Tracing the causes of heart failure

Dr. Michael Gotthardt and his co-workers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, together with Professor Hendrikus Granzier from Washington State University in Pullman, USA, have been able to demonstrate that an elastic region of titin, N2B for short, is responsible for this filling process during the relaxing phase of the cardiac cycle, the diastole. The findings of the researchers in Berlin and Pullman have now been published in the Proceedings of the National Academy of Sciences (PNAS).

N2B is only present in cardiac titin and helps adjust the diastole to the heart rate. For example during physical exercise with an increased heart rate, there is less time for the heart muscle to relax and provide enough blood for the next heartbeat, unless the elastic properties of the heart change. Modulating titin based elasticity thus allows the adequate filling of the heart.

To be able to investigate the function of N2B in the heart muscle, the researchers created a knockout model that lacks only this region of the titin-gene. This results in expression of a shorter titin protein with a reduced heart size, and limited filling capacity. A healthy heart compensates such an insufficiency, by beating either faster or stronger. However, without N2B, the elastic properties and consequently relaxation of the heart muscle are disturbed. It is this malfunction that eventually leads to the development of heart disease.

Comprised of almost 30,000 building blocks (amino acids), titin is the biggest protein in humans. Found in the heart and skeletal muscle, it is an important part of the smallest mechanical unit of the muscle, the sarcomere. Only recently, Dr. Gotthardt and his collaborators where able to demonstrate that titin is involved in the contraction of muscles and the related signalling processes.