Raphael Schiffmann M.D.

McCullough, P. A., A. Vasudevan, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and T. Bottiglieri (2016). “Oxidative stress reflected by increased F2-isoprostanes is associated with increasing urinary 11-dehydro thromboxane B2 levels in patients with coronary artery disease.” Thromb Res 148: 85-88.

Full text of this article.

Our study demonstrated that: 1) CAD patients with higher levels of 8-isoPGF2α had higher levels of 11dhTxB2, which could be related to poor inhibition of COX-1 pathway in spite of adequate ASA treatment, 2) 8-isoPGF2α is an independent determinant of 11dhTxB2 and 3) 8-isoPGF2α levels were significantly higher in females and patients with diabetes and COPD. Patients with diabetes and central obesity have been observed to have an incomplete ASA response manifested as incomplete inhibition of thromboxane production, in a pro-inflammatory background with enhanced oxidative stress. Oxidative stress enhances the production of platelet isoprostanes and is believed to mitigate the aspirin mediated TxA2 inhibition among diabetic patients on low-dose aspirin [9]. Among F2-isoprostanes metabolites, 8-isoPGF2α is a marker of in vivo oxidative stress, which has been shown to stimulate the activation of platelets by direct binding to the thromboxane platelet receptor. Elevated 8-isoPGF2α levels in our ASA-treated CAD patients indicate the presence of an active oxidative stress environment that is not affected by ASA treatment. Because ASA inhibits over 95% of platelet COX-1 activity in practically all subjects, the residual platelet activation in poor ASA responders can be explained by alternative sources of TxA2 produced by non-platelet inflammatory COX-2 pathways. Our findings are congruent with the notion that oxidative stress mechanisms play an important role in platelet activation in addition to their role on the initiation, progression, and consequences of atherogenesis. Excessive production of ROS may damage lipoproteins creating an inflammatory and atherogenic background and also enhance the arachidonic acid production of F2-isoprostanes that are capable of activating platelets and making them resistant to the therapeutic effect of ASA. These observations support the concept that oxidative stress maintains platelet hyperactivity linking proatherogenic mechanisms to platelet dysfunction in patients with stable CAD. Considering that thromboxanes are not the only factor contributing to platelet activation and atherothrombosis, it is not surprising that a single anti-platelet agent such as ASA does not prevent all adverse events. Cyclo-oxygenase-1 derived TxA2 activates the same and nearby platelets in an autocrine signaling fashion. Due to the very short half-life of TxA2 (20–30 s) and low concentrations (1–60 pg/mL), a constant production of TxA2 is necessary to maintain a homeostatic (physiologic) control of platelet activity. However, the half-life of 8-isoPGF2α is much longer (10 min), with concentrations that are thirty-fold higher. If 8-isoPGF2α can bind and stimulate thromboxane platelet receptors with similar affinity, its longer half-life and concentration makes it a relevant agonist for platelet activation in patients with an underlying oxidative process. Because ASA blocks most of COX-1 activity reducing the production of TxA2, it is possible that the thromboxane platelet receptor can still be activated by TxA2 produced via the 8-isoPGF2α pathway. In this situation, blocking 8-isoPGF2α TPR stimulation could be a potential therapeutic target instead of increasing the dose of ASA. Sex related differences in platelet function and ASA pharmacokinetics exist with female gender associated with elevated 11dhTxB2. We found that females had significantly higher 8-isoPGF2α levels, suggesting an enhanced oxidative stress and lesser attenuation of TxA2. Elevated 11dhTxB2 was found to increase the risk of adverse events in patients with stable CAD and myocardial infarction. (Excerpt from text, p. 86-87.)

Schiffmann, R., D. A. Hughes, G. E. Linthorst, A. Ortiz, E. Svarstad, D. G. Warnock, M. L. West and C. Wanner (2016). “Screening, diagnosis, and management of patients with fabry disease: Conclusions from a “kidney disease: Improving global outcomes” (kdigo) controversies conference.” Kidney Int: 2016 Dec [Epub ahead of print].

Full text of this article.

Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics 47(6): 349-354.

Full text of this article.

Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2016). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis: 2016 Dec [Epub ahead of print].

Full text of this article.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

Schiffmann, R., M. Fuller, L. A. Clarke and J. M. Aerts (2016). “Is it fabry disease?” Genet Med 18(12): 1181-1185.

Full text of this article.

Fabry disease is caused by mutations in the GLA gene that lower alpha-galactosidase A activity to less than 25-30% of the mean normal level. Several GLA variants have been identified that are associated with relatively elevated residual alpha-galactosidase A. The challenge is to determine which GLA variants can cause clinical manifestations related to Fabry disease. Here, we review the various types of GLA variants and recommend that pathogenicity be considered only when associated with elevated globotriaosylceramide in disease-relevant organs and tissues as analyzed by mass spectrometry. This criterion is necessary to ensure that very costly and specific therapy is provided only when appropriate.