Laboratory of Experimental Pathology of the Heart

The laboratory of myocardial physiology was founded in 1978 and renamed into the laboratory of experimental pathology of the heart in 1986.

Main areas of research

• Interconnection of ion transport, energy supply and myocardial contractile function

• Pathogenesis of cardiomyopathy

• Chronic heart failure

• Search and testing of new cardiotropic drugs

• Blood circulation regulation

The most significant research results of recent years

• When studying the pathogenesis of chronic heart failure (CHF) in rats induced by different doses of isoproterenol or doxorubicin it was found that the ratio of diastolic to systolic dysfunction of the heart was altered. Hearts of animals received lower cumulative dose of isoproterenol (200-240 mg/kg) or doxorubicin (8-10 mg/kg) were characterized by a predominance of diastolic dysfunction while hearts of animals that received higher doses of drugs showed the predominance of systolic dysfunction. When extending the period of observation all hearts have showed the presence of systolic dysfunction with pronounced dilatation of the heart. Thus, 1) diastolic dysfunction with normal ejection fraction represents the first stage of CHF and 2) the development of heart failure occurs with a predominant violation of the relaxation process, and 3) a lengthening of the preejection period and the duration of systole can serve as early criteria for the formation of systolic dysfunction.

In the same models, a slowing of myocardial relaxation and increased left ventricular diastolic pressure were found at the invasive studies in all rats while, in addition, a lengthening of preejection phase and systole duration were noted at systolic dysfunction, indicating reduced myocardial contractility. These symptoms may serve as criteria for the determination of early systolic dysfunction.

Several potentially cardiotropic compounds have been tested in CHF models.

 • Dinitrosyl iron complexes (DNIC), a natural depot of nitric oxide in the body, when administered intravenously have a sustained hypotensive effect on systemic arterial pressure, due to slow release of nitric oxide from the complexes.

This distinguishes them from other nitric oxide donors having only transient action. The form of DNIC with glutathione as a ligand, called Oxacom, created by prof. A.F.Vanin in our center, exerted a stable hypotensive effect in rats, rabbits and monkeys. Noteworthy, spontaneously hypertensive rats were especially sensitive to Oxacom. The effect of the drug was maintained with subcutaneous and intramuscular administration, but it was not so fast. The drug has no analogues, it has successfully passed the necessary pharmacological studies and two phases of clinical trials. Its introduction to patients in the dose of 1.5 mg/kg can keep the blood pressure at a reduced level for 6-10 hours.

In both models of heart failure, Oxacom restored decreased contractility and relaxation of the myocardium. It also reduced the pressure in the small circle in rats with pulmonary arterial hypertension caused by monocrotaline. In experiments in isolated rat heart underwent to hypoxia-reoxygenation, the addition of Oxacom (30 nM) to hypoxic perfusate retained the contractile activity of the heart and reduced both hypoxic and reoxygenation contracture. Oxacom almost completely prevented reoxygenation arrhythmias and contributed to a more rapid and better recovery of developed pressure, and also ensured the preservation of the ability of the heart to reproduce a high rate of stimulation.

• The oxidative stress is an obligatory component of the pathogenesis of CHF. We have studied a possible protective action of a new mitochondrial antioxidant, plastomitin, created in the Institute of Mitoengeneering, MSU. Plastomitin given along with doxorubicin for 4 weeks prevented the development of LV systolic dysfunction and maintained normal heart rate, ejection fraction and both myocardial contractility and relaxability. Thus, a reduction of oxidative stress severity at the beginning of the pathological process can reduce negative remodeling of the heart.

• On the model of chronic heart failure in rats induced by isoproterenol, the effect of the synthetic analogue II fragment of native apelin (apelin-12) was investigated. The cardiotropic effect of 4 synthetic analogues was previously studied, of which analog II (methylin) was selected as the most effective. The bolus or infusion administration of methylin increased the indices of contractility and relaxation of the myocardium to a greater extent than the initial apelin-12. At present, the stage of preclinical study of the drug is being completed.

• In continuation to studies in the laboratory of regulation of the cardiovascular system (supervisor - Professor V.M. Khayutin, 1924-2010) more precise studies were performed using the electrical impedance method for dynamic non-invasive assessment of LV contractility in humans. The method was verified in experiments in rats by simultaneous recording of pressures in the ascending aorta and LV with the help of a precision (Millar) catheter sensor. The complex of methods has been created for use in the clinic providing the possibility of studying cardiac inotropic responses in a variety of physiological tests, including samples with active muscular load. The method of detailed study of the duration of the LV pre-ejection period in each cardiocycle showing inotropic and chronotropic reactions in stress tests with a reliable determination has been implemented.

• The laboratory pursues the studies focused on the control of hydraulic resistance in arteries under changes in blood flow velocity, which were initiated by Prof. V. M. Khayutin as early as 1980s. This control is based on endothelial ability to release nitric oxide, a well-known smooth muscle relaxing agent, in response to augmenting viscous friction force (shear stress) at the vascular wall. Our in situ experiments with the major arteries in rats and rabbits showed that the role of shear stress receptor is given to the fibers of endothelial glycocalyx, which is the layer of macromolecules lining the luminal surface of endotheliocytes. In addition, we employed the culture of human umbilical vein to demonstrate that namely endothelial glycocalyx is the barrier, which prevents adhesion of the platelets to vascular wall. The harvested data suggest that lesion to glycocalyx is the first stage in the chain of events leading to damage of endothelial function and finally to atherosclerotic lesion of the blood vessels.

Head of the laboratory - Professor Valeriy I. KAPELKO