טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMolcho Almpertos
SubjectQuantification of Sarcomere Dynamics During Relaxation;
Identification of the Underlying Mechanisms
DepartmentDepartment of Biomedical Engineering
Supervisor Professor Amir Landesberg


Abstract

Diastolic dysfunction is the cause for heart failure in more than half of the heart failure patients. There are various etiologies for diastolic dysfunction and we focus on the isovolumic relaxation phase of the cardiac cycle. To treat diastolic dysfunction, it is essential to understand the normal control of relaxation. Current theories fail to explain how the relaxation rate is as fast as the contraction rate, when cross-bridges (XBs) detachment rate is significantly slower than XB attachment rate.

We hypothesize that XB density distribution is a function of the energy and time. The XBs are recruited with quanta of energy and drop-off after they have consumed their energy. The magnitude and shape of the XB cluster is determined by the rate of XB recruitment and the cluster transport rate. The latter is a linear function of the filament sliding velocity. This theory was denoted as the “Transported-XB Cluster” theory.

A novel system for sarcomere length (SL) measurement was developed, with spatial resolution of <2nm and temporal resolution of 0.15 msec. The twitch forces and sarcomere lengths of isolated trabeculae that contract at muscle-isometric regime but at various preloads were measured and simulated. Three type of models were developed and compared; Hill’s model, Force-State model and the Transported-XB Cluster model. In the Four-State model the number of recruited XBs is only a function of time. In the Transported-XB Cluster model the XB distribution is a function of energy and time.

The experimental studies have revealed that relaxation of cardiac fibers at muscle-isometric regime is characterized by: 1) Prolongation of relaxation at higher loading. 2) The force relaxation rate is close to force development rate. 3). Parallel increase in the contraction and relaxation rates with the preload. 4) The time points of maximum force relaxation are close to the time points of maximum lengthening velocity, at the different preloads.

The Four-State model explained the steep force-length relationship and the effects of the preload on the relaxation rates. However, the relaxation rates are markedly slower than the force development rate. Calcium dissociation rate is significantly slower than the calcium binding rate and XB weakening rate is about four time slower than the rate of XB transition from the weak to the strong state. Moreover, sarcomere lengthening further decreases the rate of XB weakening and prolongs the relaxation rate. The Transported-XB Cluster model overcomes these limitations. The rate of relaxation in the Transported-XB Cluster model is determined by the shape of the cluster distribution and the transport velocity. The shape of the cluster is determined by the recruitment rate and the transport velocity. Thus, a faster recruitment rate (contraction) is associated with a faster relaxation rate. The simulation successfully describes the above four characteristics of relaxation.

Conclusions: The novel “Transported XB Cluster theory”, provides explanations for the basic features of cardiac relaxation. The study provides better understanding of the sarcomeric control of relaxation, and how changes in calcium kinetics and XB cycling that determine cardiac contraction interact and affect the relaxation rate.