The Molecular Basis of the Frank-Starling Law of the Heart: A Possible Role for PIEZO1?

The Frank-Starling Law was proposed over 100 years ago, but it remains to be fully explained at the molecular level. The Law states that when the volume of blood returning to the heart suddenly increases, it stretches cardiomyocytes that instantly respond by increasing ejection pressure, thereby ensuring that the heart deals efficiently with beat-to-beat changes in the circulation. Here we review: The history of the Otto Frank and Ernest Starling role in formulating the Law; The key contractile proteins involved (Myosin ATPase, Titin, cMyBP-C); The role of Super Relaxation; and the contribution of computational analyses. We then propose two pathways by which PIEZO1 (a mechanosensitive Ca2+ permeable channel that recently was the subject of the 2021 Nobel Prize) may play a role in the Frank-Starling Law. In Mechanism 1, PIEZO1 is a non-specific Ca2+ channel expressed in the T tubules adjacent to TRPM4 which together activate the sarcoplasmic reticulum to release more Ca2+ causing a cascade of events resulting in contraction. In Mechanism 2, stretch of the heart chamber wall is sensed by PIEZO1 in the cardiomyocyte intercalated discs, which is directly connected to titin molecules that activate myosin crossbridges at their S1-S2 via myosin binding protein C (cMyBP-C).