Many of the same factors that regulate HR also impact cardiac function by altering SV. While several variables are involved, SV is ultimately dependent upon the difference between EDV and ESV. The three primary factors to consider are preload, or the stretch on the ventricles prior to contraction; the contractility, or the force or strength of the contraction itself; and afterload, the force the ventricles must generate to pump blood against the resistance in the vessels.

Venous return

Simply put venous return is the rate at which blood return back to the heart. There are several factors that can affect venous return such as total blood volume, the respiratory and skeletal muscle pumps, venous tone, and torsion of the heart. People that have larger blood volume will likely have a greater venous return. The simple act of breathing will affect venous return, with inspiration increasing venous return and expiration decreasing venous return (this will be discussed in more detail later). Skeletal muscle contractions help propel blood to the heart, which increases venous return. While it might seem counterintuitive, when veins have a smaller radius, or are constricted, venous return increases. This is because venoconstriction limits venous pooling, thus making it easier for blood to return to the heart. Finally, as the heart contracts it actually twists and creates a torsional force. This torsion creates a suction effect that allows the right side of the heart to pull blood into from the systemic venous circulation.

Preload

Preload is the degree to which cardiac muscle cells are stretched from filling of the ventricles prior to contraction. Therefore, preload is another way of expressing EDV. With increasing ventricular filling, both EDV or preload increase, and the cardiac muscle itself is stretched to a greater degree. At rest, there is little stretch of the ventricular muscle, and the sarcomeres remain short. With increased ventricular filling, the ventricular muscle is increasingly stretched and the sarcomere length increases. As the sarcomeres reach their optimal lengths, they will contract more powerfully, because more myosin heads bind to actin and form cross bridges, which increasethe strength of contraction and SV. If this process were to continue and the sarcomeres stretched beyond their optimal lengths, the force of contraction would decrease. However, due to the physical constraints of the location of the heart, this excessive stretch is not a concern.

One of the primary factors to consider is filling time, or the duration of ventricular diastole during which filling occurs. The more rapidly the heart contracts, the shorter the filling time becomes, and the lower the EDV and preload are. This effect can be partially overcome by increasing the second variable, contractility, which raises the SV, but over time, the heart is unable to compensate for decreased filling time, and preload also decreases.

The relationship between ventricular stretch and contraction has been stated in the well-known Frank-Starling mechanism. This principle states that, within physiological limits, the force of heart contraction is directly proportional to the initial length of the muscle fiber. This means that the greater the stretch of the ventricular muscle, the more powerful the contraction is, which in turn increases SV. Therefore, by increasing preload, you increase contractility.

Any sympathetic stimulation to the venous system will increase venous return to the heart, which contributes to ventricular filling, and EDV and preload. While much of the ventricular filling occurs while both atria and ventricles are in diastole, the contraction of the atria, the atrial kick, plays a crucial role by providing the last 20–30 percent of ventricular filling.

Contractility

It is virtually impossible to consider preload or ESV without including the concept of contractility. Indeed, the two parameters are intimately linked. Contractility refers to the force of the contraction of the heart muscle, which controls SV, and is the primary parameter for impacting ESV. The more forceful the contraction is, the greater the SV and smaller the ESV are. Less forceful contractions result in smaller SVs and larger ESVs. Factors that increase contractility are described as positive inotropic factors, and those that decrease contractility are described as negative inotropic factors (ino- = “fiber;” -tropic = “turning toward”).

Not surprisingly, sympathetic stimulation is a positive inotrope. Sympathetic stimulation triggers the release of NE at the neuromuscular junction from the cardiac nerves and stimulates the adrenal cortex to secrete epinephrine and NE. In addition to their stimulatory effects on HR, as positive chronotropic factors, they also bind to both alpha and beta receptors on the cardiac muscle cell membrane to increase metabolic rate and the force of contraction. This combination of actions has the net effect of increasing SV and leaving a smaller residual ESV in the ventricles.

NE has multiple effects on cardiac muscle cells. First, it increases calcium permeability which allows extracellular calcium to enter the cell. Second, NE activates the Gαq pathway which ultimately results in calcium being released from the sarcoplasmic reticulum (SR). Both of these lead to an increased amount of intracellular calcium, allowing for more cross-bridge formation, and stronger contractions. Additionally, NE activates a protein called phospholamban, which regulates the activity of the calcium pump on the SR. Activation of phospholamban increases the activity of this pump, which brings increases calcium concentration in the SR. This increased concentration creates a larger calcium gradient between the SR and sarcoplasm, which allows more calcium to be released during the next contraction, resulting in the formation of more cross-bridges.

Several synthetic drugs, including dopamine and isoproterenol, have been developed that mimic the effects of epinephrine and NE by stimulating the influx of calcium ions from the extracellular fluid. Higher concentrations of intracellular calcium ions increase the strength of contraction. Excess calcium (hypercalcemia) also acts as a positive inotropic agent. The drug digitalis is a negative chronotropic factor because it lowers HR and it increases the strength of the contraction, acting as a positive inotropic agent by blocking the sequestering of calcium ions into the sarcoplasmic reticulum. This leads to higher intracellular calcium levels and greater strength of contraction.

Negative inotropic agents include hypoxia, acidosis, hyperkalemia, and a variety of synthetic drugs. These include numerous beta blockers and calcium channel blockers. Early beta blocker drugs include propranolol and pronethalol and are credited with revolutionizing treatment of cardiac patients experiencing angina pectoris. There is also a large class of dihydropyridine, and calcium channel blockers that may be administered decreasing the strength of contraction and SV.

Afterload

Afterload refers to the tension or force that the ventricles must develop to pump blood effectively against the resistance in the vascular system. Any condition that increases resistance such as vasoconstriction or the disease atherosclerosis requires a greater afterload to force open the semilunar valves and pump the blood. Damage to the valves, such as stenosis, which makes them harder to open will also increase afterload. Any decrease in resistance as with vasodilation, decreases the afterload. With regards to the left ventricle, afterload is synonymous with aortic pressure, since the left ventricle has to generate enough pressure to open the aortic semilunar valve. Increased afterload will lead to a decreased ejection time, which will reduce stroke volume.

Adapted from Anatomy & Physiology by Lindsay M. Biga et al, shared under a Creative Commons Attribution-ShareAlike 4.0 International License, chapter 19