Antonios Halapas

Mechanisms of bone metastasis in prostate cancer: clinical implications

Prostate cancer shows a strong predilection to spread to the bones. Once prostate tumour cells are engrafted in the skeleton, curative therapy is no longer possible and palliative treatment becomes the only option. Herein, we review the multifactorial mechanisms and complex cellular interactions that take place inside the bone metastatic microenvironment. Emphasis is given to the detection and treatment of the micrometastatic stage of prostate cancer, as well as our recent attempts to target the bone metastasis microenvironment-related survival factors using an anti-survival factor manipulation which can increase the efficacy of anticancer therapies such as androgen ablation therapy and chemotherapy in advanced prostate cancer.

IGF-1 Expression in Infarcted Myocardium and MGF E Peptide Actions in Rat Cardiomyocytes in Vitro

Insulinlike growth factor-1 (IGF-1) expression is implicated in myocardial pathophysiology, and two IGF-1 mRNA splice variants have been detected in rodents, IGF-1Ea and mechano-growth factor (MGF). We investigated the expression pattern of IGF-1 gene transcripts in rat myocardium from 1 h up to 8 wks after myocardial infarction induced by left anterior descending coronary artery ligation. In addition, we characterized IGF-1 and MGF E peptide action and their respective signaling in H9C2 myocardial-like cells in vitro. IGF-1Ea and MGF expression were significantly increased, both at transcriptional and translational levels, during the late postinfarction period (4 and 8 wks) in infarcted rat myocardium. Measurements of serum IGF-1 levels in infarcted rats were initially decreased (24 h up to 1 wk) but remained unaltered throughout the late experimental phase (4 to 8 wks) compared with sham-operated rats. Furthermore, specific anti-IGF-1R neutralizing antibody failed to block the synthetic MGF E peptide action, whereas it completely blocked IGF-1 action on the proliferation of H9C2 cells. Moreover, this synthetic MGF E peptide did not activate Akt phosphorylation, whereas it activated ERK1/2 in H9C2 rat myocardial cells. These data support the role of IGF-1 expression in the myocardial repair process and suggest that synthetic MGF E peptide actions may be mediated via an IGF-1R independent pathway in rat myocardial cells, as suggested by our in vitro experiments.

The Role of the Immunogenetic Background in the Development and Recurrence of Acute Idiopathic Pericarditis

Objectives: We assessed the role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis (AIP). Methods: Fifty-five patients with a first episode of AIP were followed for 23.8 ± 6.3 months and recurrences were recorded. The control group consisted of 246 healthy individuals. In all subjects, genomic human leukocyte antigen (HLA) typing was performed. Moreover, circulating lymphocyte subpopulations were studied in 44 randomly selected patients and in 20 controls. Results: An increased frequency of HLA-A*02, -Cw*07 and -DQB1*0202 alleles, and a decreased frequency of the -DQB1*0302 allele was detected in patients with AIP. The recurrence rate was 40% and time to recurrence was 202.8 ± 164.1 days. In patients with idiopathic recurrent pericarditis (RP), increased frequencies of HLA-A*02, -Cw*07 and -DQB1*0202 alleles were found. Notably, no patient with RP exhibited HLA-DRB1*04 and -DQB1*0302 alleles. Patients with RP exhibited lower CD4+/CD45RA+ naïve T cells (p = 0.03) than controls, and higher CD8+DR+ activated T cells (p = 0.01) than patients without recurrence and controls. Conclusions: HLA alleles may confer either susceptibility or resistance to AIP and RP. Circulating T-cell subpopulations may also predict RP. A combination of the above parameters might help to better define patients prone to recurrence.

Serum levels of the osteoprotegerin, receptor activator of nuclear factor κ-B ligand, metalloproteinase-1 (MMP-1) and tissue inhibitors of MMP-1 levels are increased in men 6 months after acute myocardial infarction

Abstract Background: Osteoprotegerin (OPG) and receptor activator of nuclear factor κ-B ligand (RANKL) are critical regulators of bone remodeling and RANKL/RANK signaling could also play an important role in the remodeling process of several tissues, such as myocardium. Therefore, we investigated whether the serum concentrations of OPG and RANKL correlate with the serum levels of metalloproteinase-1 (MMP-1), MMP-9 and tissue inhibitors of MMP-1 (TIMP-1), which are known regulators of myocardial healing in acute myocardial infarction (AMI) patients. Methods: We analyzed blood samples from 51 consecutively hospitalized men with AMI, 12 men with established ischemic heart failure (New York Heart Association category II, NYHA-II) and 12 healthy men age-matched to the NYHA-II patients. Serum levels of MMP-1, MMP-9, TIMP-1, OPG and RANKL were quantified using commercially available ELISA kits. AMI patients were sampled 4 days and 6 months after MI. Results: Our data revealed increased serum levels of OPG, RANKL, MMP-1 and TIMP-1 levels and significant correlations between increased RANKL levels and MMP-1 and TIMP-1 serum levels 6 months after MI. In addition, the ratio OPG/RANKL was very low 6 months after MI, suggesting that the nuclear factor κ-B signaling is possibly more active 6 months post-MI than it is on day 4 post-MI. Conclusions: Our data suggest that OPG, RANKL, MMP-1 and TIMP-1 serum levels can be potential mediators of myocardial healing after MI. However, further large studies are needed to confirm the utility of OPG and RANKL as markers of healing after ST elevation in MI. Clin Chem Lab Med 2008;46:510–6.

Experimental hyperthyroidism increases expression of parathyroid hormone‐related peptide and type‐1 parathyroid hormone receptor in rat ventricular myocardium of the Langendorff ischaemia–reperfusion model

Parathyroid hormone‐related peptide (PTHrP) is released under ischaemic conditions and it improves contractile function of stunned myocardium. The actions of PTHrP are mediated primarily by the type 1 parathyroid hormone receptor (PTH.1R), while PTHrP and PTH.1R expression levels are increased in ventricular hypertrophy associated with experimental hyperthyroidism. Since chronic administration of thyroxine (T4) improves postischaemic recovery in isolated heart models subjected to ischaemia–reperfusion stress, we tested the hypothesis that experimentally induced hyperthyroidism is associated with elevated expression of PTHrP and PTH.1R in rat myocardium. Hyperthyroid and control male Wistar rats were subjected to ischaemia–reperfusion stress using the Langendorff technique, and the PTHrP and PTH.1R expression was assessed by relative quantitative reverse transcriptase‐polymerase chain reaction, Western blot analysis and immunohistochemistry. In the Langendorff model, the recovery of left ventricular developed pressure at the end of the stablization period and 45 min into the reperfusion period was used to assess the cardioprotective actions of T4 administration. Our data show that hyperthyroid animals had increased tolerance to the ischaemia–reperfusion stress and that this was associated with an increase of PTHrP and PTH.1R expression levels compared with those of control animals. In the control animals, the expression of PTHrP was increased 45 min into the reperfusion phase, while the PTH.1R expression pattern was significantly and gradually decreased throughout the ischaemia and reperfusion phases. In the hyperthyroid animals, the PTHrP and PTH.1R expression pattern was significantly higher throughout the ischaemia and reperfusion phases compared with that of control hearts. Our data suggest that increasing levels of PTHrP and PTH.1R expression can mediate, at least in part, the T4 administration‐induced cardioprotection in rat ventricular myocardium.

Transcatheter Aortic Valve Replacement in a Patient with Dextrocardia and Situs Inversus Totalis

This report presents the case of an 82-year-old man with known dextrocardia and situs inversus totalis who presented with increasing dyspnea on exertion and was diagnosed with severe aortic stenosis. Transcatheter aortic valve replacement was performed and required deviation from standard techniques for patients with normal anatomy and left-sided aortic arch. We describe two technical differences required for patients with dextrocardia and right-sided aortic arch that facilitate transcatheter aortic valve replacement in this patient group.

Transcatheter MitraClip implantation facilitated by transthoracic echocardiography

Edge-to-edge mitral valve repair with the MitraClip (Abbott Vascular) is, at present, the most widely used and clinically relevant method for transcatheter repair of severe mitral regurgitation (TMVr); [1–3]. Procedural success relies heavily on imaging with twoand three-dimensional transesophageal echocardiography (TEE) [4, 5]. In the absence of adequate imaging in the final stages of the procedure (positioning and leaflet grasping), transthoracic echocardiography with a matrix three-dimensional transducer (3D-TTE) may play a complementary and highly effective role, and make the difference between an aborted procedure and a successful one. Patient 1: A 69-year old male was referred for TMVr due to severe functional ischemic mitral regurgitation (Fig. 1a). Intraoperatively, TEE imaging was sufficient for transseptal puncture and steering in the left atrium to position the clip over the midline of the mitral valve; however, there was a critical limitation in that the grasping views (long axis at 120°–150°) were poor, with insufficient visualization of the posterior leaflet. Transthoracic imaging proved highly valuable. Images were obtained from the apical position starting with a two-chamber view (i.e., the commissural view for medial–lateral orientation) with simultaneous projection in X-plane mode of the long-axis “grasping view” (for anterior–posterior orientation) (Fig. 1b). This allowed positioning of the MitraClip in the A2-P2 region, advancement in the left ventricle, and grasping of the leaflets (Fig. 1c). Subsequent evaluation of leaflet insertion, degree of mitral regurgitation reduction, and transvalvular gradients was performed with the use of both transthoracic and transesophageal imaging (Fig. 1d). After confirming acute procedural success, the clip was released and the procedure was completed uneventfully. Patient 2: A 78-year old male with severe functional ischemic mitral regurgitation in the New York Heart Association (NYHA) functional class IV was referred for TMVr (Fig. 1e). Intraoperative TEE was fairly limited to allow guidance during the steering of the MitraClip over the mitral valve and during the grasping phase. The initial steps of transseptal puncture, guide catheter insertion, and steering of the clip into the left atrium were performed with TEE guidance. For the orientation of the clip over the mitral valve, transthoracic imaging was employed using an apical two-chamber view (i.e., the commissural view) for medial–lateral orientation and a simultaneous longaxis three-chamber view (i.e., a view very similar to the long-axis TEE view commonly obtained at 120°–150°) for anterior–posterior orientation (Fig. 1f). These two views facilitated clip advancement and leaflet grasping was successfully performed (Fig. 1g, h), allowing for completion of the procedure.

LONG-TERM OUTCOMES IN PATIENTS RECEIVING PERMANENT PACEMAKER AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT

Permanent pacemaker implantation (PPI) is common after transcatheter aortic valve replacement (TAVR), but there are limited data about this complication. We investigated the clinical long-term outcomes in patients receiving PPI after TAVR with Medtronic CoreValve (MCV) and Edwards Sapien XT (EXT).