According to modern concepts, mitochondrial dysfunction may be the fundamental basis for the
development and progression of CHF, including in patients undergoing myocardial
revascularization. The processes of mitochondrial fusion, division and mitophagy are aimed at
maintaining cellular homeostasis. A change in the balance of these processes can lead to the
accumulation of damaged organelles with impaired functions. In patients with CHF,
dysfunctional mitochondria are characterized by size dispersion, crist disorganization, and
localization changes relative to myofibrils.
At the same time, the topic of the influence of mitochondrial dysfunction on the prognosis
and clinical course of CHF remains debatable today. Direct study of the structural and
functional features of mitochondria in human cardiomyocytes is an extremely difficult task,
and therefore, such studies are carried out extremely rarely and on very limited cohorts. In
the planned study, due to the long time of the study material recruitment, the ultrastructure
of mitochondria in a large cohort of patients, ranging from 45 to 60 people, will be studied.
The aim of this study is to study the association of mitochondrial dysfunction with the
clinical course and outcomes of CHF of ischemic etiology, as well as to assess the degree of
compliance of indirect criteria of mitochondrial dysfunction with direct ultrastructural
characteristics of mitochondria in cardiomyocytes.
This single-center prospective cohort study will involve 45-60 patients. The patients will
have biopsy samples taken from the right auricle, as well as blood collection and
preservation and its derivatives. Electron microscopy of myocardial samples will be performed
to assess the ultrastructure of mitochondria of cardiomyocytes. The results of a direct study
of mitochondria will be compared with indirect signs of mitochondrial dysfunction: the
registration of the phenomenon of increased leaching of radiopharmaceuticals from the
myocardium, an increase in the number of copies of mitochondrial DNA and the concentration of
cytochrome C in the blood, the affiliation of mitochondrial DNA to haplogroup K. The results
obtained in each of the research tasks will have high scientific significance and publication
potential.
The results of the study will be obtained by solving the following tasks:
To investigate the clinical and prognostic significance of mitochondrial dysfunction,
confirmed by direct and indirect methods of investigation, in patients with CHF with
stenosing atherosclerosis of the coronary arteries who underwent surgical myocardial
revascularization in the prospective cohort study;
To study ultrastructural characteristics of mitochondria of cardiomyocytes from the
auricle of the right atrium using a transmission electron microscope JEM-1400 (JEOL,
Japan) in patients with CHF with reduced or mildly reduced left ventricular ejection
fraction (HFrEF, HFmrEF) and stenosing atherosclerosis of the coronary arteries;
To evaluate the features of the mitochondrial genome, in particular, to determine
whether the mitochondrial DNA belongs to haplogroup K, which may be associated with
impaired adaptation to hypoxia due to the negative effect of guanine replacement on
adenine at position 9055 (G9055A) [Strauss K.A. et al. Severity of cardiomyopathy
associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA
haplogroup. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3453-8. doi:
10.1073/pnas.1300690110] and its relation to the prognosis of the disease and the
ultrastructure of mitochondria according to electron microscopy;
To study the association of the number of copies of mitochondrial DNA in blood plasma
with ultrastructural signs of mitochondrial dysfunction in CMC;
To evaluate the content of the biochemical marker of mitochondrial damage - cytochrome C
in the blood serum of patients with CHF and to identify the correlation of its
concentration with the severity of structural and functional changes in mitochondria;
To assess the significance of the phenomenon of enhanced leaching of the
radiopharmaceutical Tc99-MIBI from the myocardium and to determine the degree of
correlation of the rate of leaching of Tc99-MIBI with the ultrastructural state of
mitochondria, as well as with the clinical course and prognosis of CHF;
Calculate statistical parameters (sensitivity, specificity, degree of concordance) for
each of the indirect signs of mitochondrial dysfunction and their totality in the
diagnosis of mitochondrial ultrastructure disorders according to electron microscopy
data and prediction of the clinical course and outcomes of CHF in patients undergoing
surgical myocardial revascularization.
Thus, it is planned to prove for the first time in the world the association of direct
ultrastructural signs of mitochondrial dysfunction with the clinical course and outcomes of
CHF in patients who underwent surgical myocardial revascularization. For the first time in
the world, the degree of compliance of available indirect signs of mitochondrial dysfunction
with the true ultrastructural state of mitochondria will be presented, with the inclusion of
45-60 patients in the study. Based on the results of the study, a parameter or a set of
parameters will be proposed that will be most associated with the clinical course of the
disease and the outcome in patients with CHF of ischemic etiology.
The results obtained will have high world-class scientific significance and importance, both
for fundamental medical science and for the practical implementation of the results.