Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1).

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular outcomes in patients with type 2 diabetes mellitus. However, systemic actions of these agents cause sympathetic activation, which is generally considered to be detrimental in cardiovascular disease. Despite significant research interest in cardiovascular biology of GLP-1, the presence of GLP-1R in ventricular cardiomyocytes remains a controversial issue, and the effects of this peptide on the electrical properties of intact ventricular myocardium are unknown. We sought to determine the effects of GLP-1R agonist exendin-4 (Ex4) on ventricular action potential duration (APD) and susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo. METHODS: Ventricular monophasic action potentials were recorded in anaesthetized (urethane) rats in vivo and isolated perfused rat hearts during sinus rhythm and ventricular pacing. RESULTS: In vivo, systemic administration of Ex4 (5 μg/kg intravenously) increased heart rate, and this effect was abolished by β-adrenoceptor blockade. Despite causing sympathetic activation, Ex4 increased APD at 90% repolarization during ventricular pacing by 7% ( P=0.044; n=6) and reversed the effect of β-adrenoceptor agonist dobutamine on APD at 90% repolarization. In isolated perfused hearts, Ex4 (3 nmol/L) increased APD at 90% repolarization by 14% ( P=0.015; n=6) with no effect on heart rate. Ex4 also reduced ventricular arrhythmia inducibility in conditions of β-adrenoceptor stimulation with isoproterenol. Ex4 effects on APD and ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase. CONCLUSIONS: These data demonstrate that GLP-1R activation effectively opposes the effects of β-adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential. The effect of GLP-1R activation on the ventricular myocardium is indirect, mediated by acetylcholine and nitric oxide and, therefore, can be explained by stimulation of cardiac parasympathetic (vagal) neurons.British Heart Foundation (RG/14/4/30736 to Drs Gourine and Tinker; RG/15/15/31742 to Dr Tinker), European Union’s Horizon 2020 research and innovation programme (Marie Skłodowska-Curie Grant No. 654691 to Dr Mastitskaya), Medical Research Council (MR/N02589X/1), and The National Institute for Health Research Barts Cardiovascular Biomedical Research Centre

Tumor size as prognostic factor in osteosarcomas

9061 Background: Multidisciplinary treatment of osteosarcoma has achieved overall survival greater than 70%. Several prognostic factors have been described. In our country it is frequent to diagnose voluminous tumors. Greater tumors usually have worst outcome because of greater chance of tumor resistance. In order to assess the relation between tumor size and prognosis in high-grade osteosarcoma, we performed the following analysis.METHODS: Retrospectively, tumor volume was determined pre and post chemotherapy in 40 patients with histological diagnosis of high-grade osteosarcoma stage IIb. All of them received neo-adjuvant chemotherapy (ifosfamide + doxorrubicin + high dose methotrexate). Tumor size was determined in plain radiography (RX) (2 dimensions) and magnetic resonance imaging (MRI) (3 dimensions), according to RECIST criteria. Tumor calcifications, pathological fracture and skip metastasis were evaluated.RESULTS: 22 men/18 women. Median age 17 years (range 11-47). Localizations: femur (25), tibia (9), fibula (3), humerus (2) and pelvis (1). Six patients presented pathological fracture and only one skip metastasis. 14 patients had systemic progression. Median survival was 96 months (IC 95%: 80-109) and median disease free survival was 84 months (IC 95%: 69-100). Tumor volume pre chemotherapy greater than &gt;1500 cm3 (MRI) was the variable most predictor of mortality (p=0.02). Median survival was 48 months (IC 95%: 27-70) in tumors greater than 1500 cm3 versus 104 months (IC 95%: 91-118) in those tumors smaller than 1500cm3 (p=0.001). Intensification of radiological calcification, pathological fracture and changes in size pre and post chemotherapy did not have prognostic value.CONCLUSIONS: tumor measurement at diagnosis can distinguish high-risk populations. MRI is superior to RX to estimate prognostic size value. MRI does not sub estimate soft parts of the tumor and allows delimiting better tumor margins. No significant financial relationships to disclose.</p

Inadequate medical intervention as prognostic factor in osteosarcoma

9041 Background: Osteosarcoma is an aggressive disease. Survival has been improved to greater than 75% in most of the last trials. This is due to progress in surgical technique, polychemotherapy and fundamentally because of the multidisciplinary work. Inadequate medical intervention (IMI) (mistakes in the biopsy planning, pathological interpretation or surgery) could impair the osteosarcoma evolution. We compare two groups of patients managed with the same standard of care in our multidisciplinary group; one had a previous IMI and the other did not (control group).METHODS: Since 11/1989 until 9/2002, 15 patients with diagnosis of osteosarcoma that had initiated treatment in other institutions and had IMI were evaluated. Nine men, median age 21,1 years (SD: 9,36), two with central localization. Overall survival (OS), disease free survival (DFS), limb sparing and relapses of these patients were evaluated.RESULTS: erroneous diagnoses were: aneurysmal bone cist (N=4), giant cell tumor (N=2), osteochondroma (N=2), osteoblastoma (N=2), fibrous dysplasia (N=1), osteomyelitis (N=1). Histological revision made by an experienced pathologist showed high-grade osteosarcoma in 11 patients and low grade in the rest. Erroneous initial diagnosis leaded to insufficient surgeries (intralesional) in 14 patients in other institutions. Limb sparing rate was lower versus our control population (p= 0.03). In the IMI group the local and systemic relapse rates were worse (40% versus 15%, p=0.000; and 60 versus 28.3%, p=0.04 respectively). Five year SV of patients with IMI was 24.9% versus 65.3% of control group (p= 0.02). DFS was lower in the IMI group: 18.5 vs. 72.2 months (p= 0.01).CONCLUSIONS: IMI modified evolution of patients with osteosarcoma dramatically. IMI reduces OS, DFS and decreases conservational possibilities. Specialized multidisciplinary teams should treat every patient with osteosarcoma suspicion. No significant financial relationships to disclose.</p