Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial

OBJECTIVES: This study sought to evaluate the antiarrhythmic effects of lipid-lowering drug therapy as assessed by ventricular tachyarrhythmia (ventricular tachycardia [VT]/ventricular fibrillation [VF]) recurrences recorded by an implantable cardioverter defibrillator (ICD) in patients with atherosclerotic heart disease (ASHD). BACKGROUND: Randomized trials of lipid-lowering drugs suggest reduction of sudden death (SD) in patients with ASHD. Because SD is usually secondary to VT/VF, this observation suggests that lipid-lowering therapy has antiarrhythmic effects. METHODS: The probability of VT/VF recurrence in patients with ASHD treated with an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial who did not receive lipid-lowering drug therapy (n = 279) was compared with that in patients who received early and consistent lipid-lowering therapy (n = 83). In addition, all-cause mortality and cardiac mortality of all patients in the AVID trial with ASHD who did not receive lipid-lowering therapy (n = 564) were compared with that of those who received early and consistent lipid-lowering therapy (n = 149). RESULTS: Using multivariate analyses, lipid-lowering therapy was associated with a reduction in the relative hazard for VT/VF recurrence of 0.40 (95% confidence interval [CI] 0.15 to 0.58) (adjusted p = 0.003) in the ICD subgroup. Lipid-lowering therapy was also associated with a reduction in the relative hazard for all-cause mortality of 0.36 (95% CI 0.15 to 0.68) (adjusted p = 0.03) and a reduction in the relative hazard for cardiac mortality of 0.39 (95% CI 0.16 to 0.78) (adjusted p = 0.04) in the larger study population. CONCLUSIONS: In patients with ASHD who have received an ICD, lipid-lowering therapy is associated with reduction in the probability of VT/VF recurrence, suggesting that part of the benefit of lipid-lowering therapy may be due to an antiarrhythmic effect.     

Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women

OBJECTIVES: To determine the effects of ultra-low-dose hormone therapy on muscle mass and physical function in community-dwelling women. DESIGN: Double-blind, placebo-controlled trial. SETTING: Clinical research center in Connecticut. PARTICIPANTS: Healthy, community-dwelling women aged 65 and older (n=167). INTERVENTION: Eligible women were randomly assigned to treatment with 0.25 mg 17-beta estradiol or placebo for 36 months. All women (estradiol or placebo) with an intact uterus received micronized progesterone 100 mg/d for 2 weeks every 6 months. All participants received 1,300 mg elemental calcium with 1,000 IU vitamin D per day. MEASUREMENTS: Appendicular skeletal muscle mass (ASM), lean body mass (LBM), and percentage body fat were measured using dual x-ray absorptiometry. Sarcopenia was defined as skeletal muscle mass (ASM/height2) 2 standard deviations or less than young, healthy reference population mean. Physical activity (Physical Activity Scale in the Elderly (PASE)) and performance were measured. Serum estrone, estradiol, and sex hormone-binding globulin were measured. RESULTS: The prevalence of sarcopenia at baseline was 13%. There were no baseline differences between groups except for PASE score and chair rise time, in which the estrogen group had better performance. No changes in ASM, LBM, percentage of body fat, or physical performance were found after 3 years of estrogen therapy. CONCLUSION: Sarcopenia was present in 13% of this group of community-dwelling, postmenopausal older women. Ultra-low-dose estrogen therapy neither improves nor harms ASM. Similarly, no changes in body fat or physical performance were detected.     

Electrocardiographic gated (99m)Tc-sestamibi SPECT immediately after primary percutaneous coronary intervention characterizes reperfusion success

Following an acute myocardial infarction, the size of the infarct and the resulting left ventricular volume and function are important predictors of mortality. Identifying patients with impaired tissue level perfusion after percutaneous coronary intervention (PCI) for myocardial infarction therefore could have prognostic implications. To obtain combined measures of left ventricular perfusion, volumes and function we applied a gated myocardial perfusion imaging by (99m)Tc-sestamibi single photon emission computerized tomography to 19 patients immediately after revascularization by PCI and repeated this after 3 months. The results of the acute myocardial perfusion imaging significantly correlated to final infarct size, left ventricular volumes and function 3 months later. It is concluded that the method holds the potential for risk stratifying patients immediately after revascularization for acute myocardial infarction.     

Effect of etanercept on serum amyloid A protein (SAA) levels in patients with AA amyloidosis complicating inflammatory arthritis

We assessed changes in serum amyloid A protein (SAA) levels during treatment with etanercept in AA amyloidosis complicating inflammatory arthritis. Five women and four men with AA amyloidosis and inflammatory arthritis received etanercept. SAA levels were recorded before and after commencement of treatment. Previous immunosuppressive drugs included cyclophosphamide (four patients), azathioprine (three patients), methotrexate (two patients) and chlorambucil (in one patient). Two patients received no disease modifying drugs between the time of diagnosis of AA amyloidosis and commencement of etanercept. In seven out of nine patients the median SAA level during etanercept treatment was lower than levels before anti-tumour necrosis factor therapy. In five out of nine patients, the median post treatment level was <11 mg/l. There were no significant changes in serum creatinine or proteinuria during periods (median, 23 months; range, 1-24 months) of etanercept therapy. The etanercept was stopped in four patients because of: acute bacterial endocarditis, psoriasiform rash, psychosis and leukopenia. In two of these patients alternative biologics were commenced (adalimumab or anakinra) and one was restarted on etanercept. One patient died of cerebral haemorrhage during the study. Etanercept therapy was associated with a fall in SAA levels in seven of nine patients, five of whom achieved levels which might be expected to be associated with stable or regressing amyloid deposits. Etanercept represents a useful alternative to immunosuppressant therapy such as cyclophosphamide or chlorambucil. Further work is needed to establish whether organ damage related to AA amyloidosis is slowed by etanercept.     

Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1

The primary identified function of complement receptor 1 (CR1/CD35) on primate erythrocytes is to bind complement-tagged inflammatory particles including microbes and immune complexes. When erythrocytes circulate through liver and spleen, sinusoidal phagocytes remove CR1-adherent particles and erythrocytes return to the circulation. This process of immune adherence clearance is important for host defense and prevention of autoimmunity. CR1 was previously described as clustered in the human erythrocyte membrane, which was thought to be necessary for binding complement-opsonized particles. In contrast, we demonstrate that on erythrocytes CR1 is not clustered, but dispersed, and able to bind complement-tagged particles. When fresh erythrocytes are solubilized by nonionic detergent, CR1 partitions to the cytoskeleton fraction. Using a PDZ-peptide array, CR1's cytoplasmic tail, which contains 2 PDZ-motifs, binds PDZ domains 2, 3, and 5 of Fas-associated phosphatase 1 (FAP-1), a scaffolding protein. We show that FAP-1, not previously recognized as an erythroid protein, is expressed on circulating erythrocytes. CR1 and FAP-1 coimmunoprecipitate, which confirms their molecular association. Disperse CR1 on erythrocytes may be advantageous for capturing immune-complexes, while ligation-induced CR1 clustering may prevent ingestion of the erythrocyte during the immune-complex transfer to the macrophages by keeping the opsonic stimulus localized thus preventing phagocyosis.     

Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants

BACKGROUND AND AIMS: Resistance is a major challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). We investigated the mechanisms of resistance in patients with progressive GISTs with primary KIT mutations and the efficacy of the kinase inhibitor PKC412 for the inhibition of imatinib-resistant mutants. METHODS: We performed a cytogenetic analysis and screened for mutations of the KIT and PDGFRA kinase domains in 26 resistant GISTs. KIT autophosphorylation status was assessed by Western immunoblotting. Imatinib-resistant GIST cells and Ba/F3 cells expressing these mutant proteins were tested for sensitivity to imatinib and PKC412. RESULTS: Six distinct secondary mutations in KIT were detected in 12 progressive tumors, with V654A and T670I found to be recurrent. One progressive tumor showed acquired PDGFRA -D842V mutation. Amplification of KIT or KIT / PDGFRA was found in 2 patients. Eight of 10 progressive tumors available for analysis showed phosphorylated KIT. Two remaining progressive tumors lost KIT protein expression. GIST cells carrying KIT -del557-558/T670I or KIT -InsAY502-503/V654A mutations were resistant to imatinib, while PKC412 significantly inhibited autophosporylation of these mutants. Resistance to imatinib and sensitivity to PKC412 of KIT -T670I and PDGFRA -D842V mutants was confirmed using Ba/F3 cells. CONCLUSIONS: This study shows the high frequency of KIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of KIT / PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant KIT -T670I and KIT -V654A and of PDGFRA -D842V mutants to PKC412.     

When to suspect and how to diagnose pulmonary lymphangioleiomyomatosis

Abstract The objective of this study was to present clinical and radiological data of eight women with histologically proven lymphangioleiomyomatosis (LAM) diagnosed between 1984 and 1994, and to suggest a diagnostic strategy when LAM is suspected. A review of case reports, including results of biopsies, lung function and radiological procedures was undertaken. The mean age of the women at start of symptoms was 36 years, and the mean age at time of diagnosis 42 years. The most frequent presenting complaint was dyspnea, either in conjunction with pneumothorax (3), chylothorax (2) or on exertion (2). All patients had airflow limitation and markedly reduced gas transfer. Five patients had 16 episodes of pneumothorax. In seven patients multiple cysts were observed on the surface of the lung during thoracotomy while computerized tomography (CT) scans revealed numerous cysts evenly distributed throughout the lung parenchyma. The procedures that confirmed the diagnosis included transbronchial lung biopsy (4), open lung biopsy (2), thoracoscopy (1), thoracotomy (3) and autopsy (1). Three specimens had to be revised before the histological diagnosis was confirmed. It was concluded that the important clues to a diagnosis of LAM are recurrent episodes of pneumothoraces in fertile women, progressive air-flow limitation, markedly reduced gas transfer and characteristic findings on thoracic CT scans. A specific request to the pathologist to stain lung tissue specimens for smooth muscle cells is mandatory.     

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.