| 1. |
- Tivesten, Åsa, 1969, et al.
(author)
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Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice.
- 2002
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In: Endocrinology. - 0013-7227. ; 143:11, s. 4235-42
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Journal article (peer-reviewed)abstract
- IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I-/- mice than in control mice. LI-IGF-I-/- mice showed impaired acetylcholine-induced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I-/- mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice.
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| 2. |
- Bollano, Entela, 1970, et al.
(author)
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Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure.
- 2003
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In: Heart (British Cardiac Society). - 1468-201X. ; 89:6, s. 621-4
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Journal article (peer-reviewed)abstract
- To determine whether patients with congestive heart failure on different beta adrenoreceptor blocking drugs have similar haemodynamic responses to dobutamine.Single centre, single blind, randomised, two period crossover study comparing carvedilol with metoprolol CR/XL.Ten patients with stable chronic congestive heart failure (ejection fraction < 40%) on chronic treatment with metoprolol CR/XL.Patients were treated with carvedilol or metoprolol CR/XL (target dose 50 mg twice daily and 200 mg once daily, respectively) for eight weeks. Stress echocardiography was undertaken at the end of each maintenance period, using dobutamine 5 and 15 microg/kg/min.No significant haemodynamic differences were seen at rest on the two treatments. There was a more pronounced increase in heart rate and cardiac output during dobutamine infusion when the patients were on metoprolol than when they were on carvedilol. Mean arterial pressure increased significantly when the patients were on carvedilol, and cardiac output increased during low dose dobutamine, without further change during high dose dobutamine. During the dobutamine infusion, there was no significant difference in ejection fraction between carvedilol and metoprolol treatment.Patients with congestive heart failure on a non-selective beta adrenoreceptor blocker or beta1 selective blocker responded differently to the inotropic drug dobutamine: the beta1 blockade caused by metoprolol could be counteracted by dobutamine, whereas with carvedilol a low dose of dobutamine increased cardiac output, and a higher dose of dobutamine caused a pressor effect. These findings may be clinically relevant when choosing an inotropic drug.
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| 3. |
- Bollano, Entela, 1970, et al.
(author)
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Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene.
- 2000
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In: Endocrinology. - 0013-7227. ; 141:6, s. 2229-35
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Journal article (peer-reviewed)abstract
- Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.
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| 4. |
- Bollano, Entela, 1970
(author)
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Structural, functional and metabolic effects of growth hormone on nomal and failing heart
- 2001
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Doctoral thesis (other academic/artistic)abstract
- The growth hormone/insulin-like growth factor I (GH/IGF-I) system plays an important role for cardiac development, structure and function. Recently, data from experimental and clinical studies have suggested the use of GH as treatment after myocardial infarction (MI) affecting cardiac remodeling and development of heart failureThe aim of this thesis was to study the effects of GH on cardiac structure, function and energy metabolism in normal and failing heart.To evaluate the effect of GH treatment on left ventricular (LV) remodeling, we used different experimental models: a rat model of experimental MI, hypophysectomised (hx) rats and transgenic mice overexpressing bovine GH (bGH). Transthoracic echocardiography and 31P magnetic resonance spectroscopy, were used to evaluate geometry, systolic and diastolic function as well as energy metabolism of LV in vivo. Biochemical analysis including high pressure liquid chromatography and histological evaluation were also performed.Three days after MI, LV internal diameter increased significantly compared with control rats. Systolic and diastolic indexes of LV function were significantly deteriorated after MI. Three weeks later a further dilatation of LV and a more spherical shape were observed in MI rats. Phosphocreatine (PCr) to ATP ratio was significantly lower in MI rats three days and three weeks after MI. Short term (9 days) treatment with GH alone or in combination with metoprolol preserved the LV systolic function after MI, whereas three weeks treatment with GH after MI preserved systolic function and attenuated the remodeling. Plasma and myocardium tissue of catecholamines and brain natriuretic peptide levels were significantly decreased after GH treatment. Moreover, three weeks treatment with GH normalized PCr/ATP in MI rats.GH administration in hx rat increase body weight, heart weight, improved LV performance and myocardial energy metabolism. In transgenic bGH mice, hypertrophy of LV with poor systolic performance was observed. Moreover, a decrease in PCr/ATP ratios associated with qualitative changes on mitochondrial structure was detected in LV from bGH mice. GH plays an important role for the maintenance of normal cardiac structure, function and myocardial energy metabolism. Short term treatment with GH after MI attenuated the LV remodeling, preserved systolic function, improved myocardial bioenergetics and decreased neurohormonal activation. Long term exposures to high levels of GH leads to cardiac hypertrophy, poor performance and decreased energy reserve.
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| 5. |
- Omerovic, Elmir, 1968, et al.
(author)
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Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.
- 2000
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In: Endocrinology. - 0013-7227. ; 141:12, s. 4592-9
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Journal article (peer-reviewed)abstract
- The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.
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| 6. |
- Omerovic, Elmir, 1968, et al.
(author)
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Growth hormone induces myocardial expression of creatine transporter and decreases plasma levels of IL-1beta in rats during early postinfarct cardiac remodeling.
- 2003
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In: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 13:5, s. 239-45
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Journal article (peer-reviewed)abstract
- Growth hormone has been proposed as a potential new therapeutic agent for treatment of myocardial infarction (MI) and congestive heart failure (CHF). The purpose of this study was to evaluate the effects of GH on: (a) myocardial expression of creatine transporter (CreaT) during early postinfarct remodeling, (b) myocardial levels of total creatine (TCr) and adenine pool (TAN) and (c) plasma levels of inflammatory cytokines interleukin-1beta (IL-1beta), tumor-necrosis-factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rat model of postinfarct cardiac remodeling. Myocardial infarction (MI) was induced by ligation of the left coronary artery in male Sprague-Dawley rats (200-250 g). Three different groups were studied: MI rats treated with GH (n=11) (3 mg/kg/day), MI rats treated with saline (n=10), and sham operated rats (n=7). In the myocardium from GH treated rats the level of mRNA CreaT expression was significantly increased (p<0.01). There was no difference in TCr between the rats with MI and sham-operated rats. Treatment with GH had no effect on TCr. GH had no effect on TAN in left ventricle. All three groups had similar levels of IL-6 and TNF-alpha in plasma. In the rats with MI, treatment with GH normalized the levels of IL-1beta (p<0.05). In conclusion GH increased the expression of CreaT and decreased levels of plasma IL-1beta during postinfarct remodeling in rats. These mechanisms may be responsible for the previously reported beneficial effects of GH on myocardial energy metabolism and preservation of cardiac function in the settings of postinfarct remodeling and CHF.
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| 7. |
- Omerovic, Elmir, 1968, et al.
(author)
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Induction of cardiomyopathy in severe combined immunodeficiency mice by transfer of lymphocytes from patients with idiopathic dilated cardiomyopathy.
- 2000
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In: Autoimmunity. - 0891-6934. ; 32:4, s. 271-80
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Journal article (peer-reviewed)abstract
- Growing evidence suggests that autoimmune mechanisms play an important role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The aim of the study was to evaluate the effects of transfer of lymphocytes from patients with DCM into severe combined immunodeficiency (SCID) mice on the heart structure and function. Thirty CB-17 SCID (6-8 weeks old) mice were used and divided into 3 groups (n = 10). Mice were injected intraperitoneally with up to 25 x 10(6) peripheral blood lymphocytes (PBL) from either patients with DCM which contain human autoantibodies against cardiac beta1-adrenergic receptors and M2-muscarinic receptors (DCM group) or PBL from healthy controls (control-H group). Ten mice did not receive any injections and were used as baseline controls (control-N group). Echocardiography and morphological studies were performed seventy five days after the transfer. Results showed that in DCM group, left ventricle dimensions (LVD) in diastole were increased (4.2 +/- 0.1mm) as compared to both control-H group (3.8 +/- 0.1mm) and control-N group (3.6 +/- 0.1 mm) (p < 0.01). Further, there was a trend for increased LVD in systole. Fractional shortening was not different between groups. Histological evaluation revealed accumulation of human lymphocytes in the capillaries and scarce infiltration of the lymphocytes in the hearts from DCM group. Diffuse fibrosis was significant increased in DCM mice as compared to mice receiving PBL from normal subjects (2.2 +/- 0.3% vs. 0.8 +/- 0.1%, p < 0.01). In conclusion, transfer of the PBL from the patients with DCM was able to induce early stage of heart dilatation in SCID mice. These data provide for the first time the direct evidence supporting that the autoimmune mechanism is important in the pathogenesis of human DCM.
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