The Frank–Starling law of the

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

(also known as Starling's law and the Frank–Starling mechanism) represents the relationship between stroke volume and

end diastolic volume In cardiovascular physiology, end-diastolic volume (EDV) is the volume of blood in the right or left ventricle at end of filling in diastole which is ammount of blood present in ventricle at the end of diastole systole. Because greater EDVs cause g ...

.Widmaier, E. P., Hershel, R., & Strang, K. T. (2016).''Vander's Human Physiology: The Mechanisms of Body Function''(14th ed.). New York, NY: McGraw-Hill Education. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction (the

), when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches cardiac muscle, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.

Physiology

The Frank-Starling mechanism occurs as the result of the length-tension relationship observed in striated muscle, including for example

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

s, arthropod muscle and cardiac (heart) muscle. As striated muscle is stretched, active tension is created by altering the overlap of thick and thin filaments. The greatest isometric active tension is developed when a muscle is at its optimal length. In most relaxed skeletal muscle fibers, passive elastic properties maintain the muscle fibers length near optimal, as determined usually by the fixed distance between the attachment points of tendons to the bones (or the exoskeleton of arthropods) at either end of the muscle. In contrast, the relaxed

sarcomere A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called mus ...

length of cardiac muscle cells, in a resting ventricle, is lower than the optimal length for contraction. There is no bone to fix sarcomere length in the heart (of any animal) so sarcomere length is very variable and depends directly upon blood filling and thereby expanding the heart chambers. In the human heart, maximal force is generated with an initial sarcomere length of 2.2 micrometers, a length which is rarely exceeded in a normal heart. Initial lengths larger or smaller than this optimal value will decrease the force the muscle can achieve. For longer sarcomere lengths, this is the result of there being less overlap of the thin and thick filaments; for shorter sarcomere lengths, the cause is the decreased sensitivity for calcium by the

myofilament Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the ''contractile proteins'' and titin is an elastic protein. The myofilaments act togethe ...

s. An increase in filling of the ventricle increases the load experienced by each cardiac muscle cells, stretching their sarcomeres toward their optimal length. The stretching sarcomeres augments cardiac

muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such a ...

by increasing the

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

sensitivity of the

myofibril A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofi ...

s,Klabunde, Richard E. "Cardiovascular Physiology Concepts". Lippincott Williams & Wilkins, 2011, p. 74. causing a greater number of

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin (M ...

cross-bridges to form within the muscle. Specifically, the sensitivity of

troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL Troponin, ...

for binding Ca²⁺ increases and there is an increased release of Ca²⁺ from the

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...

. In addition, stretch of cardiac myocytes increases the releasability of Ca²⁺ from the internal store, the

, as shown by an increase in Ca²⁺ spark rate upon axial stretch of single cardiac myocytes. Finally, there is thought to be a decrease in the spacing between thick and thin filaments, when a cardiac muscle is stretched, allowing an increased number of cross-bridges to form. The force that any single cardiac muscle cell generates is related to the sarcomere length at the time of muscle cell activation by calcium. The stretch on the individual cell, caused by ventricular filling, determines the sarcomere length of the fibres. Therefore the force (pressure) generated by the cardiac muscle fibres is related to the end-diastolic volume of the left and right ventricles as determined by complexities of the force-sarcomere length relationship. Due to the intrinsic property of

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

that is responsible for the Frank-Starling mechanism, the heart can automatically accommodate an increase in venous return, at any heart rate. The mechanism is of functional importance because it serves to adapt left ventricular output to right ventricular output. If this mechanism did not exist and the right and left cardiac outputs were not equivalent, blood would accumulate in the pulmonary circulation (were the right ventricle producing more output than the left) or the systemic circulation (were the left ventricle producing more output than the right).

Clinical examples

Premature ventricular contraction

Premature ventricular contraction causes early emptying of the

left ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...

(LV) into the

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...

. Since the next ventricular contraction occurs at its regular time, the filling time for the LV increases, causing an increased LV end-diastolic volume. Due to the Frank–Starling mechanism, the next ventricular contraction is more forceful, leading to the ejection of the larger than normal volume of blood, and bringing the LV end-systolic volume back to baseline.

Diastolic dysfunction – heart failure

Diastolic dysfunction Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the l ...

is associated with a reduced compliance, or increased stiffness, of the ventricle wall. This reduced compliance results in an inadequate filling of the ventricle and a decrease in the end-diastolic volume. The decreased end-diastolic volume then leads to a reduction in stroke volume because of the Frank-Starling mechanism.

History

The Frank–Starling law is named after the two physiologists, Otto Frank and

Ernest Henry Starling Ernest Henry Starling (17 April 1866 – 2 May 1927) was a British physiologist who contributed many fundamental ideas to this subject. These ideas were important parts of the British contribution to physiology, which at that time led the world. ...

. However, neither Frank nor Starling was the first to describe the relationship between the end-diastolic volume and the regulation of cardiac output. The first formulation of the law was theorized by the Italian physiologist

Dario Maestrini Dario Maestrini (23 March 1886 – 28 October 1975) was a 20th-century Italian physiologist and scientist. He was noted in the national scientific community for his research on heart, in particular for the first formulation of the Frank-Starling ...

, who on December 13, 1914, started the first of 19 experiments that led him to formulate the ''"legge del cuore" ''. Otto Frank's contributions are derived from his 1895 experiments on frog hearts. In order to relate the work of the heart to skeletal muscle mechanics, Frank observed changes in diastolic pressure with varying volumes of the frog ventricle. His data was analyzed on a pressure-volume diagram, which resulted in his description of peak isovolumic pressure and its effects on ventricular volume. Starling experimented on intact mammalian hearts, such as from dogs, to understand why variations in arterial pressure, heart rate, and temperature do not affect the relatively constant cardiac output. More than 30 years before the development of the

sliding filament model Sliding may refer to: * Sliding (dance), also floating or gliding, a group of footwork-oriented dance techniques * Slide (baseball), an attempt by a baseball runner to avoid getting tagged out *Sliding (motion) Sliding is a type of frictional mo ...

of muscle contraction and the understanding of the relationship between active tension and sarcomere length, Starling hypothesized in 1914, "the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fiber." Starling used a volume-pressure diagram to construct a length-tension diagram from his data. Starling's data and associated diagrams, provided evidence that the length of the muscle fibers, and resulting tension, altered the systolic pressure.

References