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Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction.

Lichtenauer M, Mildner M, Baumgartner A, Hasun M, Werba G, Beer L, Altmann P, Roth G, Gyöngyösi M, Podesser BK, Ankersmit HJ - Basic Res. Cardiol. (2011)

Bottom Line: A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells.Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue.The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University Vienna, Währinger Gürtel 18-20, Vienna, Austria.

ABSTRACT
Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

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Results of in vivo rat experiments after 6 weeks. a Hearts of apoptotic cell injected animals explanted 6 weeks after LAD ligation evidence less myocardial damage compared to controls. Hearts from medium or viable cell injected animals appear more dilated and show a greater extension of fibrotic tissue. b Statistical analysis of data obtained from planimetric evaluation of specimens collected 6 weeks after LAD ligation shows a mean scar extension of 25% in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC. c–e Results obtained by echocardiography 6 weeks after AMI (shortening fraction; left ventricular enddiastolic diameter, LVEDD; left ventricular endsystolic diameter, LVESD). Functional parameters were improved in comparison to medium or viable cell injected animals
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Fig2: Results of in vivo rat experiments after 6 weeks. a Hearts of apoptotic cell injected animals explanted 6 weeks after LAD ligation evidence less myocardial damage compared to controls. Hearts from medium or viable cell injected animals appear more dilated and show a greater extension of fibrotic tissue. b Statistical analysis of data obtained from planimetric evaluation of specimens collected 6 weeks after LAD ligation shows a mean scar extension of 25% in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC. c–e Results obtained by echocardiography 6 weeks after AMI (shortening fraction; left ventricular enddiastolic diameter, LVEDD; left ventricular endsystolic diameter, LVESD). Functional parameters were improved in comparison to medium or viable cell injected animals

Mentions: Cardiac tissue specimens obtained 6 weeks after ligation of the LAD and stained according to the Elastica van Gieson protocol showed that hearts from rats injected with apoptotic PBMC suspensions showed a highly significant reduction of infarction area. Figure 3a shows representative images which evidence that rats treated with apoptotic cells demonstrate a significantly greater extent of viable myocardium within the anterior free wall of the left ventricle. In contrast, collagen deposition and scar formation extended through almost the entire left ventricular wall thickness in rats receiving control medium. Compared to controls and viable injected animals the left ventricular geometry was almost completely preserved in rats treated with irradiated apoptotic cell suspensions. The area of fibrosis as calculated by planimetry was 25% (percent of the left ventricle) in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC suspensions (p < 0.01 vs. controls, p < 0.05 vs. viable cell injected animals, n = 10–12 per group) (Fig. 2a,b).Fig. 2


Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction.

Lichtenauer M, Mildner M, Baumgartner A, Hasun M, Werba G, Beer L, Altmann P, Roth G, Gyöngyösi M, Podesser BK, Ankersmit HJ - Basic Res. Cardiol. (2011)

Results of in vivo rat experiments after 6 weeks. a Hearts of apoptotic cell injected animals explanted 6 weeks after LAD ligation evidence less myocardial damage compared to controls. Hearts from medium or viable cell injected animals appear more dilated and show a greater extension of fibrotic tissue. b Statistical analysis of data obtained from planimetric evaluation of specimens collected 6 weeks after LAD ligation shows a mean scar extension of 25% in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC. c–e Results obtained by echocardiography 6 weeks after AMI (shortening fraction; left ventricular enddiastolic diameter, LVEDD; left ventricular endsystolic diameter, LVESD). Functional parameters were improved in comparison to medium or viable cell injected animals
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105227&req=5

Fig2: Results of in vivo rat experiments after 6 weeks. a Hearts of apoptotic cell injected animals explanted 6 weeks after LAD ligation evidence less myocardial damage compared to controls. Hearts from medium or viable cell injected animals appear more dilated and show a greater extension of fibrotic tissue. b Statistical analysis of data obtained from planimetric evaluation of specimens collected 6 weeks after LAD ligation shows a mean scar extension of 25% in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC. c–e Results obtained by echocardiography 6 weeks after AMI (shortening fraction; left ventricular enddiastolic diameter, LVEDD; left ventricular endsystolic diameter, LVESD). Functional parameters were improved in comparison to medium or viable cell injected animals
Mentions: Cardiac tissue specimens obtained 6 weeks after ligation of the LAD and stained according to the Elastica van Gieson protocol showed that hearts from rats injected with apoptotic PBMC suspensions showed a highly significant reduction of infarction area. Figure 3a shows representative images which evidence that rats treated with apoptotic cells demonstrate a significantly greater extent of viable myocardium within the anterior free wall of the left ventricle. In contrast, collagen deposition and scar formation extended through almost the entire left ventricular wall thickness in rats receiving control medium. Compared to controls and viable injected animals the left ventricular geometry was almost completely preserved in rats treated with irradiated apoptotic cell suspensions. The area of fibrosis as calculated by planimetry was 25% (percent of the left ventricle) in medium injected controls, 14% in viable cell injected animals compared to 6% (IV) and 8% (IM) in rats treated with apoptotic PBMC suspensions (p < 0.01 vs. controls, p < 0.05 vs. viable cell injected animals, n = 10–12 per group) (Fig. 2a,b).Fig. 2

Bottom Line: A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells.Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue.The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University Vienna, Währinger Gürtel 18-20, Vienna, Austria.

ABSTRACT
Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

Show MeSH
Related in: MedlinePlus