Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty.

PURPOSE: To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. METHODS: C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. RESULTS: Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p<0.001) 8 hours post intervention. During the follow-up period, 70 (53%) patients developed restenosis. Increasing levels of C5a (quartiles) at baseline were significantly associated with an increased risk for restenosis (p=0.0092). Adjusted hazard ratios (95% confidence intervals) for restenosis with increasing quartiles of baseline serum C5a levels were 1.24 (0.60 to 2.58), 1.93 (0.95 to 3.93), and 2.08 (1.02 to 4.21), respectively, compared to the lowest quartile. This effect was independent of nonspecific inflammation as reflected by plasma levels of C-reactive protein. CONCLUSION: Inflammatory mechanisms play a major role in the development of restenosis after angioplasty. The complement component C5a exerts strong chemotactic and proinflammatory effects. Enhanced complement activation prior to PTA, as measured by higher levels of C5a, was significantly associated with restenosis after SFA balloon angioplasty. Pathways of complement inhibition thus may be worth investigating with respect to improving patency rates.     

A novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP

Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP [mean age at death 65.5 years (±8.1), 40% female]. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset (p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases.     

New aspects in thrombosis research: possible role of mast cells as profibrinolytic and antithrombotic cells

Venous thromboembolism represents a significant cause of morbidity worldwide. The factors that underly thrombophilia are manifold. The concept of Virchow defines the well known triad of stasis, humoral factors, and pathologies of the vascular wall. In the current article, an additional factor, the "accumulation of repair cells" is discussed. This novel concept highlights the mast cell that accumulates around thrombosed vessels and provides a number of important repair molecules including heparin, profibrinolytic tPA, and fibrinogenolytic beta-tryptase. Thus, mast cell recruitment and activation may result in local thrombolysis and prevention of coagulation. In line with this concept, mast cell-deficient mice are more susceptible to lethal thrombogenic stimuli compared to normal mice. The factors (cytokines) that trigger mast cell accumulation and release of repair molecules have also been identified - the most important one appears to be stem cell factor (SCF). All in all. our novel concept suggests that the patho-physiology of thrombosis may involve a "physiologic" cell that provides the same repair molecules that are used for treatment of thrombotic disorders by the physician. Whether an altered availability of components of this cellular repair system can predispose for thrombophilia remains to be determined.     

The adaptive immune system and long-term outcome in patients with stable coronary disease. Predictive value of routine laboratory measurements

Components of the adaptive immune system, in particular lymphocytes and immunoglobulin, play a major role in advanced atherosclerotic lesions. We sought to determine whether routine, measurements of the relative number of circulating lymphocytes (%L) and gamma-globulin (%G) reflecting immunoglobulin are related to event-free survival in patients with stable coronary artery disease (CAD). We prospectively studied the combined endpoint all-cause mortality, myocardial infarction and coronary revascularization procedures in 141 patients after successful percutaneous coronary intervention during a median follow-up time of 13.2 years. Using Cox regression, we found a significant influence of %L on event-free survival (P=0.007) with a relative risk of 2.21 comparing third to first tertile. Subjects with higher %G values likewise had a shorter event-free survival (P=0.008) with a relative risk of 1.67 comparing third to first tertile. The predictive value of %L and %G remained significant after adjustment for demographic data, cardiovascular risk factors, extent of CAD and other inflammatory markers. We conclude that the fraction of gamma-globulin and in particular the relative lymphocyte cell count may serve as readily available and reliable prognostic tools for the long-term outcome in patients with stable CAD.     

Ultrasound thrombolysis

Cardiovascular diseases are a major cause of mortality in the developed world. Efficacy of thrombolysis plays an important role in the management of acute myocardial infarction and cerebral insult both in the acute event and in the long-term outcome of these patients. New adjunctive strategies have been tested, therefore, to make thrombolytic therapies more effective and safer. Ultrasound Thrombolysis is a technique which showed promising results under in vitro conditions and in animal studies. Now clinical trials have to prove if it is also feasible for clinical application. This report gives an overview on different technical approaches and their current performances in the clinical setting. All original articles are chronologically ordered in tables providing detailed information on each study concerning experimental design, acoustical parameters and thrombolysis outcome.