Faculty Bibliography

BACKGROUND: Randomized trials using measurement of fractional flow reserve (FFR) to guide percutaneous coronary intervention (PCI) have demonstrated both safety and efficacy with regard to cardiac events. Real-world, long-term outcomes using an FFR-based revascularization strategy are unknown. METHODS: Prospective clinical data were collected on consecutive patients referred for coronary angiography and found to have lesions of intermediate severity where the operators were unable to make a decision regarding revascularization based on angiographic, clinical, and stress testing parameters. FFR was measured on intermediate lesions, and revascularization was deferred on those lesions with a measurement >0.8. Clinical outcomes of interest included death, myocardial infarction, and late revascularization status. RESULTS: A total of 151 patients were included in this study. Fifty-seven patients (37.7%) underwent revascularization based on their FFR measurement. The mean length of follow-up was 6.1 years (range, 5-10 years). Follow-up was completed in 97.0%. At the end of the follow-up period, 107 patients (70.9%) were alive. Late revascularization had been performed in 18 patients (11.9%). Comparing the initial revascularization group with the group in which revascularization was deferred, 64.9% and 74.5% were alive, respectively (P=.29). Of the initial revascularization group, 12.3% had undergone late revascularization of the lesion on which FFR was originally performed, compared with 11.7% in the deferred group (P=.99). CONCLUSIONS: FFR is a useful adjunct to coronary angiography in selecting patients with lesions of intermediate angiographic severity in whom coronary revascularization may be safely deferred.

BACKGROUND: The Occluded Artery Trial (OAT) was a large, randomized controlled trial published in 2006 that demonstrated no benefit to routine percutaneous coronary intervention (PCI) of persistently totally occluded infarct-related arteries (IRA) identified a minimum of 24 hours (on calendar days 3-28) after myocardial infarction (MI). The purpose of this study was to determine the impact of OAT results and consequent change in guideline recommendations for PCI for treatment of persistently occluded IRAs. METHODS: We identified all patients enrolled in the CathPCI Registry, from 2005 to 2008, undergoing catheterization more than 24 hours after MI with a totally occluded native coronary artery and no major OAT exclusion criteria. We examined trends in monthly rates of PCI for occlusions after OAT publication and after guideline revisions. Because reporting of diagnostic catheterizations was not mandatory, we examined trends among hospitals in the highest quartile for reporting of diagnostic procedures. RESULTS: A total of 28 780 patient visits from 896 hospitals were included. Overall, we found no significant decline in the adjusted monthly rate of PCI of occlusions after publication of OAT (odds ratio [OR], 0.997; 95% confidence interval [CI], 0.989-1.006) or after guideline revisions (OR, 1.007; 95% CI, 0.992-1.022). Among hospitals consistently reporting diagnostic catheterizations, there was no significant decline after OAT publication (OR, 1.018; 95% CI, 0.995-1.042), and there was a trend toward decline after guideline revisions (OR, 0.963; 95% CI, 0.920-1.000). CONCLUSION: These findings suggest that the results of OAT and consequent guideline revisions have not, to date, been fully incorporated into clinical practice in a large cross-section of hospitals in the United States

The commitment of Plasmodium merozoites to invade red blood cells (RBCs) is marked by the formation of a junction between the merozoite and the RBC and the coordinated induction of the parasitophorous vacuole. Despite its importance, the molecular events underlying the parasite's commitment to invasion are not well understood. Here we show that the interaction of two parasite proteins, RON2 and AMA1, known to be critical for invasion, is essential to trigger junction formation. Using antibodies (Abs) that bind near the hydrophobic pocket of AMA1 and AMA1 mutated in the pocket, we identified RON2's binding site on AMA1. Abs specific for the AMA1 pocket blocked junction formation and the induction of the parasitophorous vacuole. We also identified the critical residues in the RON2 peptide (previously shown to bind AMA1) that are required for binding to the AMA1 pocket, namely, two conserved, disulfide-linked cysteines. The RON2 peptide blocked junction formation but, unlike the AMA1-specific Ab, did not block formation of the parasitophorous vacuole, indicating that formation of the junction and parasitophorous vacuole are molecularly distinct steps in the invasion process. Collectively, these results identify the binding of RON2 to the hydrophobic pocket of AMA1 as the step that commits Plasmodium merozoites to RBC invasion and point to RON2 as a potential vaccine candidate.

Highly active antiretroviral therapy has led to significant declines in infection-related mortality in HIV-infected patients. Cardiovascular disease has emerged as a leading cause of morbidity and mortality in this population, and is likely related to both an increased prevalence of traditional cardiovascular risk factors and HIV-specific factors associated with antiretroviral therapy, chronic inflammation, and direct viral effects. Accurate clinical assessment of cardiovascular risk in HIV-infected patients is a critical challenge now facing practitioners. Multiple modes of noninvasive vascular imaging are available to enhance the ability to identify patients at high cardiovascular risk, and may ultimately assist in targeting use of intensive medical therapy to reduce cardiac events in this population. This review will examine several of these noninvasive tests and is intended to aid practitioners making cardiovascular risk assessments in HIV patients

Among potential new targets for antimalarial chemotherapy are Plasmodium falciparum cysteine proteases, known as falcipains. Falcipain-2 and falcipain-3 are food vacuole hemoglobinases that may have additional functions. The function of falcipain-1 remains uncertain. To better characterize the role of falcipain-1 in erythrocytic parasites, we disrupted the falcipain-1 gene and characterized recombinant parasites. Disruption of the falcipain-1 gene was confirmed with Southern blots, and loss of expression of falcipain-1 was confirmed with immunoblots and by loss of labeling with a specific protease inhibitor. Compared with wild-type parasites, falcipain-1 knockout parasites developed normally, with the same morphology, multiplication rate, and invasion efficiency, and without significant differences in sensitivity to cysteine protease inhibitors. In wild-type and knockout parasites, cysteine protease inhibitors blocked hemoglobin hydrolysis in trophozoites, with a subsequent block in rupture of erythrocytes by mature schizonts, but they did not inhibit erythrocyte invasion by merozoites. Our results indicate that although falcipain-1 is expressed by erythrocytic parasites, it is not essential for normal development during this stage or for erythrocyte invasion.

Plasmodium falciparum invades erythrocytes through multiple ligand-receptor interactions, with redundancies in each pathway. One such alternate pathway is the trypsin-resistant pathway that enables P. falciparum to invade trypsin-treated erythrocytes. Previous studies have shown that this trypsin-resistant pathway is dependent on glycophorin B, as P. falciparum strains invade trypsin-digested glycophorin B-deficient erythrocytes at a highly reduced efficiency. Furthermore, in a recent study, the P. falciparum 7G8 strain did not invade glycophorin B-deficient erythrocytes, a finding that was not confirmed in the present study. To analyze the degree of dependence on glycophorin B for invasion by P. falciparum through the trypsin-resistant pathway, we have studied the invasion phenotypes of five parasite strains, 3D7, HB3, Dd2, 7G8, and Indochina I, on trypsin-treated normal and glycophorin B-deficient erythrocytes. Invasion was variably reduced in glycophorin B-deficient erythrocytes. Four strains, 3D7, HB3, Dd2, and Indochina I, invaded trypsin-treated erythrocytes, while invasion by the 7G8 strain was reduced by 90%. Among the four strains, invasion by 3D7, HB3, and Dd2 of trypsin-digested glycophorin B-deficient erythrocytes was further reduced. However, Indochina I invaded trypsin-digested glycophorin B-deficient erythrocytes at the same efficiency as its invasion of trypsin-digested normal erythrocytes. This strongly suggests that the Indochina I strain of P. falciparum is not dependent on glycophorin B to invade through a trypsin-resistant pathway as are the strains 3D7, HB3, and Dd2. Thus, P. falciparum is able to invade erythrocytes through a glycophorin B-independent, trypsin-resistant pathway.

Immunity to Plasmodium falciparum in African children has been correlated with antibodies to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant gene family expressed on the surface of infected red cells. We immunized Aotus monkeys with a subregion of the Malayan Camp variant antigen (MCvar1) that mediates adhesion to the host receptor CD36 on the endothelial surface and present data that PfEMP1 is an important target for vaccine development. The immunization induced a high level of protection against the homologous strain. Protection correlated with the titer of agglutinating antibodies and occurred despite the expression of variant copies of the gene during recurrent waves of parasitemia. A second challenge with a different P. falciparum strain, to which there was no agglutinating activity, showed no protection but boosted the immune response to this region during the infection. The level of protection and the evidence of boosting during infection encourage further exploration of this concept for malaria vaccine development.