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Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences.

Tintu A, Rouwet E, Verlohren S, Brinkmann J, Ahmad S, Crispi F, van Bilsen M, Carmeliet P, Staff AC, Tjwa M, Cetin I, Gratacos E, Hernandez-Andrade E, Hofstra L, Jacobs M, Lamers WH, Morano I, Safak E, Ahmed A, le Noble F - PLoS ONE (2009)

Bottom Line: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis.Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass.This cardiomyopathy persists into adulthood.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.

ABSTRACT

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.

Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.

Principal findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.

Conclusions/significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

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Hypoxia-induced dilated cardiomyopathy persists in adult chickens.A and B, morphology of adult hearts showing LV dilatation in adult chickens prenatally exposed to hypoxia (P-H) compared with adult chickens prenatally exposed to normoxia (P-N). C to E, trichrome Masson staining of left ventricular myocardium of adult chickens showing increased interstitial collagen deposition in hearts from adult animals prenatally exposed to hypoxia, both n = 6. Collagen content is significantly higher in hypoxic hearts (E). F, generated LV contractility was lower in muscle bundles from P-H animals. G, relaxation properties of LV muscle bundles isolated from adult chicken hearts. The time to 50% relaxation in response to increasing calcium concentrations is significantly prolonged in P-H animals, n = 7 in each group. Data are shown as mean±SE; * P<0.05, ** P<0.01 P-H versus P-N.
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pone-0005155-g005: Hypoxia-induced dilated cardiomyopathy persists in adult chickens.A and B, morphology of adult hearts showing LV dilatation in adult chickens prenatally exposed to hypoxia (P-H) compared with adult chickens prenatally exposed to normoxia (P-N). C to E, trichrome Masson staining of left ventricular myocardium of adult chickens showing increased interstitial collagen deposition in hearts from adult animals prenatally exposed to hypoxia, both n = 6. Collagen content is significantly higher in hypoxic hearts (E). F, generated LV contractility was lower in muscle bundles from P-H animals. G, relaxation properties of LV muscle bundles isolated from adult chicken hearts. The time to 50% relaxation in response to increasing calcium concentrations is significantly prolonged in P-H animals, n = 7 in each group. Data are shown as mean±SE; * P<0.05, ** P<0.01 P-H versus P-N.

Mentions: Adult chickens that had been exposed to hypoxia during embryonic development displayed severe LV dilatation in later life (Figure 5A, B). LV cavity cross-sectional area was approximately 4-fold larger than that of adult hearts prenatally exposed to normoxia (18.6±1.3 mm2 versus 4.6±0.6 mm2; n = 7; P<0.05). LV dilatation was accompanied by increases in myocardial collagen content (Figure 5C–E). Both the contractile responses and relaxation times to increasing calcium concentrations were significantly impaired in isolated LV muscle bundles from chickens prenatally exposed to hypoxia (Figure 5F–G).


Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences.

Tintu A, Rouwet E, Verlohren S, Brinkmann J, Ahmad S, Crispi F, van Bilsen M, Carmeliet P, Staff AC, Tjwa M, Cetin I, Gratacos E, Hernandez-Andrade E, Hofstra L, Jacobs M, Lamers WH, Morano I, Safak E, Ahmed A, le Noble F - PLoS ONE (2009)

Hypoxia-induced dilated cardiomyopathy persists in adult chickens.A and B, morphology of adult hearts showing LV dilatation in adult chickens prenatally exposed to hypoxia (P-H) compared with adult chickens prenatally exposed to normoxia (P-N). C to E, trichrome Masson staining of left ventricular myocardium of adult chickens showing increased interstitial collagen deposition in hearts from adult animals prenatally exposed to hypoxia, both n = 6. Collagen content is significantly higher in hypoxic hearts (E). F, generated LV contractility was lower in muscle bundles from P-H animals. G, relaxation properties of LV muscle bundles isolated from adult chicken hearts. The time to 50% relaxation in response to increasing calcium concentrations is significantly prolonged in P-H animals, n = 7 in each group. Data are shown as mean±SE; * P<0.05, ** P<0.01 P-H versus P-N.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663815&req=5

pone-0005155-g005: Hypoxia-induced dilated cardiomyopathy persists in adult chickens.A and B, morphology of adult hearts showing LV dilatation in adult chickens prenatally exposed to hypoxia (P-H) compared with adult chickens prenatally exposed to normoxia (P-N). C to E, trichrome Masson staining of left ventricular myocardium of adult chickens showing increased interstitial collagen deposition in hearts from adult animals prenatally exposed to hypoxia, both n = 6. Collagen content is significantly higher in hypoxic hearts (E). F, generated LV contractility was lower in muscle bundles from P-H animals. G, relaxation properties of LV muscle bundles isolated from adult chicken hearts. The time to 50% relaxation in response to increasing calcium concentrations is significantly prolonged in P-H animals, n = 7 in each group. Data are shown as mean±SE; * P<0.05, ** P<0.01 P-H versus P-N.
Mentions: Adult chickens that had been exposed to hypoxia during embryonic development displayed severe LV dilatation in later life (Figure 5A, B). LV cavity cross-sectional area was approximately 4-fold larger than that of adult hearts prenatally exposed to normoxia (18.6±1.3 mm2 versus 4.6±0.6 mm2; n = 7; P<0.05). LV dilatation was accompanied by increases in myocardial collagen content (Figure 5C–E). Both the contractile responses and relaxation times to increasing calcium concentrations were significantly impaired in isolated LV muscle bundles from chickens prenatally exposed to hypoxia (Figure 5F–G).

Bottom Line: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis.Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass.This cardiomyopathy persists into adulthood.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.

ABSTRACT

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.

Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.

Principal findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.

Conclusions/significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Show MeSH
Related in: MedlinePlus