Molecular Pathogenesis and the Possible Role of Mitochondrial Heteroplasmy in Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is a life-threatening condition associated with high mortality, in which the aortic wall is deformed due to congenital or age-associated pathological changes. The mechanisms of TAA development remain to be studied in detail, and are the subject of active research. In this review, we describe the morphological changes of the aortic wall in TAA. We outline the genetic disorders associated with aortic enlargement and discuss the potential role of mitochondrial pathology, in particular mitochondrial DNA heteroplasmy, in the disease pathogenesis.

[Inflammatory infiltrates, vasa vasorum, and endothelial NO synthase in the wall of thoracic aortic aneurysm]. / Vospalitel'nye infil'traty, vasa vasorum i NO-sintaza éndoteliia v stenke anevrizmy grudnogo otdela aorty.

OBJECTIVE: To elucidate whether there is a relationship between inflammation of the wall of aortic aneurysm and the number of vasa vasorum in it. MATERIAL AND METHODS: The investigation material was aortic aneurysm wall segments obtained during surgery. Among the patients, there were 20 men and 5 women. The patients' age ranged from 33 to 69 years. The investigation used monoclonal antibodies to macrophages (CD68), T cells (CD3, CD4, and CD8) and antibodies to von Willebrand factor, endothelial NO synthase, and alpha smooth muscle actin. A morphometric study was conducted. RESULTS: Calculation of the number of vasa vasorum (including newly formed vessels) in the adventitia of aortic aneurysm revealed that there was a statistically significant difference between the number of vasa vasorum in patients with an active inflammatory response (Group 1) versus Group 2 patients with a moderate inflammatory process in the aneurysm wall (p≤0.05) and a statistically significant difference between Groups 1 and 3 (without inflammatory infiltrates) (p≤0.05). Endothelial vasa vasorum heterogeneity was found in case of an immune response to NO synthase. At the same time individual vasa vasorium did not contain NO synthase, this enzyme was identified in the endothelium in a number of nearby vessels. CONCLUSION: The increase in the number of vasa vasorum in the aneurysm wall in patients with abundant inflammatory infiltrates is due to the fact that some of the inflammatory cytokines of T-cells and macrophages also contribute to angiogenesis.

The value of cardiovascular magnetic resonance in myocarditis with different clinical presentation.

AIM: to assess the diagnostic meaning of cardiac magnetic resonance imaging (CMR) in various clinical forms of myocarditis. MATERIALS AND METHODS: 11 (8 men, mean age 32.8±11.1 years) patients (pts), hospitalized with suspected acute coronary syndrome, while an acute myocardial infarction was excluded during the examination (group I); 48 pts (31 men, 43.1±12.7 years), with clinical and instrumental signs of dilated cardiomyopathy (DCM) - group II; and 20 patients (12 men, 39.5±14 years), with episodes of ventricular tachycardia (group III) underwent cardiac magnetic resonance imaging (CMRI). In 38 patients endomyocardial biopsy (EMB) was performed. RESULTS: According to EMB, signs of active myocarditis were revealed in 10 (34.5%) group II pts and in 3 (37.5%) group III pts; signs of resolved myocarditis - in 8 (27.6%) patients in group II and in 3 (37.5%); minimal morphological changes - in 11 (37.9%) patients of group II and in 2 (25%) patients of group III. In 9 (81.9%) patients of group I MRI data allowed to establish the diagnosis of acute myocarditis. Signs of active inflammation from MRI data were detected in myocardium 5 (10.4%) in group II pts and 7 (35%) in group III pts. In 22 (45.8%) pts in group II and 10 (50%), CMR data corresponded to the picture of resolved myocarditis. In 21 (43.8%) cases of group II and 3 (15%) of group III, MRI revealed minimal structural changes. In pts with clinical and instrumental signs of DCM and/or ventricular tachycardia MRI allows to identify signs of "active myocarditis" with a sensitivity of 37.5% with a specificity of 83.4%. At the same time, in cases of resolved myocarditis and minimal morphological changes MRI has high sensitivity (70 and 71.5%) and specificity (71.5 and 75%, respectively). CONCLUSION: CMR has high diagnostic significance in patients with infarct-like course of myocarditis. In patients with clinical syndrome of dilated cardiomyopathy or arrhythmias, the sensitivity of MRI in detecting active myocarditis is low (37.5%) with high specificity (83.4%). In cases of minimal structural changes in the myocardium and resolved inflammation, CMR is a good alternative to EMB.

[Giant Aneurysms in Coronary Arteries of a Young Woman].

Coronary arteries aneurysms with their thrombotic occlusion are known to be detected in young patients who have suffered Kawasaki disease in childhood. The other vascular beds are usually not involved. In the literature one can find not enough information regarding diagnostics of this pathology, as well as no specific treatment algorithm. We present here a clinical case of re-emergence of giant aneurysms of coronary arteries in the young female patient with subsequent immuno-histological confirmation of previous Kawasaki disease.

[Gigantic aneurysm of the coronary artery]. / Gigantskaia anevrizma koronarnoi arterii.

The paper describes a clinical case of gigantic aneurysm of one of the coronary arteries. It considers the morphological and immunohistochemical characteristics of the wall of the blood vessel with the detected signs of coronaritis. The authors have determined that Kawasaki disease could be retrospectively diagnosed in early childhood.

[Adhesion Molecules and Subpopulation of Mononuclear Cells in Pulmonary Arteries].

Atherosclerosis is associated with increased expression of adhesion molecules by vascular endothelium. AIM: to study endothelial expression of platelet endothelial cellular adhesion molecules (PECAM) (CD31), intercellular adhesion molecules (ICAM-1), vascular cell adhesion molecules (VCAM-1F) as well as T-cells and monocytes adhered to endothelium. METHODS: Research materials were en face specimens.

[Adhesion molecules and mononuclear cell subpopulations in the coronary and pulmonary arteries of patients with coronary heart disease].

UNLABELLED: Atherosclerosis is a multifactor disease, in which dysfunction of the endothelium leads to the emergence of its adhesion molecules. OBJECTIVE: to investigate the expression of the endothelial adhesion molecules PECAM (CD31), ICAM, and VCAM, as well as adherent endothelial T cells and monocytes. The material examined was en face pulmonary and coronary artery samples taken during autopsies (10 men), and en face specimens obtained from the coronary artery fragments taken from coronary heart disease patients during endarterectomy (37 men). This investigation used antibodies to the adhesion molecules ICAM-1, VCAM-1, and PECAM and those to CD3, CD4, CD8 T-cells and CD68 monocytes. RESULTS: The endothelial cells in the atherosclerotically intact coronary arteries had an elongated shape and were aligned along the blood flow. Those located above atheromas and fibroatheromas changed their shape from elongated to polygonal. Above the fatty streaks and atheromas, the reaction with antibodies to CD31 antigens became weaker at the edge of endothelial cells and disappeared in places. While the atherosclerotic process progressed, the reaction with the CD31 antigen at the edge of endothelial cells was similar in intensity to that on the surface of the endothelium. Adhesion of T cells and monocytes to the endothelium of coronary arteries increased as the atherosclerotic vascular process progressed. T cells and monocytes more often adhered to the endothelium at the sites where the endothelial cells contacted each other. CONCLUSION: Heterogeneity was found in the endothelial cells: their shape, the expression of adhesion molecules, and the adhesion of lymphocytes and monocytes to them changed during the progression of the atherosclerotic process.

[Assessment of clinical-instrumental, morphological data and expression of coxsackie adenovirus receptor in patients with inflammatory cardiac pathology].

In 22 patients with heart failure and/or ventricular arrhythmias presumably of inflammatory etiology the results of clinical and instrumental investigation were analyzed and compared to the endomyocardial biopsy data. In the subgroup of patients with left bundle branch block (LBBB) we revealed features indicative of lesser contribution of inflammatory destruction in pathogenesis of cardiomyopathy. The only virus, detected in biopsy samples, was parvovirus B19. Its persistence in myocardium was not related to activity of inflammation and severity of clinical course. Increased expression of Coxsackie adenovirus receptor (CAR) was found in 20 patients. It was not related to inflammatory cells infiltration and virus persistence in myocardium. Patients with most prominent CAR expression were characteried by right heart dilatation, more severe heart failure and absence of LBBB. Enhancement of CAR expression could reflect the attempt of organism to repair intercellular communications between cardiomyocites and to protect cells from the products of necrotic lysis during long standing inflammation.

[T-cell subpopulations and macrophages in stable and unstable coronary atherosclerotic plaques].

Unstable atherosclerotic plaques are a cause of acute myocardium infarction. Because peripheral blood mononuclear cells are often present in atherosclerotic plaques, we've examined T-cells (CD4, CD8) and macrophages (CD68) in the different areas of atherosclerotic plaques. The cells were counted individually in the center, shoulder at the bottom and in the cap of plaque. All types of studied cells prevailed in the unstable plaque cap than in the stable one (p < 0.05). CD4 and CD68 cells dominated in the shoulder of atherosclerotic plaque (p < 0.05). The difference between the numbers of macrophages at the bottom or in the center of stable and unstable plaques was statistically insignificant (p > 0.05). Prevalence of peripheral blood mononuclears in the cap and at the periphery of unstable plaques points their participation in the development of atherosclerotic plaque instability.

[Adhesion of T cells and macrophages to the coronary artery endothelium in patients with coronary heart disease].

The study has found a close relationship between the early signs of atherosclerosis, i.e. between the fine-dropwise (dust-like) lipid deposition in the intima and the adhesion of monocyte clusters to the endothelium in these places. In the intimal areas without lipid depositions, adherent monocytes were absent or detectable as single cells in the field of vision. The coronary arteries displayed large clusters of T cells (CD4, CD8) adhered to the endothelium and migrated into the intima. The clusters of these cells were encountered not only in the vascular atherosclerotic lesion areas, but also in the invisibly altered ones. Some patients (with atheromas and fibroatheromas in the coronary artery segments) were found to have en face specimens with endothelial layer damages, with one or 3-5 cells being absent in the endothelial layer. The bottom of such microerosions was lined by T-cell and macrophage infiltrations and it was part of the cap of an atherosclerotic plaque. These surface erosions may be considered as an early developmental stage of an unstable plaque.

[Anti-inflammatory properties of statins in the study of atherosclerotic plaques in the endartectomized coronary arteries].

Statin therapy reduces blood cholesterol and lipids and exerts an anti-inflammatory effect. Certain statins bind adhesion molecules, including functional leukocytic antigen-1, and therefore block their interaction with T lymphocytes and macrophages expressing the counter-receptor intercellular adhesion molecule-1 (ICAM-1). Quantitation of endothelium-adherent T cells and macrophages revealed much smaller numbers of these cells in patients receiving statins. The authors consider that the lower count of T lymphocytes and macrophages in the upper layers of the intima and atherosclerotic plaques may facilitate the conversion of unstable to stable plaques, which reduces the risk of atherosclerotic plaque rupture and resultant vascular thrombosis.

[Immunomorphological study of angiotensin-converting enzyme in coronary shunts].

Coronary bypass surgery is the operation of choice in patients with coronary atherosclerosis. However, some time later, venous shunts frequently stop functioning after successful surgery. The reasons for this include intimal hyperplasia occurring in response to release of cytokines, angiotensin II in particular. In man, the latter is formed by angiotensin-converting enzyme or chimase. The findings show that elevated ATF concentrations are found in some cells in the area of intimal hyperplasia, in macrophages and smooth muscle cells of the shunt hyperplastic intima. The increased ATF concentration in the aorto-coronary shunt cells results in the elevated levels of angiotensin II, the migration of smooth muscle cells, their hypertrophy and hyperplasia, the formation of atherosclerotic plaques, thrombosis, and circulatory disorders.

[Inflammatory cell reaction and mast cells in aortic intima and pulmonary artery of humans at early stages of atherosclerosis].

The study of inflammatory reaction and morphofunctional characteristics of mast cells in aortic intima and pulmonary artery at initial stages of atherosclerosis was performed in 62 persons who had died of accidental causes at the ages of 4-49 years and 44 males who had died of myocardial infarction at the age of 42-73 years. Histological, histochemical and immunocytochemical tests showed permanent presence of lymphocyte-monocytic cell reaction in combination with mast cell infiltration in arterial intima that progressed with age and development of atherosclerosis. Lipoidosis was associated with an increase of T lymphocytes with (CD4+) domination, monocytes/macrophages (CD11+) and mast cells in different functional activity. Marked hyperplasia and high secretory activity of mast cells (expressed in their massive degranulation) were observed in acute myocardial infarction in aortic intima and pulmonary artery.

[Major types of unstable atherosclerotic plaques and their distribution in coronary arteries in acute myocardial infarction].

A pathomorphological investigation of unstable atherosclerotic plaques and their distribution in coronary arteries were studied on successive (5 mm) transverse sections of autopsy material from 60 patients with acute myocardial infarction (AMI). Two morphological types of such plaques were distinguished: lipid one (70%) and dystrophic-necrotic (30%). Unstable plaques in AMI are spread. Numerous unstable plaques were more frequently observed in AMI with preceding unstable angina pectoris but single plaques were found in cases with absence of coronary anamnesis. There were no significant age, sex and risk factor differences between cases with multiple and single atherosclerotic plaques.

[Immunomorphological study of coronary grafts].

Most patients subjected to coronary artery bypass grafting develop graft occlusions in some time after successful coronary surgery. Causes of graft occlusions comprise hyperplasia of intima occurring as a response to release of cytokines and angiotensin II. Angiotensin II is formed in human body with participation of angiotensin converting enzyme (ACE) or chymase. We found high concentrations of ACE in some smooth muscle cells in hyperplasia zone. Proliferation of smooth muscle cells, their hypertrophy and increased synthesis of intercellular space proteins facilitate graft occlusion. Moreover ACE was found in cytoplasm of macrophages infiltrating graft's intima. Thus ACE can be an important contributor to the process of coronary artery bypass graft obstruction.

[Effect of granulocyte-macrophage colony stimulating factor on the function and regeneration of myocardium in rats with experimental infarction].

To test the reparative capacity of stromal cells in myocardial infarction, rats were injected with granulocyte-monocyte-colony stimulating factor (GM-CSF) (leukomax), a cytokine known by its ability to raise a level of stromal cells in the blood, during first three days after coronary artery ligation. Only 10 of 17 rats (59%) survived 4 weeks in this group compared with 16 of 24 (67%) among rats not treated with leukomax. Echocardiographic and electromanometric studies showed that in both groups ventricular (LV) dilatation which developed during first hours after surgery persisted throughout 6-8 weeks and was combined with decreased ejection fraction and elevated LV end diastolic pressure. These alterations correlated with infarct size which varied from 0 to 28% of left ventricular weight in both groups. There were no statistically significant differences in functional and morphometric measurements between groups receiving and not receiving GM-CSF. However this result may be inconclusive due to small number of investigated animals and broad variation of ischemic zone size in each group.

[Inflammatory-immunological cellular reaction in intima of the aorta and pulmonary artery and development of atherosclerosis]. / Vospalitel'no-immunologicheskaia kletochnaia reaktsiia v intime aorty i legochnoi arterii i razvitie ateroskleroza.

AIM: To assess morphological manifestations of inflammation at initial stages of atherosclerosis development in intima of the aorta and pulmonary artery both in its intact (lipid free) zones and those with lipoidosis. METHODS: Histological, histochemical and immune cytochemical methods with the use of monoclonal antibodies to monocytes/macrophages (CD-11) and T-lymphocytes (CD-4, CD-5, CD-8) were applied for the study of cellular elements in membranous preparations of intima and transverse cross-sections of the aorta and pulmonary artery from 64 apparently healthy persons aged 4 months-49 years who died of accidental causes. RESULTS: Signs of inflammatory cellular reaction (infiltration with monocytes/macrophages) were permanently present in aortic and pulmonary artery intima and progressed with age. This cellular reaction was consistently accompanied by infiltration of intima with mast cells. Compared with intact intima infiltration with lymphocytes/monocytes was more pronounced in zones with lipoidosis where helper-lymphocytes prevailed among T-cells and number of monocytes/macrophages was substantially increased. CONCLUSION: Mononuclear cellular infiltration with participation of mast cells was persistently present in aortic and pulmonary artery intima and obviously preceded its atherosclerotic changes. However there was no straightforward relationship between severity of this reaction and development of atherosclerosis in the aorta and especially in pulmonary artery.

[Pathomorphological features of atherosclerotic plaques in acute coronary syndrome]. / Patomorfologicheskie osobennosti ateroskleroticheskikh bliashek pri ostrom koronarnom sindrome.

We studied transverse cross-sections (5 mm apart) of coronary arteries of 45 men and women who died of acute myocardial infarction at the age of 41-79 years. Both stable and unstable atherosclerotic plaques were found in all cases. Stable plaques consisted of solid fibrous tissue with small amount of lipids and cellular elements. Unstable plaques were represented by 2 types: lipid (75.6%) and dystrophic necrotic (24.4%). Various degree of inflammatory cellular reaction was present in all lipid plaques. Factors associated with fibrous cap rupture were identified. Lipid plaques were more frequent in subjects with elevated while dystrophic-necrotic - with normal levels of blood lipids (measured during life).

[Hyperplasia and degranulation of mast cells in intima of the aorta and pulmonary artery in acute myocardial infarction]. / Giperplaziia i degranuliatsiia tuchnykh kletok intimy aorty i legochnoi arterii pri ostrom infarkte miokarda.

AIM: To study morphological and functional state of mast cells from intima of the aorta and pulmonary artery associated with acute cardiovascular failure due to myocardial infarction. MATERIAL: Vessels of 44 men who died of acute myocardial infarction at the age of 42-73 years. METHODS: Intimal cellular elements were analyzed in membranous preparations of intima and transverse cross-sections of vessels. Parameters studied were density of mast cells (number per unit of intima area), percent of mast cells in the state of degranulation, degree of polymorphism of mast cells. Data obtained in victims of myocardial infarctions were compared with those from apparently healthy persons who died of accidental causes. RESULTS: Intima of both the aorta and pulmonary artery in all cases of myocardial infarction was characterized by: 1. hyperplasia of mast cells (44.9 cells/mm(2) compared with 9.6 in controls); 2. substantially increased number of cells in the state of secretory activity (36.9 cells/mm(2) compared with 4.0 in controls); 3. pronounced polymorphism of mast cells reflecting disturbed balance between processes of degranulation and regranulation. Increased number of mast cells in intima was accompanied by elevated content of various T-lymphocytes and monocytes. Changes of mast cell population in main vessels of the body observed in this study can be considered as reaction aimed at stabilization of circulation in acute myocardial infarction.

[Features of atherosclerosis in the ascending human aorta and the link between its development and the main risk factors of ischemic heart disease in patients after aortocoronary shunting]. / Osobennosti ateroskleroza v voskhodiashchei aorte cheloveka i sviaz' ego razvitiia s osnovnymi faktorami riska ishemicheskoi bolezni serdtsa u bol'nykh, perenesshikh aortokoronarnoe shuntirovanie.

Atherosclerosis was found in all ascending aorta biopsies of 125 patients aged 42 to 65 years who underwent aortocoronary bypass surgery. Lipid spots only were found in 91.2% of cases, in 11 patients (8.8%) there were lipid plaques. Three main types of lipid spots were recognized: type I--primary extracellular lipoidosis (40.0%); type II--mainly intracellular lipoidosis (24.8%) and type III--cell lipoidosis with a pronounced component of secondary extracellular lipoidosis (26.4%). A specific feature of ascending aorta atherosclerosis is a frequent combination of intima lipoidosis with media lipoidosis: 92% in type I, 100% in type II and 93.9% in type III. This is probably an important way of lipid elimination from the intima and this predetermines a "mild" course of atherosclerosis in this part of the aorta. Types II and III of lipoidosis occurred more frequently in lipid metabolism disturbances and only under these conditions clusters of foam cells were observed. Arterial hypertension and smoking have a leading role in development of intimal hyperplasia. When assessing atherosclerosis activity in the operated patients not only risk factors of ischemic heart disease but also the results of aorta biopsies studies should be taken into consideration.