Ural Federal University: Scientists Discovered New Patterns of the Heart

The mechanical properties of the papillary muscles located in the ventricles of the heart and other regions of the ventricular myocardium differ at the cellular level, scientists at Ural Federal University, the Institute of Immunology and Physiology (UB RAS) and Freiburg University (Germany) found out. The work may contribute to the development of methods for targeted drug delivery to the heart. An article on the content and results of the pioneering research conducted by the colleagues was published in the scientific Journal of Molecular and Cellular Cardiology.

Since 1980s scientists know that different regions (sections) of the myocardium – the muscle tissue of the heart, which, by contracting, ensures blood flow in the body – are structurally and functionally heterogeneous (before that the heart was considered to be a homogeneous organ consisting of homogeneous cells). Later, the structural and functional heterogeneity of myocardial cells – cardiomyocytes – was revealed. Using methods of mathematical modeling and computer analysis, it was shown that their heterogeneity was intended to optimize the heart’s work.

The studies carried out by the authors of the article during the last five years are aimed at deep penetration into the nature of heterogeneity of single cardiomyocytes of the left ventricular heart. This phenomenon is also known to the world science, but has not been sufficiently studied.

“The novelty of our research, firstly, is that the studies were conducted not on small rodents – mice and rats, guinea pigs, but on large mammals – rabbits, in which the structure, electrophysiology and mechanics of the heart are closer to those in humans. Secondly, along with cardiomyocytes of six regions of the left ventricular wall we were the first to analyze the “behavior” of papillary muscles cardiomyocytes. Being inside the ventricle, these muscles are connected to the flaps of the valve, which is located between the ventricle and the atrium, and are responsible for its stable operation,” explains Anastasia Khokhlova, representative of the Ural Scientific School of Myocardial Physiology and Biophysics, research leader, associate professor of the Department of Experimental Physics at UrFU, senior researcher of the Laboratory of Translational Medicine and Bioinformatics at the the Institute of Immunology and Physiology.

The function of the papillary muscles is different from that of the ventricular myocardium. During atrial contraction, the valve is open and blood flows into the ventricle. Then, the valve closes and blood is pumped to the vessels of the great circle of circulation due to contraction of the left ventricle. The papillary muscles, by contracting, prevent the valve from sagging inside the atrium.

Using equipment from the University of Freiburg, the scientists applied a unique method of carbon fibers in studies of papillary muscle cardiomyocytes.

“The disadvantage of experiments on the single cell model is that it is “ripped out” from the real environment of the myocardium, where it neighbors and interacts with other cells. However, a special setup provided by the German colleagues made it possible to attach carbon fibers 10-12 micrometers thick, which is smaller than a human hair, to the membrane of the cardiomyocyte. This allowed us to subject the cell to mechanical loading, creating conditions close to the real ones – for example, when the body experiences physical exertion, the ventricle pumps more blood than usual, and the walls of the ventricle (respectively, the cells) are stretched,” emphasizes Anastasia Khokhlova.

By stretching the cells using the described technique and comparing their behavior with that of unstretched cells, scientists analyzed how mechanical loading affects cardiomyocytes and how the force of contraction changes. Creating conditions close to the real physiological conditions of mechanical loading is a big step in studies on single cardiomyocytes.

According to the results of the experiments, the scientists found that the mechanical properties – amplitude of contraction force, contraction duration and change of contraction force during stretch – of cardiomyocytes of papillary muscles, inner and outer layers of the left ventricle differ (thus, it was found that contraction parameters of papillary muscle cells are smaller compared with contraction parameters of the inner layer of the ventricle). The researchers concluded that mechanical loading contributes to the heterogeneity of cardiomyocytes by regulating their responses to influences.

“Another important discovery. At the beginning of our studies we assumed that the electrical impulse coming through the conduction system from inside the ventricular myocardium first activates and makes the papillary muscles contract, then the inner layer of the ventricle and only in the last turn the outer layer. We expected that the contractile properties of cardiomyocytes depended on their anatomical location, adjusting to the sequence of their activation. However, during the experiments we found that the system is more complex and the contractility of cardiac cells does not depend on their proximity or distance from the ventricular center, but is determined mainly by their function in the heart. It turned out that the inner layer has the highest contractile potential, the outer layer has a slightly lower contractile potential, and the papillary muscle cells have the weakest contractile resource,” describes Anastasia Khokhlova.

The conducted studies open up opportunities to study pharmacological sensitivity of papillary muscles, their reactions to exposure to those or other drugs.

“We now believe that myocardial regions will behave differently when subjected to pharmacological action, that even individual cells should be affected differently. This knowledge is important for the development of technologies for targeted drug delivery to a diseased organ or its specific area, in our case, to the myocardium and its regions. These technologies are also being actively developed at Ural Federal University. In the future, the results of our research may help to clarify the doses of drugs and save patients from unwanted side effects,” comments Anastasia Khokhlova.

Given the importance of the work of Russian and German scientists, its implementation was supported by the Russian state program to support basic scientific research, as well as by grants from the German Research Foundation and the Boehringer Ingelheim Foundation (Germany). It is planned that further research will study the response of myocardial cells from different regions of the heart under conditions of cardiac pathologies and develop methods for its normalization.

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