Acute Myocardial Response to Stretch: What We (don't) Know

Abstract

Myocardial stretch, as result of acute hemodynamic overload, is one of the most frequent challenges to the heart and the ability of the heart to intrinsically adapt to it is essential to prevent circulatory congestion. In this review, we highlight the historical background, the currently known mechanisms, as well as the gaps in the understanding of this physiological response. The systolic adaptation to stretch is well-known for over 100 years, being dependent on an immediate increase in contractility-known as the Frank-Starling mechanism-and a further progressive increase-the slow force response. On the other hand, its diastolic counterpart remains largely unstudied. Mechanosensors are structures capable of perceiving mechanical signals and activating pathways that allow their transduction into biochemical responses. Although the connection between these structures and stretch activated pathways remains elusive, we emphasize those most likely responsible for the initiation of the acute response. Calcium-dependent pathways, including angiotensin- and endothelin-related pathways; and cGMP-dependent pathways, comprising the effects of nitric oxide and cardiac natriuretic hormones, embody downstream signaling. The ischemic setting, a paradigmatic situation of acute hemodynamic overload, is also touched upon. Despite the relevant knowledge accumulated, there is much that we still do not know. The quest for further understanding the myocardial response to acute stretch may provide new insights, not only in its physiological importance, but also in the prevention and treatment of cardiovascular diseases.

Keywords: cardiac function; frank starling mechanism; myocardial stretch; neurohumoral adaptation; slow force response.

Figure 1

Acute cardiac overload. Schematic example of the normal intrinsic adaptation of the left ventricle to acute increase in preload. In this example, the additional modulation by autonomic nervous system is ignored, in order to highlight the intrinsic myocardial response to acute stretch. Myocardial stiffness changes in response to acute myocardial stretch have not yet been adequately evaluated. EDP, End Diastolic Pressure; VR, Venous Return; CO, Cardiac Output; AT, Active Tension; St, Myocardial Stiffness.

Figure 2

Myocardial mechanosensing. Acute myocardial stretch induces an increased myocardial tension that can be sensed by several potential mechanosensors.The connections between mechanosensors and activated signaling pathways are not yet fully understood. CN, calcineurin; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; PDE, phosphodiesterase; PKC, protein kinase C; SAC, stretch-activated channel.

Figure 3

Integrated signaling pathways. Diagram representing the molecular interplay between the various players in the acute response to stretch. The same mediators may exert different effects depending on the subcellular compartment. Question marks indicate yet unknown mechanisms. The proposed model is based on data obtained from different species and experimental models. Some signaling pathways may differ between species. ANG-II, angiotensin-II; CNH, cardiac natriuretic hormone; EGFR, epidermal growth factor receptor; ET, endothelin; ERK, extracellular signal-regulated kinase; HBEGF, heparin-binding epidermal growth factor; MMP, matrix metalloproteinase; NCX, sodium-calcium exchanger; NHE, sodium-proton exchanger; nNOS, neuronal NO synthase; PDE, phosphodiesterase; pGC-A, particulate guanylate cyclase A; PK, protein kinase; PLB, phospholamban; PLC, phospholypase C; ROS, reactive oxygen species; Ryr2, ryanodine receptor 2; sGC, soluble guanylate cyclase.