Figure 1
Pulmonary artery pressures were elevated in sickle mice and associated with decreasing cardiac output and right-heart failure with advancing age. (A) Elevated pulmonary artery pressures in younger sickle mice (3 to 5 months old, n = 7) were associated with normal right atrial pressures. (B) Elevated cardiac output in younger sickle mice contrasted with low cardiac output in older sickle mice (13 to 15 months old, n = 4). (C) The Fulton ratio of ventricular weights (right ventricle–left ventricle including septum) indicated disproportionately heavier right ventricles in sickle mice than in hemizygous controls (n = 11 and 16, respectively). Hearts were excised and sectioned using the method of Fulton55,56 from younger mice not used for other cardiac studies. (D) Thoracic micro-CT of the hemizygous control in vivo demonstrated normal heart size, lung vasculature, and lung aeration. (E) CT in vivo of the sickle mouse at the same axial level showed an enlarged heart. Lungs were very similar to normal, except for dilated pulmonary vessels and mildly increased attenuation with a speckled pattern consistent with perfusion heterogeneity (n = 11). (F) Hemizygous control mouse lung histology at low magnification had normal lung parenchyma and vascularity and (G) at high magnification demonstrated normal thin alveolar capillaries. (H) Sickle mouse lung histology at low magnification confirmed the radiologic findings of dilated pulmonary vessels and patchy vascular congestion. However, pulmonary arterial walls were not significantly thickened, and no plexiform lesions were observed. (I) Histology at high magnification showed engorged alveolar capillaries. No sickle mouse of any age had intra-alveolar edema, fat and/or bone marrow emboli, thromboemboli, pulmonary infarcts, or significant interstitial fibrosis. *P < .05 versus age-matched hemizygous control. ***P < .001 versus age-matched hemizygous control. CT scans (panels D-E) acquired by MicroCAT II (Imtek, Knoxville, TN) were processed by image analysis software (Amira 3.0, TGS Inc, San Diego, CA) and formatted using Adobe Photoshop (Adobe Systems, San Jose, CA). Photomicrographs of lung sections stained with hematoxylin and eosin (panels F-I) were visualized using an Olympus IX70 microscope equipped with UPlanFl 10×/0.30 numerical aperture (NA) and LCPlanFl 40×/0.60 NA PH2 objective lenses (Olympus, Melville, NY); images were acquired by Spot Flex digital camera (Spot Diagnostic Instruments, Sterling Heights, MI) with Spot 3.02 application software, and were formatted using Adobe Photoshop (Adobe Systems, San Jose, CA) and ImageJ software (National Institutes of Health, Bethesda, MD).

Pulmonary artery pressures were elevated in sickle mice and associated with decreasing cardiac output and right-heart failure with advancing age. (A) Elevated pulmonary artery pressures in younger sickle mice (3 to 5 months old, n = 7) were associated with normal right atrial pressures. (B) Elevated cardiac output in younger sickle mice contrasted with low cardiac output in older sickle mice (13 to 15 months old, n = 4). (C) The Fulton ratio of ventricular weights (right ventricle–left ventricle including septum) indicated disproportionately heavier right ventricles in sickle mice than in hemizygous controls (n = 11 and 16, respectively). Hearts were excised and sectioned using the method of Fulton55,56  from younger mice not used for other cardiac studies. (D) Thoracic micro-CT of the hemizygous control in vivo demonstrated normal heart size, lung vasculature, and lung aeration. (E) CT in vivo of the sickle mouse at the same axial level showed an enlarged heart. Lungs were very similar to normal, except for dilated pulmonary vessels and mildly increased attenuation with a speckled pattern consistent with perfusion heterogeneity (n = 11). (F) Hemizygous control mouse lung histology at low magnification had normal lung parenchyma and vascularity and (G) at high magnification demonstrated normal thin alveolar capillaries. (H) Sickle mouse lung histology at low magnification confirmed the radiologic findings of dilated pulmonary vessels and patchy vascular congestion. However, pulmonary arterial walls were not significantly thickened, and no plexiform lesions were observed. (I) Histology at high magnification showed engorged alveolar capillaries. No sickle mouse of any age had intra-alveolar edema, fat and/or bone marrow emboli, thromboemboli, pulmonary infarcts, or significant interstitial fibrosis. *P < .05 versus age-matched hemizygous control. ***P < .001 versus age-matched hemizygous control. CT scans (panels D-E) acquired by MicroCAT II (Imtek, Knoxville, TN) were processed by image analysis software (Amira 3.0, TGS Inc, San Diego, CA) and formatted using Adobe Photoshop (Adobe Systems, San Jose, CA). Photomicrographs of lung sections stained with hematoxylin and eosin (panels F-I) were visualized using an Olympus IX70 microscope equipped with UPlanFl 10×/0.30 numerical aperture (NA) and LCPlanFl 40×/0.60 NA PH2 objective lenses (Olympus, Melville, NY); images were acquired by Spot Flex digital camera (Spot Diagnostic Instruments, Sterling Heights, MI) with Spot 3.02 application software, and were formatted using Adobe Photoshop (Adobe Systems, San Jose, CA) and ImageJ software (National Institutes of Health, Bethesda, MD).

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