2 Molecular and Cellular Basis of Myocardial Contractility Arnold

The heart’s pumping action is made possible by interactions between myosin, the major protein of the thick filaments, and actin, which makes up the backbone of the thin filaments. These interactions, which are activated by calcium, are regulated by tropomyosin and troponins C, I, and T that are present along with actin in the thin filaments. The signaling process that initiates cardiac systole, called excitation–contraction coupling, begins when an action potential depolarizes the plasma membrane. Opening of L-type calcium channels during the action potential plateau allows a small amount of calcium to enter the cytosol from the extracellular fluid. This calcium triggers the opening of calcium-release channels in the sarcoplasmic reticulum that admit a much larger amount of this activator to the cytosol from stores within this intracellular membrane system. Most of the calcium that binds to troponin C in the adult human heart is derived from the sarcoplasmic reticulum (intracellular calcium cycle); only a small fraction enters the cells from the extracellular fluid during the action potential (extracellular calcium cycle). The heart relaxes when calcium is transported out of the cytosol. Most of this activator is transported back into the sarcoplasmic reticulum by an ATP-dependent calcium pump in the sarcoplasmic reticulum membrane. A smaller amount of calcium is transported from the cytosol into the extracellular space by a plasma membrane calcium pump and sodium/calcium exchanger. Two mechanisms are traditionally viewed as regulating the heart’s contractile performance. The first, length-dependent regulation (Starling’s Law of the Heart), is brought about by variations in end-diastolic volume. The second, changes in myocardial contractility, occurs when the ability of the myocardium to do work is modified by factors other than altered fiber length. Most of the rapidly occurring changes in myocardial contractility are brought about by variations in the amount of calcium delivered to the contractile proteins during excitation–contraction coupling. Contractility is also regulated by posttranslational changes in the contractile proteins, ion channels, ion pumps and exchangers, and other structures that participate in excitation–contraction coupling and relaxation. Myocardial contractility is also modified by altered synthesis of the contractile proteins and membrane structures that participate in contraction, excitation–contraction coupling, and relaxation. These slowly evolving changes in contractility, which are important in hypertrophied and failing hearts, are mediated by altered transcriptional signaling.