. GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure. Am J Physiol Heart Circ Physiol 289: H1643-H1651, 2005. First published June 10, 2005; doi:10.1152/ajpheart.01042.2004.-Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 g/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.

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Earlier studies showed that melatonin reduced the growth of 17-beta-estradiol (E(2))-induced rat pituitary prolactin-secreting tumor (prolactinoma) in vivo. The mechanisms of melatonin's inhibitory action on the prolactin-secreting tumor were further explored by investigating the in vitro effects of melatonin on the growth of pituitary prolactin-secreting tumor cells. Primary cultured prolactinoma cells from E(2)-induced rat pituitary prolactin-secreting tumor were treated with 10(-5), 10(-4) or 10(-3) m melatonin for 5 days. Apoptosis was evaluated using flow cytometry and the TdT-mediated dUTP nick-end labeling (TUNEL) method. In addition, cell viability was analyzed by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. It was found that incubation of prolactinoma cells with 10(-5), 10(-4) or 10(-3) m melatonin for 5 days inhibited cell growth and increased cell apoptosis. Furthermore, melatonin increased caspase-3 activity, Bax mRNA expression, and cytochrome c protein expression. Conversely, Bcl-2 mRNA expression and mitochondrial membrane potential were inhibited by melatonin treatment. Our results further suggest that melatonin inhibits tumor growth by inducing apoptosis of rat pituitary prolactin-secreting tumor directly via the damage of mitochondria.

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Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

Background: Native T1 mapping is an emerging cardiac magnetic resonance technique for quantitative evaluation of cardiomyopathies. This study aimed to investigate the usefulness of native T1 mapping in characterizing myocardial abnormalities in left ventricular non-compaction (LVNC) by comparing it with late gadolinium enhancement (LGE). Methods and Results:The study group of 31 LVNC patients and 8 normal controls underwent cardiovascular magnetic resonance to acquire the native T1 maps and LGE images. Of the 31 LVNC patients, 14 had LGE. The mean native T1 value of the normal controls, LGE(−) and LGE(+) patients was 1,098.8±40.8 ms, 1140.6±32.8 ms, and 1181.4±53.7 ms, respectively. Significant differences were found in native T1 between any 2 groups (F=9.74, P<0.001). In discriminating the presence of LGE in LVNC patients, the odds ratio and corresponding 95% confidence interval (CI) of native T1 were, respectively, 2.966 (95% CI: 1.123-7.835, P=0.028) and 4.348 (95% CI: 1.155-16.363, P=0.030) before and after adjusting for confounding factors with an increment of 1 standard deviation. Conclusions:The finding that LGE(−) patients had elevated native T1 compared with normal controls suggested native T1 mapping can be used earlier than LGE imaging to detect myocardial fibrosis in LVNC patients. Furthermore, higher native T1 values in LGE(+) patients than in the LGE(−) group suggested native T1 mapping is more sensitive than LGE imaging for identifying myocardial fibrosis in LVNC patients. 1211 Native T1 Mapping Evaluates Myocardium Abnormality factors for cardiac disease (diabetes mellitus, hypertension, and smoking) were enrolled as normal controls. The age and sex of the normal volunteers were matched with the LVNC patient group. Clinical information was collected from the medical record. The study protocol was approved by the local Institutional review board and written informed consent was given by all subjects. CMR ProtocolThe CMR imaging was performed with a 3.0-T MR system (Achieva TX, Philips Healthcare, Best, The Netherlands) using a 32-channel phased array heart coil (InVivo, Gainesville, FL, USA). The cine, phase-sensitive inversion recovery (PSIR), and modified look-locker inversion recovery (MOLLI) image sequences were acquired. 16 The ECG-gated balanced steadystate free precession (bSSFP) cine images of the long-and short-axis (SAX) images covering the entire LV were acquired with the following parameters: TR/TE 2.7/1.3 ms with 30 heart phases; voxel size 1.8×1.5×8.0 mm 3 ; slice thickness 8 mm; and slice spacing 2 mm. The PSIR sequence was acquired 15±5 min after the injection of 0.2 mmol/kg of gadolinium-DTPA (Magnetism, Bayer Schering Pharma, Guangzhou, China) with flow rate of 3 ml/s and 20 ml saline for flushing. The LGE images were obtained during mid-diastole in the same SAX orientations as cine, covering the whole LV, with the following imaging

To compare magnetic resonance (MR) imaging, computed tomography (CT) and radiography for the detection of arthropathies in patients with haemophilia. Forty-one symptomatic joints in 14 men with haemophilia, ages 11-24 years (mean age 17.5 +/- 3.9 years) were examined with radiography, CT and MR. Images of each joint were acquired on the same day. The precontrast MR examination obtained coronal spin-echo T1 images and gradient echo with rephasing T2* images, as well as sagittal, axial gradient echo with rephasing T2* images using a low-field-strength 0.3-T MR imager. For the postcontrast MR examination, coronal, sagittal and axial images were acquired using the same precontrast T1 sequence. Thirteen joints were also examined on enhanced MR. The severity of damage was classified using conventional radiographical staging. Severely affected haemophilic arthropathy (HA) patients (stage 5) were excluded. Findings of soft tissue swelling, osteoporosis, epiphyseal overgrowth, joint erosion, cysts, joint space narrowing, bone marrow oedema, joint effusion, haemorrhage, synovial hypertrophy and widened intercondylar notches as well as anterior and posterior cruciate ligaments (for the knee) were used in all imaging comparisons. The joints were classified by radiographical criteria into stage 0 (n = 5), stage 1 (n = 7), stage 2 (n = 6), stage 3 (n = 8) and stage 4 (n = 15). Soft tissue swelling or joint effusion was observed in 33 joints on radiographs, in 34 on both CT and MR; joint erosions were observed in 34 joints on MR, 33 on CT and 20 on radiographs. Joint cysts appeared in 21 joints on MR, 18 on CT and 9 on radiographs. Significant differences in detection of erosion and cysts were found between radiography and CT (P < 0.05) and radiography and MR imaging (P < 0.05), not between CT and MR (P > 0.05). MR was better for detecting foci of both erosion and cysts than CT and radiography, and CT was better than radiography. MR imaging, CT and radiography were equally effective in showing the changes of epiphyseal overgrowth in 26 joints, joint space narrowing in 14 joints and widened intercondylar notches in 20 knee joints. However, only MR imaging detected tears in 17 anterior and 13 posterior cruciate ligaments in the 20 knee joints with widened intercondylar notches. Bone marrow oedema in 14 joints, haemorrhage in 34 joints and synovial hypertrophy in 27 joints were seen on MR images, but not on CT or radiography. MR imaging is superior to CT and conventional radiography for detecting abnormal changes and should be considered the first choice among imaging modalities in evaluating HAs.