Cardiac myocytes and the cardiac action potential

Functional anatomy of the cardiac myocyte

Cardiac myocytes are the contractile cells of the heart and constitute the bulk of heart mass. There are differences between the myocytes of the ventricles, the atria, and the conduction system: ventricular myocytes are elongated cells and packed with myofibrils (the contractile apparatus) and mitochondria (for ATP production).

The myofibrils are repeating units (sarcomeres) made up of thin actin filaments anchored at the Z discs at either end of the sarcomere, and thick myosin filaments which interdigitate and interact with the thin filaments. Contraction results from sarcomere shortening produced by the ATP-dependent movement of the thin and thick filaments relative to one another. Atrial myocytes are long and slender, and differ in some of the features of ventricular myocytes. For example, transverse tubules (T-tubules) which are involved in entry of Ca²⁺ into the ventricular myocyte are essentially absent but there are more caveolae. Myocytes of the conduction system are small cells that possess only a rudimentary myofibrillar structure.

Myocytes are attached to their neighbours and to the extracellular matrix to allow transmission of force. At some regions of contact (the intercalated discs), specialized structures (the gap junctions) contain channels which form contiguous electrical connections between a myocyte and its neighbours, and allow passage of ions and small molecules.

Cardiac action potential

There is a potential difference (the membrane potential) across the plasma membrane such that the inside of the cell is negative compared to the outside by about 80 mV. This is caused largely by the efflux of K⁺ from the cell through K⁺ channels and down its concentration gradient until the electronegative force retaining K⁺ in the cell balances the tendency for efflux.

The sarcoplasmic reticulum (SR) is a lace-like membranous structure that surrounds the myofibrils and is a reservoir of the Ca²⁺ which participates in myofibrillar contraction. The plasma membrane of the ventricular myocyte contains deep, finger-like indentations (the T-tubules) that abut with the SR at junctional regions in register with the Z discs of the superficial sarcomeres.

When a myocyte is electrically excited, Na⁺ channels open and Na⁺ enters the cell down its own concentration gradient, thus producing an inward current and depolarizing the cell towards its equilibrium potential. This represents the initial phase (phase 0) of the action potential. As the myocyte depolarizes, the l-type Ca²⁺ channels in the T-tubules and plasma membrane open and Ca²⁺ enters the cell down its concentration gradient. The Na⁺ channels close rapidly, but the l-type Ca²⁺ channels remain open for longer and produce further depolarization. This is followed by phases 1 and 2 of the action potential where the tendency to depolarize is balanced by repolarizing outward current flow carried by a variety of K⁺ channels. The membrane potential in phase 2 is relatively stable and hence this phase is also known as the plateau phase.

The entry of Ca²⁺ in close apposition to the junctional SR causes the SR Ca²⁺-release channels to open, discharging about half of the SR Ca²⁺ reservoir into the cytoplasm in a process known as Ca²⁺-induced Ca²⁺-release. This increase in Ca²⁺ concentration (the Ca²⁺ transient) is sensed by a Ca²⁺-binding protein (troponin C) that is a component of the thin filament regulatory complex (the troponin–tropomyosin complex). This initiates myofibrillar contraction, which starts about halfway though phase 2.

As the l-type Ca²⁺ channels close, outward current flow though K⁺ channels predominates and the myocyte repolarizes towards the K⁺ equilibrium potential (phase 3). Ca²⁺ is removed from the cytoplasm and returned to the SR in an ATP-requiring process mediated by the sarcoplasmic/endoplasmic Ca²⁺ ATPase (SERCA2). Ca²⁺ is also expelled from the cell by the plasma membrane Na⁺,Ca²⁺ exchanger, which is electrogenic (three Na⁺ exchanged for one Ca²⁺) and tends to prolong the plateau phase. The behaviour of the Na⁺,Ca²⁺ exchanger is complex because—depending on the Na⁺ and Ca²⁺ concentrations and the membrane potential—it can reverse, thus mediating Ca²⁺ entry and repolarization. This occurs at depolarized potentials, and more so when intracellular Na⁺ is increased. In phase 4, repolarization is complete and the myocyte is electrically quiescent until the next depolarization.

Cardiac pacemaker and regulation of contractility

The ‘pacemaker’ or sinoatrial node contains myocytes that exhibit a different form of action potential from the ventricular myocytes because of differences in the expression of ion channels. The Na⁺ channel is essentially absent and depolarization is mediated by Ca²⁺ channels. The cell depolarizes spontaneously and gradually during phase 4 until the Ca²⁺ channels open and an action potential is produced. This partly results from the presence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which are absent from ventricular myocytes and which carry an inward-depolarizing Na⁺ current. The stimulus is then transmitted in a controlled manner via the conduction system to all regions of the heart.

Cardiac contractility is controlled largely by the sympathoadrenal system and the parasympathetic nervous system. β-Adrenergic stimulation increases the tendency of the l-type Ca²⁺ channel to open (positive inotropism). β-Stimulation also increases relaxation (positive lusitropism) by stimulation of SERCA2 and an increased rate of release of Ca²⁺ from the troponin complex. The positive chronotropic effects of β-stimulation result from increased HCN channel opening, causing an increased frequency of pacemaker depolarization. These effects are all opposed by the (cholinergic) muscarinic receptors of the parasympathetic nervous system.