Ultrastructural Characteristics of Mitochondria in Cardiomyocytes in Heart Failure

Официальное название

Association of Ultrastructural Characteristics of Mitochondria in Cardiomyocytes and Signs of Mitochondrial Dysfunction With the Clinical Course and Outcomes of Heart Failure

Обзор

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.

Подробное описание

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:

1. 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; 2. 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; 3. 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; 4. To study the association of the number of copies of mitochondrial DNA in blood plasma with ultrastructural signs of mitochondrial dysfunction in CMC; 5. 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; 6. 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; 7. 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.

Вмешательства

• Процедура coronary artery bypass grafting
  Coronary artery bypass grafting

Первичные конечные точки

• Combined primary endpoint (percentage) [Срок оценки: 12 months]

Вторичные конечные точки (3)

• Hospital stay (days) [Срок оценки: 30 days]
• Postoperative complications during hospitalization (percentage) [Срок оценки: 30 days]
• Incidence of patients with HF worsening (percentage) [Срок оценки: 12 months]

Критерии участия

Критерии включения

• The presence of HFrEF or HFmrEF (EF of LV <50%)
• Obstructive multivessel coronary atherosclerosis as an indication for cardiac surgical correction of coronary blood flow (coronary bypass surgery)
• Signed informed consent to participate in the study, separate consents for biomaterial sampling and genetic research

Критерии исключения

• Refusal of revascularization or participation in the study
• Additional cardiac surgery other than coronary bypass surgery (valves, aneurysm)
• Oncological diseases in the active stage;
• The presence of implanted devices (EX, AICD, CT);
• Severe renal dysfunction (GFR <30 ml/min/1.73 m2);
• Infiltrative heart diseases (sarcoidosis, amyloidosis, accumulation diseases);
• Autoimmune diseases;
• Acute infectious and exacerbations of chronic somatic diseases
• Type 1 or type 2 diabetes mellitus
• Contraindications to myocardial scintigraphy, cardiopulmonary stress test
• Impossibility of prescribing optimal drug therapy after cardiac surgery

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Россия · 1 центр

• Tomsk National Research Medical Center, Russian Academy of Sciences — Tomsk

Публикации

• Garganeeva A.A., Kuzheleva E.A., Tukish O.V., Vitt K.N., Andreev S.L., Muslimova E.F., Korepanov V.A., Afanasiev S.A., Gulya M.O., Syromyatnikova E.E., Vladimirova E.A., Stepanov I.V. Possibilities of diagnosis of mitochondrial dysfunction in chronic heart failure. Siberian Journal of Clinical and Experimental Medicine. 2024;39(3):51-57. https://doi.org/10.29001/2073-8552- 2024-39-3-51-57.
• Muslimova E.F., Kuzheleva E.A., Garganeeva A.A., Afanasiev S.A. Association of mitochondrial DNA C7028T, G3010A, G9055A polymorphisms and the severity of chronic heart failure of ischemic genesis. Siberian Journal of Clinical and Experimental Medicine. 2025;40(4):123-130. https://doi.org/10.29001/2073-8552-2025-40-4-123-130
• Garganeeva AA, Korepanov VA, Kuzheleva EA, Tukish OV, Vitt KN, Muslimova EF, Afanasiev SA. Chronic heart failure with reduced and mildly reduced left ventricle ejection fraction: relationship between mitochondrial respiratory dysfunction of peripheral blood mononuclear cells and iron deficiency. J Geriatr Cardiol. 2025 Sep 28;22(9):812-817. doi: 10.26599/1671-5411.2025.09.004. PMID 41143166
• Garganeeva AA, Kuzheleva EA, Kazakov EP, Syromyatnikova EE, Tukish OV, Kireev II. Association of Cardiomyocyte Mitochondrial Ultrastructure Features with the Severity of Clinical Manifestations in Heart Failure. Kardiologiia. 2026 Jan 14;65(12):13-19. doi: 10.18087/cardio.2025.12.n3062. English, Russian. PMID 41531353
• Kuzheleva EA, Garganeeva AA, Tukish OV, Vitt KN, Andreev SL, Syromyatnikova EE, Vladimirova EA. Total Area of Interfibrillar Mitochondria in the Right Atrial Appendage Cardiomyocytes as an Index of the Functional State of the Cardiovascular System in Chronic Heart Failure. Bull Exp Biol Med. 2025 Feb;178(4):486-490. doi: 10.1007/s10517-025-06361-7. Epub 2025 Mar 26. PMID 40138111
• Garganeeva A.A., Tukish O.V., Kuzheleva E.A., Gulya M.O., Muslimova E.F., Zhargasova V.A., Popov S.V. Heart failure and mitochondrial dysfunction: research methods in experiment and clinical practice. Acta biomedica scientifica. 2025; 10(1): 103-114. doi: 10.29413/ABS.2025-10.1.11
• Garganeeva AA, Kuzheleva EA, Tukish OV, Vitt KN, Kondratiev MY, Syromyatnikova EE, Andreev SL, Arsenieva YA, Korepanov VA, Afanasiev SA. Acute Decompensated Heart Failure: Structural and Functional Changes in Mitochondria. Kardiologiia. 2024 Dec 24;64(12):12-18. doi: 10.18087/cardio.2024.12.n2737. English, Russian. PMID 39784128
• Liao M, Men L, Gong M, Li Y, Wang Y, Xu D, Luan J, Zhou H, Liu M, Chen M. Mitophagy: a novel avenue for herbal medicines alleviating myocardial ischemia/reperfusion injury. Apoptosis. 2025 Dec;30(11-12):2676-2693. doi: 10.1007/s10495-025-02178-x. Epub 2025 Sep 12. PMID 40938522

Идентификаторы

NCT: NCT05770349 · 23-75-00009

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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