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Growth hormone prolongs survival in experimental postinfarction heart failure

Antonio Cittadini, MD^*, J.örgen Isgaard, MD, Maria Gaia Monti, PhD^*, Cosma Casaburi, MD^*, Angela Di Gianni, MD^*, Raffaella Serpico, MD^*, Guido Iaccarino, MD^* and Luigi Saccà, MD^*,*

^* Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy
Research Center for Endocrinology and Metabolism, Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

View larger version (12K): [in a new window]   Figure 1 Kaplan-Meier curves in rats with myocardial infarction treated with placebo or growth hormone (GH). Thirteen-month mean survival time was 267 and 323 days in placebo and GH-treated rats, respectively.

View larger version (98K): [in a new window]   Figure 2 Collagen content and morphology in remote zones from infarction in placebo (left column) and growth hormone (GH)-treated rats (right column), picrosirius red staining. In the placebo group (A), collagen fibers (in red) appear shorter and thicker than in the GH group (B). Compared with panel D, panel C exhibits a marked deposition of collagen fibers that encapsulate cardiomyocytes and fill the interstitial gaps. Panels E and F show collagen I antibody stain in the placebo and GH groups, respectively. In panels G and H collagen I appears red-yellowish, whereas collagen III appears green under polarized light. Collagen III is substantially reduced in panel G (placebo) compared with panel H (GH). Collagen I is the major component of thick and short collagen fibers in panel G and of long and thin fibers in panel H, where also a weak collagen III network can be appreciated. Bar = 20 µm.

View larger version (111K): [in a new window]   Figure 3 Collagen morphology in infarcted areas from placebo (left) and growth hormone (GH)-treated rats (right). Panels A and B depict picrosirius red staining observed under white light. Note that the placebo group (A and C) exhibits disarrayed collagen deposition, whereas in GH group (B and D) the collagen network appears better preserved, with collagen scar fibers organized in parallel bundles. In both groups, scars are mainly made of collagen I fibers, as shown under polarized light microphotographs. Bar = 20 µm.

View larger version (21K): [in a new window]   Figure 4 Prevalence of cardiomyocyte apoptosis in the two study groups as measured by terminal deoxynucleotidyl transferase (TdT) and hairpin assays. The apoptotic index was assessed as described in Methods and yielded similar results with the two techniques. *p < 0.05 vs. placebo group. GH = growth hormone.

View larger version (80K): [in a new window]   Figure 5 Cardiomyocyte apoptosis in remote areas from infarction observed under fluorescent light. Panels A, B, and F depict representative triple staining obtained in the same microscopic fields from a growth hormone (GH)-treated rat euthanized at one month. Panel A shows cardiomyocyte and non-cardiomyocyte nuclei stained with DAPI. Panel B depicts cardiomyocyte immunostained with anti-sarcomeric actin. Panels C to F depict detection of terminal UTP nick end labeling (TUNEL)-positive cardiomyocyte nuclei. Panels C and D are representative images from placebo and GH group, respectively, after the 13-month observation period. Panels E and F are representative images from placebo and GH rats, respectively, euthanized at one month. Note the higher percentage of positive nuclei in the placebo-treated animals. Panel G: Immunostaining for activated caspase-3 antibody. Panel H: Double-exposure photomicrograph of dual labeled cardiomyocytes for activated caspase-3 (red signal) and TUNEL. Note the co-localization of caspase activity and TUNEL-positivity in the same cardiomyocyte. Overlapped signals result in yellow fluorescence. Bars = 20 µm.

View larger version (15K): [in a new window]   Figure 6 Detection of apoptosis in cardiomyocyte nuclei of left ventricular area remote from infarction by hairpin probe. The oligo was recognized by a streptavidin fluorescin conjugate. Panels A and B are representative images from the placebo and the growth hormone (GH) group, respectively, after the 13-month observation period. Panels C and D are representative images from placebo and GH rats euthanized soon after the active treatment period (1 month). Bar = 20 µm.