Frank–Starling law

The Frank-Starling mechanism occurs as the result of the length-tension relationship observed in striated muscle, including for example skeletal muscles, arthropod muscle and cardiac (heart) muscle. An increase in filling of the ventricle increases the load experienced by each cardiac muscle cells, stretching their sarcomeres toward their optimal length. causing a greater number of actin-myosin cross-bridges to form within the muscle. Specifically, the sensitivity of troponin for binding Ca2+ increases and there is an increased release of Ca2+ from the sarcoplasmic reticulum. In addition, stretch of cardiac myocytes increases the releasability of Ca2+ from the internal store, the sarcoplasmic reticulum, as shown by an increase in Ca2+ spark rate upon axial stretch of single cardiac myocytes. Cardiomyocytes that are stretched past their resting length are capable of generating the same force with lower concentrations of Ca2+ when compared to cardiomyocytes at rest. Another way that the longitudinal stretching of sarcomeres augments the force generated by cardiac muscle contraction is through decreased interfilament distances. Decreased distance between thin and thick filaments allows for more cross-bridges to be formed, and the myosin heads of the thick filament collectively exert a greater force on the thin filament. When the sarcomeres in cardiac muscle are stretched, the distance between the thin filament (actin) and the thick filament (myosin) is decreased. This has been confirmed via X-ray diffraction on the cross-sectional lattice structure of striated muscle within cardiac tissue. Other biochemical pathways, including the phosphorylation of troponin I and troponin C, have been shown to decrease the interfilament distance between the thin and thick filaments as confirmed by X-ray diffraction. As the end-diastolic volume increases, there is a decrease in interfilament distance, resulting in a greater number of cross-bridges, and a subsequent greater force (pressure) generated by the ventricle. 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 fibers. 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 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. ==Clinical examples==

Premature ventricular contraction Premature ventricular contraction causes early emptying of the left ventricle (LV) into the aorta. 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 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. Otto Frank published his results on experiments on frog hearts in 1895. 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. The first description of the relation between filling pressure and contraction pressure of the heart in the scientific literature however appears to be from 1869. Joseph Coats and Henry Pickering Bowditch found this relation on frog hearts at the Physiological Institute of Carl Ludwig in Leipzig. Further contributions were published by the Italian physiologist Dario Maestrini, who on December 13, 1914, started the first of 19 experiments that led him to formulate the "legge del cuore" . While many renowned German and British scientisits were known for their contributions in describing the cardiac contractile response to volume, Starling's work was recognized for the synthesis of these ideas, and the establishment of a law. The cellular mechanism underlying the Frank-Starling law remained incompletely understood until 1963, when American cardiologist Edmund Sonnenblick used quantitative electron microscopy to demonstrate that the law reflects the length-dependent overlap of thick and thin filaments within the cardiac sarcomere—directly linking the macroscopic observation that Starling had described to the sliding filament structure of cardiac muscle. ==See also==