Beneficial effects of complement inhibition with soluble complement receptor 1 (TP10) during cardiac surgery: is there a gender difference?

BACKGROUND: TP10, a potent inhibitor of complement activation during cardiopulmonary bypass (CPB) has been shown to significantly reduce the incidence of death and myocardial infarction (MI) in high-risk male patients undergoing cardiac surgery. However, the effect of TP10 in females was undefined because of the limited number of females studied. To examine the possibility of a gender effect, this phase 2 multi-center trial was undertaken to determine whether TP10 would also limit ischemic damage in a larger sample size of high-risk females undergoing cardiac surgery on cardiopulmonary bypass (CPB). METHODS AND RESULTS: This prospective, double-blind, placebo-controlled, multi-center trial involved 297 high-risk (urgent surgery, CABG + Valve, reoperations, ejection fraction <30%) female patients randomized to receive a 5 mg/kg dose of TP10 (n=150) or placebo (n=147) as a 30-minute intravenous infusion before surgery. The primary end point was the incidence of death or MI at 28 days after surgery. Complement activation was assessed by levels of CH50 and SC5b-9 during and after CPB. TP10 was well tolerated and there were no differences in the safety profiles of the 2 groups. Although TP10 effectively suppressed complement activation (at 2 hours after CPB CH50 (mean+SD % change from baseline) 50+/-17% placebo versus 4+/-14% TP10; P=0.0001; SC5b-9 (ng/mL) 917+/-1067 placebo versus 204+/-79 TP10; P=0.0001), there was no difference in the primary end point between the groups (17% placebo versus 21% TP10; P=0.2550). CONCLUSIONS: The benefits of TP10 appear to be gender-related. and mechanisms other than complement activation may be responsible for myocardial injury in high-risk female patients during cardiac surgery on CPB.

Vascular endothelium summary statement VI: Research directions for the 21st century.

Effective translation of research advances from the bench to clinical and public health practice at the bedside and in the community at large represents an important step in the health research discovery enterprise. Increasingly, the gap in translating these advances into practice is being recognized. Successfully addressing this translational gap for the prevention and control of chronic diseases will require the development of novel, innovative, and, if necessary, nontraditional approaches. Participants in the 8th International Conference on Vascular Endothelium discussed a variety of novel approaches that have significant promise. Three of these approaches-vaccine development, genomics and proteomics, and tissue engineering-are highlighted in this position statement and strategies for public health practice and research are suggested.

Vascular endothelium summary statement II: Cardiovascular disease prevention and control.

The prevention and control of cardiovascular disease (CVD), principally ischemic heart disease and stroke, are a major clinical and public health challenge. Worldwide, CVD accounts for substantial morbidity and mortality. The major modifiable CVD risk factors are known and all of them cause endothelial activation and dysfunction. Preventing and controlling the established risk factors are associated with preserved endothelial function and reduced risk of CVD. Research advances that improve our understanding of strategies to preserve endothelial function or make the endothelial cells resilient to environmental insults may help improve our preventive interventions. This summary statement addresses the current state of the science with respect to endothelial dysfunction and CVD pathogenesis, diagnostic evaluation, and suggested strategies for public health practice and research.

Vaccines for the prevention of cardiovascular disease.

Atherosclerosis, especially coronary heart disease (CHD), remains a most significant global public health problem. Highly effective LDL-lowering therapies have gained widespread adoption in the United States and throughout the developed world, but therapeutic options for raising low HDL, a key independent risk factor for CHD, remain limited. We are developing a vaccine approach to raising HDL, by inducing an immune response to endogenous cholesteryl ester transfer protein (CETP), and have demonstrated proof of principle in preclinical and clinical models. This vaccine approach may offer the opportunity to address low HDL with a cost-effective semi-annual injection.

Advances in the development of bacterial vector technology.

The demand for new and improved vaccines against human diseases has continued unabated over the past century. While the need continues for traditional vaccines in areas such as infectious diseases, there is an increasing demand for new therapies in nontraditional areas, such as cancer treatment, bioterrorism and food safety. Prompted by these changes, there has been a renewed interest in the application and development of live, attenuated bacteria expressing foreign antigens as vaccines. The application of bacterial vector vaccines to human maladies has been studied most extensively in attenuted strains of Salmonella. Live, attenuated strains of Shigella, Listeria monocytogenes, Mycobacterium bovis-BCG and Vibrio cholerae provide unique alternatives in terms of antigen delivery and immune presentation, however and also show promise as potentially useful bacterial vectors.

A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing.

In developed nations, monitoring for drug-induced liver injury through serial measurements of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] in at-risk individuals is the standard of care. Despite the need, monitoring for drug-related hepatotoxicity in resource-limited settings is often limited by expense and logistics, even for patients at highest risk. This article describes the development and clinical testing of a paper-based, multiplexed microfluidic assay designed for rapid, semiquantitative measurement of AST and ALT in a fingerstick specimen. Using 223 clinical specimens obtained by venipuncture and 10 fingerstick specimens from healthy volunteers, we have shown that our assay can, in 15 min, provide visual measurements of AST and ALT in whole blood or serum, which allow the user to place those values into one of three readout "bins" [<3× upper limit of normal (ULN), 3 to 5× ULN, and >5× ULN, corresponding to tuberculosis/HIV treatment guidelines] with >90% accuracy. These data suggest that the ultimate point-of-care fingerstick device will have high impact on patient care in low-resource settings.

Enterotoxigenic Escherichia coli virulence factors and vaccine approaches.

Enterotoxigenic Escherichia coli (ETEC) is recognized as one of the major causes of infectious diarrhea in developing countries. Worldwide, the incidence of ETEC infections is estimated to result in 650 million cases of diarrhea and 380,000 deaths in children under 5 years of age. ETEC is also an important cause of travelers' diarrhea in people traveling to endemic regions of the world. Although ETEC is an uncommon cause of infections in the USA, there have been 14 reported outbreaks of ETEC in the USA and seven on cruise ships over the 20-year period between 1975 and 1995. ETEC strains are comprised of a large number of serotypes that produce a variety of colonization factors and enterotoxins. On infection, ETEC first establishes itself by adhering to the epithelium of the small intestine via one or more colonization factor antigens or coli surface proteins. Once established, ETEC expresses one or more enterotoxin(s), which results in the production of secretory diarrhea. While the need for an efficacious, easily administered vaccine is great, there are currently no licensed ETEC vaccines available for use in endemic countries or for US travelers.

Lung retinol storing cells synthesize and secrete retinoic acid, an inducer of alveolus formation.

Retinoids play a key role in the formation of pulmonary alveoli. Lipid interstitial cells (LICs) of the alveolar wall store retinol and are concentrated at sites of alveolus formation, suggesting they are an endogenous source of retinoids for alveolus formation. We show in cultured rat lung cells that LICs synthesize and secrete all-trans retinoic acid (ATRA); its secretion is halved by dexamethasone, an inhibitor of alveolus formation. In a second alveolar wall cell, the pulmonary microvascular endothelial cell (PMVC), ATRA increases expression of the mRNA of cellular retinol binding protein-I (CRBP-I), a protein involved in ATRA synthesis. Serum-free, exogenous ATRA-free medium conditioned by LICs rich in retinol storage granules caused a 10-fold greater increase of CRBP-I mRNA in PMVCs than media conditioned by LICs with few retinol storage granules. This action of medium conditioned by retinol storage granule-rich LICs is decreased by a retinoic acid receptor pan-antagonist and by a retinoid X receptor pan-antagonist, suggesting the responsible molecule(s) is a retinoid and that retinoid signaling occurs in a paracrine fashion.