The heart’s ability to pump blood results from the coordinated contraction of heart muscle cells, known as cardiomyocytes. This process is governed by calcium ions, which act as messengers linking the electrical signal that depolarizes the cell with the physical act of contraction. Each time the heart beats, every cardiomyocyte experiences a rapid, temporary increase in its internal calcium concentration. This event, called a calcium transient, is the trigger for heart muscle contraction.
The Mechanism of the Calcium Transient
A calcium transient begins with an electrical signal, or action potential, from the heart’s pacemaker cells. This wave spreads across the cardiomyocyte’s surface membrane (sarcolemma) and travels into invaginations known as T-tubules. This depolarization opens L-type calcium channels embedded in the T-tubule membrane. Their opening allows a small amount of calcium to flow from outside the cell into the cytoplasm.
This initial influx of calcium is a trigger, not the main source for contraction. It enters a narrow space where L-type calcium channels are positioned opposite channels on an internal storage organelle, the sarcoplasmic reticulum (SR). These SR channels, called ryanodine receptor 2 (RyR2), are sensitive to calcium. The binding of this trigger calcium causes the RyR2 channels to open in a process termed calcium-induced calcium release (CICR).
The opening of many RyR2 channels releases a large wave of calcium from the SR, which stores a high concentration of these ions. This release rapidly elevates the calcium concentration throughout the cytoplasm, forming the peak of the calcium transient. The synchronized opening of RyR2 clusters creates localized release events known as “calcium sparks.” The summation of thousands of these sparks generates the global calcium transient that initiates a uniform contraction.
For the heart muscle to relax, the high concentration of cytoplasmic calcium must be quickly reduced. This removal is accomplished by two protein pumps. The primary mechanism is the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) pump, which uses energy to transport calcium from the cytoplasm back into the SR. In humans, SERCA2a removes approximately 70% of the calcium from the cytoplasm.
A secondary removal pathway is the sodium-calcium exchanger (NCX), located on the cell’s surface membrane. The NCX extrudes one calcium ion out of the cell in exchange for three sodium ions. This exchanger accounts for most of the remaining calcium removal, returning the intracellular calcium concentration to a low resting level. The efficiency of these removal systems ensures the transient is temporary, allowing for the relaxation phase of the cardiac cycle.
Function in Cardiac Contraction
The surge of calcium into the cytoplasm during a transient initiates muscle contraction. This process involves calcium interacting with proteins attached to the cell’s contractile filaments. The mechanism is described by the sliding filament theory, where thick myosin filaments pull on thin actin filaments, causing the cell to shorten. Under resting conditions, this interaction is blocked by a regulatory protein complex.
When calcium is available, it binds to a subunit of this complex called troponin C. This binding changes the shape of the entire troponin-tropomyosin complex. This change pulls the tropomyosin protein away from the actin filament, uncovering previously blocked binding sites. The exposure of these sites allows myosin heads to attach to the actin filament, forming cross-bridges.
Once cross-bridges form, the myosin heads pivot, pulling the actin filaments toward the center of the sarcomere, the basic contractile unit. This “power stroke” generates force and shortens the cardiomyocyte. After the power stroke, ATP binds to the myosin head, causing it to detach from actin, reset, and prepare for another cycle. The collective action of millions of these sliding filaments results in the contraction of the heart muscle.
The characteristics of the calcium transient influence the heartbeat’s properties. The amplitude, or peak calcium concentration, determines the number of cross-bridges that form, which dictates the contraction force. A larger calcium transient leads to a stronger heartbeat. The rate of calcium removal from the cytoplasm determines relaxation speed. Faster calcium decay allows the heart muscle to relax more quickly, enabling the ventricles to fill with blood, especially at high heart rates.
Dysregulation in Heart Disease
Alterations in the machinery controlling calcium transients are a feature of many forms of heart disease, particularly heart failure. In a failing heart, the regulation of calcium handling is impaired, leading to problems with both contraction and relaxation. These changes involve the proteins responsible for calcium release and reuptake. For instance, the function and expression of the SERCA2a pump are reduced in heart failure.
This reduction in SERCA2a activity means calcium is removed from the cytoplasm more slowly after each beat. The slower decay of the calcium transient impairs the muscle’s ability to relax, a condition known as diastolic dysfunction, making it difficult for the heart’s chambers to fill. Because SERCA2a is less effective at refilling the sarcoplasmic reticulum, the calcium available for the next release is diminished. This leads to a weaker calcium transient and a weaker contraction (systolic dysfunction).
Ryanodine receptors can also become unstable in heart failure. These RyR2 channels may become “leaky,” allowing calcium to spontaneously escape from the SR during the heart’s resting phase. This calcium leak depletes the SR’s stores, contributing to weaker contractions. The leak also raises the baseline calcium concentration during diastole, which can activate processes that contribute to adverse remodeling and disease progression.
Spontaneous calcium leaks from dysfunctional RyR2 channels are also a cause of cardiac arrhythmias. When calcium leaks from the SR during the resting phase, it can activate the sodium-calcium exchanger (NCX), generating a small inward electrical current. If this current is large enough, it can trigger an unplanned action potential, leading to an ill-timed heartbeat. This phenomenon can initiate sustained irregular heart rhythms, showing how a breakdown in calcium transient control can have serious consequences.