Dexamethasone inhibits regeneration and causes ventricular aneurysm in the neonatal porcine heart after myocardial infarction.

AIMS: Recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after postnatal day 3. However, it is unknown if corticosteroid, a broad anti-inflammatory agent, will abrogate the regenerative capacity in the hearts of neonatal pigs. The aim of the current study is to evaluate the effect Dexamethasone (Dex), a broad anti-inflammatory agent, on heart regeneration, structure, and function of the neonatal pigs' post-myocardial infarction (MI). METHODS AND RESULTS: Dex (0.2 mg/kg/day) was injected intramuscularly into the neonatal pig (age: 2 days postnatal) during the first week post-MI. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine (BrdU) pulse-chase labeling, histology, immunohistochemistry, and flow cytometry were performed to determine inflammatory cell infiltration, CM cytokinesis, and myocardial fibrosis. Dex injection during the first-week suppressed acute inflammation post-MI in the pig hearts. It inhibited BrdU incorporation to pig CMs and CM cytokinesis via inhibiting aurora-B protein expression which was associated with mature scar formation and thinned walls at the infarct site. CMR imaging showed Dex caused left ventricular aneurysm and poor ejection fraction. CONCLUSIONS: Dex inhibited CM cytokinesis and functional recovery and caused ventricular aneurysm in the hearts of 2-day old pigs post-MI.

[TRANSPORT OF OXYGEN DURING GEOMETRICAL RECONSTRUCTION OF THE LEFT VENTRICLE IN CONJUNCTION WITH CORONARY ARTERY BYPASS GRAFTING AND USING OF HIGH THORACIC EPIDURAL ANESTHESIA AS A MAJOR COMPONENT OF GENERAL ANAESTHESIA].

UNLABELLED: The purpose of the study is to examine the perioperative dynamics of strategic blood oxygen transport indicators: delivery (DO2), consumption (VO2), the coefficient of oxygen uptake (CUO2) and their composition, as well as the dynamics of blood lactate indicators in patients with ischaemic heart disease (IHD) who underwent surgery under cardiopulmonary bypass with high thoracic epidural anaesthesia (HTEA) as the main component of anesthesia. MATERIALS AND METHODS: Research was conducted in 30 patients with a critical degree of operational risk, during the correction of post-infarction heart aneurysmn using the V. Dor method in combination with coronary artery bypass grafting. RESULTS: The strategic blood oxygen transport indicators (delivery, consumption and the oxygen uptake coefficient) showed a statistically significant decrease compared to the physiological norm and to the initial data at two points of the research: the intubation of the trachea and during cardiopulmonary bypass. The system components of oxygen were influenced at problematic stages by the dynamics of SvO2 (increase), AVD (decrease), hemodilution withe fall of the HIb- in the process of JR in the persence of superficial hypothermia. The maintenance of optimal CA in the context of HTEA, combined with a balanced volemic load and a minimized cardiotonic support ensured the stabilisation of strategic blood oxygen transport indicators aithe postperfusion stage and during the immediate postoperative period CONCLUSION: The article is dedicated to the study of strategic blood oxygen transport indicators and their components during the operation of geometric reconstruc-tion of the left ventricle combined with coronary artery-bypass using cardiopulmonary bypass and with high thoracic epidural anesthesia as the main component of general anaesthesia. The analysis has covered the stagewise delivery dynamics, consumption and the oxygen uptake coefficient at II stages of the operation and of the immediate postoperative period. The study has ident (fled the causes qf reduced oxygen transport during the preperfu- sion and postperfusion periods, under IR and during the immediate postoperative period. Values of CA, SvO2, AVD, Hb, hemnodilution, T qf the body in oxygen transport indicator dynamics have been proven. A way of maintaining oxygen transport indicators close to the physiological norm in the immediate postoperative period has been justified.

Immunohistochemical detection of uPA, PAI-1, and alpha-SMA in aneurysms of patients with perimembranous ventricular septal defect.

BACKGROUND AND AIM OF THE STUDY: A perimembranous ventricular septal defect (PMVSD) may be partially or completely occluded by aneurysms that originate from the tricuspid valve leaflets, though the exact mechanisms of closure remain unknown. It is hypothesized that valvar interstitial cells (VICs) mediate extracellular matrix (ECM) remodeling in aneurysms via the secretion of a serine proteinase and its inhibitor. METHODS: The functional characteristics of VICs in 15 aneurysms and in four normal tricuspid valve leaflets obtained at autopsy were evaluated by detecting the expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and alpha-smooth muscle actin (alpha-SMA) in the specimens, using immunohistochemical methods. RESULTS: uPA and alpha-SMA were recognized predominantly in VICs located mainly in regions adjacent to the endothelium and smooth muscle cells of blood vessels. PAI-1 was identified in VICs found mainly in granulation tissues, and in endothelial cells. Two types of granulation tissue (myxoid and fibrous tissue) were associated with aneurysms. Nine aneurysms expressed a high uPA activity and a low PAI-1 activity (uPA/PAI-1 ratio 1.78), while six aneurysms expressed a low uPA activity and a high PAI-1 activity (uPA/PAI-1 ratio 0.14). CONCLUSION: The expression of uPA, PAI-1 and alpha-SMA in VICs suggests that interactions among these molecules contribute to ECM remodeling during aneurysm formation and development. This provides a potential mechanism for defect closure in patients with PMVSD.

[Left ventricular heart aneurism--a new source of resident cardiac stem cells].

In the past few years it has been established that the heart contains a reservoir of stem and progenitor cells that have the ability to differentiate in vitro and in vivo toward vascular and cardiac lineages and that show cardiac regeneration potential in vivo following injection into the infracted myocardium. The aim of the present study was to characterize cardiac stem cells in the tissue of chronic left ventricular aneurism. It was shown that human c-kit positive cells were scattered in fibrous, muscle and adipose parts of aneurism tissue. C-kit positive cells localized mainly in fibrous tissue nearby large vessels, however, c-kit positive cells did not express endothelial, smooth muscle or cardiomyocyte cell markers. Co-localization experiments demonstrated that all c-kit positive cells were of non-hematopoietic origin, since they did not express markers such as CD34 and CD45. Majority of c-kit positive cells expressed MDR1, but showed no proliferation activity (Ki67). It thus appears that aneurism tissue could be an alternative source of autologous cardiac stem cells. However, their regeneration capacity should be further explored.

[Impact of viable myocardium assessed by 99Tcm-MIBI SPECT and 18F-FDG PET imaging on clinical outcome of patients with left ventricular aneurysm underwent revascularization].

OBJECTIVE: To evaluate the impact of viable myocardium assessed by (99)Tc()m-MIBI SPECT and (18)F-fluorodeoxyglucose (FDG) PET imaging in patients with left ventricular aneurysm (LVA) underwent revascularization (RVS). METHODS: Forty-six consecutive patients with LVA (mean LVEF 36% +/- 7%), underwent (99)Tc(m)-sestamibi SPECT and (18)F-FDG PET examinations and received RVS therapy, were followed-up for a mean period of 80 +/- 27 months. Viable myocardium in aneurysm was defined as perfusion-metabolism mismatch score (MMS) >/= 2.0. Patients were divided into four groups by aneurysm viability and aneurysmectomy. Group A1 (n = 8): viability-; Group A2 (n = 15): viability-, aneurysmectomy; Group B1 (n = 10): viability +; and Group B2 (n = 13): viability +, aneurysmectomy. RESULTS: The cardiac event rates during follow up were similar among groups [A1 (25%, 2/8), B1 (40%, 6/15), A2 (20%, 2/10) and B2 (31%, 4/13; P > 0.05)]. After revascularization, LVEF was improved (> 10%) in groups A2, B1 and B2 (P < 0.05). Multivariate logistic regression analysis showed that LV-MMS (OR = 2.34, 95% CI 1.08 - 5.06, P < 0.05), distal vessel disease (OR = 0.008, 95% CI 0.001 - 0.560, P < 0.05) and nonaneurysm perfusion score (OR = 0.24, 95% CI 0.07 - 0.85, P < 0.05) were significantly associated with the improvement of LVEF after revascularization. CONCLUSIONS: Long term cardiac events rate post revascularization was not affected by viable myocardium or aneurysmectomy in LVA patients. Viable myocardium in LVA patients was associated with better LVEF improvement after revascularization.

Changes in B-type natriuretic peptides after surgical ventricular restoration.

OBJECTIVE: The aim of this study was to prospectively investigate changes in brain natriuretic peptide (BNP) and amino terminal pro-BNP (NT-pro-BNP) in relation to functional status after surgical ventricular restoration (SVR). METHODS: Between March 2003 and May 2006, 29 patients (20 men and 9 women, mean age 65 years, mean ejection fraction 24%) with post-infarction left ventricular aneurysm and depressed left ventricular function underwent SVR according to the Dor technique at our institution. Twenty-two patients (76%) were in New York heart association (NYHA) functional class III or IV. Multi-vessel disease was present in 26 patients. Natriuretic peptides, functional status, ejection fraction and left ventricular volumes were analyzed at baseline, after 6 months, and late postoperatively. RESULTS: There was no early mortality. Survival at 24 months was 93%. Six months postoperatively 25/29 (86%) patients were in NYHA class I and II (p<0.001) and at late (mean 21 months) follow-up, all patients were in NYHA class I and II. There was a persistent reduction of NT-pro-BNP (2406 pg/ml vs 1510 pg/ml; p=0.03 and 975 pg/ml; p=0.03) and BNP (312 pg/ml vs 228 pg/ml; p=0.12 and 191 pg/ml; p=0.20) 6 months postoperatively and at late follow-up, respectively. Ejection fraction improved from 24% to 37% (p<0.001) at 6 months. End-diastolic (110 ml/m(2) vs 90 ml/m(2), p=0.009) and end-systolic (75 ml/m(2) vs 52 ml/m(2), p=0.006) volume index were reduced at 6 months. Functional improvement correlated significantly with reduction in BNP (r=0.61, p=0.01) and NT-pro-BNP (r=0.58, p=0.003) 6 months after surgery. Ejection fraction correlated inversely with BNP (r=-0.58, p=0.02) and NT-pro-BNP (r=-0.51, p=0.04), and end-systolic volume correlated with BNP (r=0.65, p=0.03) and NT-pro-BNP (r=0.62, p=0.03) 6 months after surgery. CONCLUSIONS: Heart failure secondary to post-infarction left ventricular remodeling can be reversed by SVR. Improvement in these patients was associated with reduced levels of B-type natriuretic peptides 6 months after surgery. Clinical improvement was maintained and peptide levels were further reduced at late follow-up.

Left ventricular aneurysm repair in rats: structural, functional, and molecular consequences.

OBJECTIVES: This study examined the effects of aneurysm repair in a rat model of myocardial infarction on functional indices and on the spatiotemporal distribution of cardiac contractile protein and natriuretic peptide messenger RNA. METHODS: In a rat infarct model, expanded left ventricular aneurysms were plicated 4 weeks after infarction. At 30 weeks, transverse heart sections were taken at 4 levels (apex [level 1] through base [level 4]) and assessed by in situ hybridization histochemistry to determine regional messenger RNA levels of pre-pro-atrial natriuretic peptide, cardiac alpha-actin, skeletal alpha-actin, myosin light chain-2v, and beta-myosin heavy chain. RESULTS: Rats with plicated left ventricular aneurysms had reduced left ventricular endocardial circumference (19%, P <.005), lower heart weight ratio (31%, P <.05), left ventricular end-diastolic pressures (51%, P <.05), and increased +/-dP/dt (34%-38%, P <.05). Cardiac messenger RNA levels of pre-pro-atrial natriuretic peptide were reduced in the septum (levels 2 and 3), and skeletal alpha-actin levels were reduced in the septum and left ventricular free wall of plicated rats (level 3). beta-Myosin heavy chain levels were markedly reduced in peri-infarct regions of the left ventricular free wall, septum, and right ventricle in plicated rats at level 4, whereas myosin light chain-2v levels were reduced at levels 2 and 4 in the left ventricular free wall and at level 4 in the right ventricle. CONCLUSIONS: Plication of left ventricular aneurysm after infarction in the rat significantly reduced cardiac hypertrophy, improved cardiac function, and reduced the upregulation of pre-pro-atrial natriuretic peptide and both fetal and adult contractile protein isoforms associated with cardiac hypertrophy.

Augmented expression of atrial myosin light chain 1 in ventricular aneurysms of human: enzyme immunoassay for atrial myosin light chain 1.

We established an enzyme immunoassay (EIA) for atrial myosin light chain 1 (ALC1) using monoclonal antibodies KA1 and KB1, which were specific for ALC1 and for both ALC1 and ventricular myosin light chain 1, respectively. The serum ALC1 levels of healthy subjects were 0.28 +/- 0.14 ng/ml (mean +/- SD). The tissue ALC1 levels of normal adult human atria were much higher than those of ventricles (p < 0.01, 2,120 +/- 1,200 in right atria, 2,180 +/- 1,450 in left atria vs. 36.0 +/- 20.2 in right ventricles, 37.7 +/- 15.3 in left ventricles, ng/mg of proteins). The tissue ALC1 levels of ventricular aneurysms were significantly higher than those of normal ventricles (p < 0.01, 206.7 +/- 101.8). These results indicate that ALC1 is augmented in aneurysms and that the EIA provides a useful tool to investigate the roles of ALC1.

[The expression of atrial natriuretic peptide in the cardiomyocytes of left ventricular aneurysms]. / Expresión del péptido natriurético auricular en los cardiomiocitos de aneurismas de ventrículo izquierdo.

We report three patients with left ventricular aneurysm who underwent coronary artery bypass grafting and resection of the ventricular aneurysm. The walls of the aneurysms were immunohistochemically investigated to study whether atrial natriuretic peptide was present or not. Immunoreactivity for atrial natriuretic peptide was observed in some of the viable cardiomyocytes within the scar tissue. Mechanisms of regulation of the expression of atrial natriuretic peptide are discussed.

Physical overdistension converts ventricular cardiomyocytes to acquire endocrine property and regulate ventricular atrial natriuretic peptide production.

Atrial natriuretic peptide (ANP) is present in adult atria but at very low concentrations in normal adult mammalian ventricles. In the atria, the production of ANP is regulated by physical distension of the atrial wall. The same phenomenon was investigated in the ventricles of rats and men. Cardiac tissues from human ventricular aneurysm (n = 5), spontaneously hypertensive rats (n = 30), and rats that had overloaded left ventricles induced by surgery (n = 84) were studied with the methods of light microscopic immunocytochemistry, electron microscopic immunogold staining, and RNA-RNA tissue in situ hybridization. It was found that the levels of ANP gene expression, ANP immunoreactivity, and ANP-containing specific granules in the overburdened ventricles were elevated and their degrees of fluctuation were directly proportional to the force of physical distension applied to the ventricular cardiomyocytes. In rats, ANP mRNA and ANP immunoreactivity returned to the control level seven days after the ventricular overload was surgically released. The changes of ANP and its mRNA in the ventricles were related more closely to the changes of intraventricular pressure than to cardiocytic hypertrophy. In addition, ANP immunoreactivity was demonstrated in Purkinje cells and periarteriolar cardiomyocytes in the ventricles of normotensive rats. In conclusion, physical overstretch of the ventricle wall is likely to be the triggering factor affecting ventricular cardiomyocytes to acquire endocrine property, and also to regulate the production of ventricular ANP, thereby contributing to the control of the blood volume and the blood pressure.

Localized endocrine conversion of ventricular cardiocytes in ventricular aneurysm.

Atrial natriuretic peptide (ANP) is synthesized and stored in the atria of the heart, but not or at very low concentrations in the ventricles. We investigated the occurrence of ANP and its messenger RNA (mRNA) in human ventricular aneurysm where the cardiocytes were physically over-stretched. The techniques of light and electron microscopic immunocytochemistry, and RNA-RNA tissue in situ hybridization were employed. A large amount of ANP immunoreactivity was found in the cytoplasm of the cardiocytes in and around the aneurysm, but not in fibrous scar tissue or in the normal ventricles. Immunoelectron microscopy localized the immunoreactivity mainly to specific secretory granules in the cytoplasm of the cardiocytes. ANP mRNA was also detected in these cardiocytes. The abundance of both was much higher than that found in the hypertrophic ventricles of other types. The highest concentration of ANP immunoreactivity and of ANP mRNA was found in the cardiocytes located at the border zone. The quantities of both ANP and its mRNA decreased in cardiocytes more distant from the lesion. Our findings suggest that human ventricular cardiocytes in and around aneurysm can convert to produce large amounts of the endocrine peptide ANP. This ventricular endocrine conversion was localized and was probably caused by physical over-stretch of the cardiocytes.

[Fibronectin and fibrinogen/fibrin at the focus of an experimental myocardial infarct]. / Fibronektin i fibrinogen/fibrin v ochage éksperimental'nogo infarkta miokarda.

The content of fibrinogen/fibrin, plasma and cellular fibronectin, the 1st type collagen, laminin and skeletal muscle myosin in the zone of experimental myocardial infarction was studied by the immunofluorescent method. The infiltration of the necrotized cardiomyocytes with fibrinogen/fibrin and plasma fibronectin was observed 3 hours and later after coronary artery ligation. Fibrinogen/fibrin and plasma fibronectin form a "primary matrix" of the granulation tissue in which the fibers of the 1st type collagen are being formed. Cellular fibronectin starts to be synthesized 3 days after the infarct development and its content in the extracellular matrix (ECM) of the granulation tissue increases 7-15 days after the infarction. The amount of the fibronectin in ECM of the scar tissue decreases 30 days after the infarct. Fibrinogen/fibrin is always found in the granulation tissue replacing the myocardial infarction but its content in ECM decreases during the scar formation.

Alterations in norepinephrine content and beta adrenoceptor regulation in myocardium bordering aneurysm in human heart: their possible role in the genesis of ventricular tachycardia.

On the assumption that alterations in the adrenergic system may play a role in generating ventricular tachycardia in patients with myocardial post-infarction apical aneurysm, we evaluated norepinephrine concentration, number and affinity of both beta 1 and beta 2 adrenoceptors in perianeurysmatic tissue in twelve patients operated upon for congestive heart failure and recurrent sustained ventricular tachycardia. Concentration of norepinephrine in perianeurysmatic tissue was 0.1 +/- 0.05 micrograms g-1 tissue (n = 8), this value being much lower than that found in papillary muscle (n = 10) from patients with mitral valve stenosis (0.8 +/- 0.02 micrograms g-1 tissue) (P less than 0.01). The total number of beta adrenoceptors (71.4 +/- 7.8 v. 48.0 +/- 5.1 fmol mg-1 protein; P less than 0.01) and the percentage of beta 1 subtype were found to be higher in perianeurysmatic tissue (approximately 90%) than in papillary muscle (approximately 68%). Out of twelve patients with aneurysm, beta 2 adrenoceptors had considerably decreased in three patients and were absent in the remaining nine. Decrease in the neuronally released norepinephrine associated with contrasting behaviours of beta 1 and beta 2 adrenoceptors suggests the presence of a profound alteration in the sympathetic innervation of the perianeurysmatic myocardial tissue that may contribute to the genesis of sustained ventricular tachycardia in patients with postinfarction apical aneurysm.

[Changes in the activity of cytoplasmic enzymes and myoglobin in muscle cells of postinfarction aneurysm of the human myocardium]. / Kharakter izmenenii aktivnosti tsitoplazmaticheskikh fermentov i mioglobina v myshechnykh kletkakh postinfarktnoi anevrizmy miokarda cheloveka.

Enzymatic sprectra were studied in myocytes of human heart aneurysm as compared with the muscle cells of intact myocardium. Activities of G-6-PDH and AK as well as content of myoglobin were increased. Activity of the other enzymes studied (CPK, AsAT, IDH, MDH, LDH, PPK) was unaltered. Alterations, specific only for the muscle cells, were detected using a new calculation technique--comparison of relative (based on creatine) concentrations of myoglobin and the enzymatic activities in aneurysm and intact myocardium.