. Afterload is the resistance felt by the ventricle during systole. An increase in afterload when preload and contractility are constant will result in a decrease in SV and subsequent decrease in CO. Preload is the passive stretch of sarcomeres in the myocyte before systole, also known as the end-diastolic length of the sarcomere. It is the amount of volume in the ventricle immediately before systole, otherwise known as end-diastolic volume. Simply, preload is analogous to venous return. As venous return increases, the EDV increases leading to a larger stretch in the sarcomere. In a normal compliant ventricle, the increased stretch of the sarcomere leads to a greater force of contraction. This is referred to as the Frank-Starling mechanism. This mechanism states that the force or tension of the myocyte will increase as the sarcomere is stretched. Although not completely understood, the increase in force due to sarcomere stretch is thought to be a result of increased myosin-actin interaction and myofilament sensitivity to calcium. As the sarcomere is lengthened, the distance between the thin and thick filaments decreases, increasing the chance for myosin-actin interaction. This phenomenon between sarcomere length and force generation only holds true up to a certain sarcomere length. Beyond this optimal length, any further preload or stretch in the sarcomere will cause a decrease in force of the myocyte (i.e. heart failure).
Contractility
Contractility refers to the intrinsic ability of the sarcomere to contract and shorten at a determined preload and afterload. At a constant preload and afterload, an increase in contractility will cause an increase in SV by decreasing the ESV with an unchanged EDV. Overall, this occurs by an increase in intracellular Ca++ and recruitment of more myosin-actin cross-bridges. Preload, afterload, and contractility are interrelated and dynamic in nature. They are constantly changing and thus, measuring contractility in the human heart is difficult to do.
Contractility may be increased by adrenergic agonists, increase in HR, and pharmacologic agents, all of which achieve an increase in intracellular calcium and/or sensitivity to calcium by various mechanisms, direct or indirect. In the resting physiologic state of the heart, the average person only supplies enough Ca++ to engage 20-25% of actin-myosin cross-bridges, leaving nearly 75-80% of the actin-myosin cross-bridges available for potential increase in contractility. This phenomenon is known as cardiac reserve.
Inotropy refers to the change in contractile force without a change in initial sarcomere length. Strength of contraction can increase with increased calcium. Positive inotropes include digoxin which blocks Na/K ATPase increasing cytosolic sodium, which inhibits Na+/Ca exchange to remove Ca2+, thus increasing cytosolic Ca2+ levels. Norepinephrine binds beta receptors which leads to phosphorylation of cAMP dependent PKA which allows Ca2+ release from sarcoplasmic reticulum. Negative inotropes include acetylcholine and calcium channel blockers. These work to inhibit adenylyl cyclase, thus decreasing intracellular cAMP working to decrease contractility.
Exercise and cardiac dynamics
Experiments measuring CO, SV, EDV, ESV and HR during exercise in adults with and without the use of ß-blockers show that in participants who do not receive ß-blockers, the CO increases substantially without any change in EDV. The increase in venous return and SV during exercise is mainly managed by an increase in HR. The increase in HR leads to an increase in intracellular Ca++ and therefore an increase in contractility. The increase in HR is beneficial in terms of CO until the HR reaches a point where the rate is too fast and diastolic filling becomes impaired, resulting in a decrease in SV and subsequent decrease in CO. This usually occurs when the HR surpasses 150-180 bpm in the normal adult.
In participants who receive ß-blockers, the HR is unable to increase enough to support the needed rise in CO due to blunting of the sympathetic system. Therefore the increase in CO has to come from an increase in EDV. If CO increases and HR is unchanged, then SV must increase. This is accomplished by an increase in preload and EDV. Laplace’s law, Tension = Pressure x Radius / Wall Thickness, demonstrates how an increase in EDV and therefore ventricular radius and wall tension would be more energetically costly than an increase in HR to maintain CO. This dynamic process also demonstrates the influence of the sympathetic nervous system on contractility, HR and CO.
Cardiac cycle
The changes that occur over the cardiac cycle can be seen in Figure 46-1.
Figure 46-1. Cardiac cycle with superimposed pressure volume loop, aortic pressure, atrial pressure and EKG tracing. (Reprinted with permission from Opie LH. Mechanisms of cardiac contraction and relaxation. In: Braunwald E, Zipes DP, Libby P, Bonow RO, eds. Heart Disease. 7th ed. WB Saunders Company 2005, Chap.19:457-489, page 475.)
Cardiac physiology in the postoperative period
Oxygen delivery, consumption, and extraction
Oxygen delivery to the tissue is determined by knowing the cardiac output and O2 concentration of the blood. Oxygen consumption of the tissue is derived by multiplying CO by the difference in arterial and venous oxygen concentrations in the blood. This is called the Fick principle, which is often used to determine cardiac output (CO = O2 consumption / O2 difference between the arterial and venous systems).
Oxygen extraction refers to the amount of O2 taken up by the tissues in the capillaries. In a normal adult, the arterial O2 saturation is 100% with an average O2 extraction around 20-30% and subsequent mixed venous O2 saturations of approximately 60-80%. Deviations in the mixed venous [O2] can point to various pathologic states including low cardiac output.
Inadequate oxygen delivery and low cardiac output
Evaluating inadequate oxygen delivery and consumption in the postoperative period relies on integration of the physical exam and objective data (temperature, pedal pulses, skin color, CVP, pulmonary capillary wedge pressure [PCWP], HR, CO). This starts with postoperative evaluation of the Hb concentration, O2 concentration and CO. After anemia and hypoxemia have been ruled out or corrected, low CO must be evaluated and treated. Normal values for CO and cardiac index (CO indexed by BSA) range from 4-8 L/min and 2.0-4.9 L/min/m2, respectively. Common etiologies for low CO in the postoperative period include bradycardia, arrhythmias, hypovolemia, increased afterload, and decreased contractility.
- HR. Normal sinus rhythm (60-100 bpm) is optimal. Options to treat postoperative bradycardia include atrial, AV, or ventricular pacing, chronotropic agents (isoproterenol) and atropine. Note that ventricular pacing does lead to loss of atrial contraction which alters CO.
- Rhythm. Arrhythmias (junctional, atrial fibrillation) can decrease CO up to 20%, largely due to a loss of atrial contraction and thus the atrial kick. Atrial fibrillation is the most common arrhythmia after cardiac surgery with an incidence as high as 20-30%. Prevention includes preoperative ß-blockers and postoperative treatment includes rate and rhythm control (ß-blockers, amiodarone).
- Hypovolemia. The Swan-Ganz catheter is used frequently to estimate the LA pressure (LAP) and left ventricular end-diastolic pressure (LVEDP), which can help determine volume status and whether preload is optimized. The Swan-Ganz catheter measures the PCWP directly, a close estimate of LAP and LVEDP. Other measurements include the PA diastolic pressure or CVP, which can also estimate the LAP/LVEDP but is not as accurate. Normal PCWP is around 8-12 mmHg with values over 18-20 mmHg being suggestive of pulmonary edema. It is usually necessary to keep the PCWP slightly elevated (12-18 mmHg) in the early postoperative period to ensure adequate preload and CO. Low CO due to hypovolemia should be expected when there is low arterial pressure, decreased CVP, and normal to decreased PCWP correlating with decreased LAP/LVEDP. SVR can be elevated in this setting due to vasoconstriction and compensation efforts by the body to maintain tissue perfusion. Administering volume (replacement fluids or blood products depending on the etiology) to maximize preload and diastolic filling will result in an increase in SV and CO due to the Frank-Starling mechanism.
- Afterload. Determined by calculating SVR (SVR = MAP – CVP / CO x 80). SVR is expressed in dynes•sec/cm5 with normal values being 1000 (800-1200) dynes•sec/cm5. Approximation of MAP = diastolic pressure + 1/3 of the pulse pressure (i.e., difference between systolic and diastolic pressures). When afterload is increased and is impeding CO, the use of vasodilators such as nitroprusside, nicardipine, or nitroglycerin can be used to decrease SVR and optimize CO.
- Contractility. After adjusting for HR, hypovolemia, rhythm, afterload and preload, one must correct contractility if CO is still low. Inotropic agents to increase contractility include dobutamine, dopamine, milrinone, and epinephrine. Milrinone has additional utility in the setting of right heart failure and decreasing PVR, but has a long half-life and can cause hypotension. Pharmacologic profiles and side effects for each agent differ and play a role in which agent is used depending on the patient and clinical situation.
- Mechanical assistance. If all non-invasive measures fail to correct CO in the intraoperative or early postoperative period, then mechanical assist devices may be necessary for survival. These briefly include intra-aortic balloon pump and ventricular assist devices (LV, RV or biventricular).
Suggested Readings
- Mill, Michael R., et al. Cardiac Surgery in the Adult, edited by Lawrence H. Cohn and David H. Adams, 5th ed., McGraw Hill Education, 2018.
- Youssef, Samuel J. TSRA Primer of Cardiothoracic Surgery, edited by Samuel J. Youssef and Jason A. Williams, Thoracic Surgery Residents Association, 2013.
