Cardiomyocytes constitute approximately 75% of total ventricular volume and 1-4 weight cheap 5 mg lipitor with amex, but only one third of the total number of cells there buy discount lipitor on-line. Approximately half of each ventricular myocyte is occupied by myofibrils of the myofibers and 30% by mitochondria (Fig purchase generic lipitor on-line. A myofiber is a group of cardiomyocytes held together by surrounding collagen connective tissue, the latter being a major component of the extracellular matrix. The action potential is conducted along the surface sarcolemma and sarcolemma that 2+ 2+ extends into the T tubules. The myofibrils are bundles of contractile proteins that are organized into a regular sarcomeric array, bounded longitudinally by Z-lines that are immediately adjacent to T tubules that run in parallel. In diastole (bottom) the thin filaments (containing mainly actin) create a cage around the thick filaments (containing mainly myosin) that have cross-bridges (myosin heads) that extend toward the thin filament. Myosin molecule tails all face the center of the sarcomere, creating a zone around the M-line devoid of myosin heads. During systole, the myosin cross-bridges pull the thin filament “cage” toward the M-line, thus shortening the sarcomere length (additional details are in subsequent figures). Ventricular myocytes are roughly brick shaped, typically 150 × 20 × 12 µm (Table 22. Atrial myocytes are smaller and more spindle shaped (<10 µm in diameter and <100 µm in length). When examined under a light microscope, atrial and ventricular myocytes have cross striations and are often branched. Each myocyte is bounded by a complex cell membrane, the sarcolemma (sarco, “flesh”; lemma, “thin husk”), and is filled with rodlike bundles of myofibrils containing the contractile elements. The sarcolemma invaginates to form an extensive transverse tubular network (T tubules) that extends the extracellular space into the interior of the cell (see Figs. Rows of mitochondria are located between the myofibrils and also immediately beneath the sarcolemma. Note the presence of numerous mitochondria (mit) sandwiched between the myofibrils and the presence of T tubules (T), which penetrate into the muscle at the level of the Z-lines. This two-dimensional picture should not disguise the fact that the Z-line is really a “Z-disc,” as is the M-line (M), also shown in Fig. A, Band of actin-myosin overlap; g, glycogen granules; H, central clear zone containing only myosin filament bodies and the M-line; I, band of actin filaments, titin, and Z-line (rat papillary muscle, 32,000×). The cytoplasm is crowded with myofilaments, but this is the fluid within which the concentration of 2+ Ca rises and falls to cause cardiac contraction and relaxation. Scaffolding proteins such as caveolin or the RyR itself bring interacting molecules closely together at these locations. These complexes can also release components that translocate and signal elsewhere in the cell, such as the nucleus, where they can signal for myocyte growth. Mitochondrial Morphology and Function The typical ventricular myocyte has approximately 8000 mitochondria, each of which is ovate with a long axis measuring 1 to 2 µm and short axis of 300 to 500 nm. These components provide reducing equivalent protons that are pumped out of the matrix by the cytochromes, and it is this proton pumping that creates the very negative voltage with + respect to cytosol (Ψ = −180 mV). The multiple control mechanisms involved in this process are not fully understood, but one is relevant to excitation-contraction coupling. Increased cardiac work in 2+ a physiologic setting is usually driven by higher-amplitude and/or more frequent Ca transients. The intramitochondrial matrix is very negative with respect 2+ 2+ to the cytosol (−180 mV). However, this would load the + + mitochondria with Na , so Na must also be extruded from the mitochondria. In the short term, 2+ 2+ mitochondria can take up large amounts of Ca to protect the cell from short-term Ca overload, but 2+ 2+ chronic high [Ca ] has dire consequences. Second, 2+ 2+ elevated [Ca ] and [Cai ] can facilitate opening of the mitochondrial permeability transition pore,m which immediately wipes out Ψ and allows the matrix contents to be released to the cytosol. This can bem the death knell for individual mitochondria, as well as the cells that rely on their function. Mitochondria can also induce mitochondrial autophagy, or mitophagy, which selectively and adaptively clears damaged mitochondria. Increased oxidative stress and apoptotic proteases can inactivate 7 mitophagy and thereby cause cell death. Contractile Proteins The two chief contractile proteins are the motor protein myosin on the thick filament and actin on the thin 2+ filament (see Figs. Ca initiates the contraction cycle by binding to the thin filament regulatory protein troponin C to relieve the inhibition otherwise exerted by this troponin complex (Fig. The thin actin filaments are connected to the Z-lines (Z for German Zuckung, “contraction”) at either end of the sarcomere, which is the functional contractile unit that is repeated through the filaments. The sarcomere is limited on either side by a Z-line, which with the thin filaments creates a “cage” around the thick myosin filament that extends from the center of the sarcomere outward toward, but not reaching, the Z-line. During contraction, the myosin heads grab onto actin and pull the actin filaments toward the center of the sarcomere. The thin and thick filaments can thus slide over each other to shorten the sarcomere and cell length, without the individual actin or myosin molecules actually changing length (Fig. The interaction of the myosin heads with actin filaments that is switched on when Ca arrives is called cross-bridge cycling. As the actin filaments move inward toward the center of the sarcomere, they draw the Z-lines closer together so that the sarcomere length shortens. The thin actin filament (A) interacts with the myosin 2+ head (B) when Ca ions arrive at troponin C (TnC) (C). This causes troponin-tropomyosin shifts to expose the actin site to which a myosin head can attach. When TnC is not activated by Ca , troponin I (TnI) stabilizes troponin T (TnT) and tropomyosin (Tm) along the actin filament to block myosin cross-bridge binding (D). B, The molecular 8 structure of the myosin head, based on Rayment and colleagues, is composed of heavy and light chains. The “neck” domain of 20 kDa, also called the “lever,” is an elongated alpha helix that extends and bends and has two light chains surrounding it as a collar. The other regulatory light chain may respond to phosphorylation to influence the extent of the actin-myosin interaction. C, TnC with sites in the regulatory domain for activation by calcium and for interaction with TnI. D, Binding of calcium to TnC causes TnI to shift binding from TnT to TnC, allowing the TnT-Tm complex to shift deeper into the actin groove and expose the myosin binding domain on actin. Titin extends from the Z-line into the thick filament, approaching the M-line, and connects the thick filament to the Z-line (see Fig. Titin has two distinct segments: an inextensible anchoring segment and an extensible elastic segment that stretches as sarcomere length increases.
With more serious bleeding discount 20mg lipitor amex, the approach is similar to that with warfarin purchase on line lipitor, except that vitamin K administration is of no benefit; the anticoagulant and any antiplatelet drugs should be withheld order genuine lipitor on line, the patient should be resuscitated with fluids and blood products as necessary, and the bleeding site should be identified and managed. Coagulation testing will determine the extent of anticoagulation, and renal function should be assessed so 66 that the half-life of the drug can be calculated. Timing of the last dose of anticoagulant is important, and oral activated charcoal may help prevent absorption of drug administered in the past 4 hours particularly in cases of overdose. If bleeding continues or is life-threatening or if it occurs in a critical organ (e. Idarucizumab is licensed for dabigatran reversal in patients with serious bleeding or in those requiring 67 urgent surgery or intervention. A humanized antibody fragment, idarucizumab binds dabigatran with 350- fold higher affinity than that of dabigatran for thrombin to form an essentially irreversible complex that is cleared by the kidneys. Until these agents are available, 4-factor 66 prothrombin complex concentrate (25 to 50 units/kg) should be given to reverse them. Its active-site serine residue has been replaced with an alanine residue to eliminate catalytic activity, and its membrane-binding domain has been removed to circumvent its incorporation into the 69 prothrombinase complex. Andexanet serves as a decoy and binds rivaroxaban, apixaban, and edoxaban and sequesters them until they can be cleared. It is administered as an intravenous bolus of 400 mg, followed by a 2-hour infusion of 480 mg, to reverse apixaban or rivaroxaban if the last dose was taken more than 7 hours previously. It is administered as an intravenous bolus of 800 mg, followed by a 2-hour infusion of 960 mg, to reverse edoxaban or rivaroxaban if the last 70,71 dose was taken within the past 7 hours. When given in this manner to patients taking these drugs who presented with serious bleeding, andexanet reversed the anti–factor Xa activity while it was administered 70,71 and appeared to restore hemostasis. When given as an intravenous bolus to volunteers who took 60 mg of edoxaban, 72 ciraparantag reduced the whole-blood clotting time in a concentration-dependent manner. Although the whole-blood clotting time may be useful for this purpose, the test is not widely available. As small molecules, the direct oral anticoagulants can all pass through the placenta. Consequently, these agents are contraindicated in pregnancy, and when used by women of childbearing potential, appropriate contraception is important. Small amounts of rivaroxaban pass into breast milk, and it is unknown whether the other direct oral anticoagulants also do so. Novel Anticoagulants in Development Although the direct oral anticoagulants represent a major advance in oral anticoagulation therapy, the search for more effective and safer anticoagulants continues. Fibrinolytic Drugs (see also Chapter 59) Used to degrade thrombi, fibrinolytic drugs are administered systemically or are delivered via catheters directly into the substance of the thrombus. Each of these agents acts by converting the proenzyme, plasminogen, to plasmin, the active 10 enzyme. There are two pools of plasminogen—circulating plasminogen and fibrin-bound plasminogen (Fig. Plasminogen activators that preferentially activate fibrin-bound plasminogen are fibrin specific. In contrast, nonspecific plasminogen activators do not discriminate between fibrin-bound and 74 circulating plasminogen. Activation of circulating plasminogen results in the generation of unopposed plasmin, which can trigger the systemic lytic state. Alteplase and its derivatives are fibrin-specific plasminogen activators, whereas streptokinase, anistreplase, and urokinase are nonspecific agents. The fibrin specificity of plasminogen activators reflects their capacity to distinguish between fibrin-bound and circulating plasminogen, which depends on their affinity for fibrin. Plasminogen activators with high affinity for fibrin preferentially activate fibrin-bound plasminogen. Fibrin-bound plasmin, which is protected from inactivation by alpha -antiplasmin, degrades2 fibrin to yield soluble fibrin degradation products. In contrast, plasminogen activators with little or no affinity for fibrin do not distinguish between fibrin-bound and circulating plasminogen. Activation of circulating plasminogen results in systemic plasminemia and subsequent degradation of fibrinogen and other clotting factors. Streptokinase Unlike other plasminogen activators, streptokinase is not an enzyme and does not directly convert plasminogen to plasmin. Instead, it forms a 1 : 1 stoichiometric complex with plasminogen, thereby inducing a conformational change in plasminogen that exposes its active site (Fig. This 75 conformationally altered plasminogen then converts additional plasminogen molecules to plasmin. Streptokinase has no affinity for fibrin, and the streptokinase-plasminogen complex activates both free and fibrin-bound plasminogen. Activation of circulating plasminogen generates sufficient amounts of plasmin to overwhelm alpha -antiplasmin. Unopposed plasmin not only degrades fibrin in the occlusive thrombus2 74 but also induces a systemic lytic state. Streptokinase binds to plasminogen and induces a conformational change in plasminogen that exposes its active site. The streptokinase/plasmin(ogen) complex then serves as the activator of additional plasminogen molecules. When given systemically to patients with acute myocardial infarction, streptokinase reduces mortality rates. For this indication the drug is usually administered as an intravenous infusion of 1. Patients who receive streptokinase can form antibodies against it, as can patients with previous streptococcal infection. Allergic reactions occur in approximately 5% of patients treated with streptokinase. They may be manifested as a rash, fever, chills, and rigors; rarely, anaphylactic reactions can occur. Transient hypotension is common with streptokinase and probably reflects plasmin-mediated release of bradykinin. The hypotension usually responds to leg elevation and administration of intravenous fluids and low doses of vasopressors, such as dopamine or norepinephrine. Anistreplase To generate anistreplase, streptokinase is mixed with equimolar amounts of Lys-plasminogen, a plasmin- cleaved form of plasminogen with a Lys residue at its N-terminal. The active site of Lys-plasminogen exposed on combination with streptokinase is then blocked with an anisoyl group. After intravenous infusion, the anisoyl group is slowly removed by natural deacylation, which yields a half-life of 76 approximately 100 minutes for the complex. Although it is more convenient to administer, anistreplase offers few mechanistic advantages over streptokinase. Like streptokinase, anistreplase does not distinguish between fibrin-bound and circulating plasminogen. Similarly, allergic reactions and hypotension are just as frequent with anistreplase as they are with streptokinase.
L. Zakosh. Dickinson State University.