L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are facilitated by transport proteins. In this respect the cationic amino acid transporters CAT1 and CAT2 (SLC7A1 and SLC7A2) and the system y⁺L amino acid transporters (SLC7A6 and SLC7A7) have been most extensively investigated, so far, but the number of transporters shown to mediate the transport of L-arginine and its derivatives is constantly increasing. In the present review we assess the growing body of evidence regarding the function, expression, and clinical relevance of these transporters and their possible relation to cardiovascular diseases.

Low plasma concentration of L-homoarginine is an independent predictor of cardiovascular events and total mortality. Experimental data indicate that supplementation of L-homoarginine may have protective effects. We aimed to elucidate the mechanisms involved in the cellular uptake of L-homoarginine, which are little understood, so far. Using human embryonic kidney (HEK293) cell lines stably overexpressing the human cationic amino acid transporters CAT1 [solute carrier family 7 (SLC7A1)], CAT2A (SLC7A2A) or CAT2B (SLC7A2B) we assessed the transport kinetics of L-homoarginine and interactions with the CAT substrates L-arginine and asymmetric dimethylarginine (ADMA). Significant uptake of L-homoarginine was observed for all three CATs with apparent K_M-values of 175 ± 7 µM for CAT1 and 523 ± 35 µM for CAT2B. Saturation of CAT2A-mediated L-homoarginine uptake could not be reached. Uptake of L-homoarginine by any of the three CATs could be inhibited by L-arginine and ADMA. Significant inhibition of CAT1-mediated uptake of L-homoarginine by L-arginine already occurred in the physiological concentration range. Taken together these data demonstrate that L-homoarginine is a substrate of CAT1, CAT2A and CAT2B and that CAT1 is a key site with regard to physiological relevance and interactions with related substrates such as L-arginine.

Background: Nitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease ( CVD ) and all‐cause mortality. Methods and Results: We assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography–mass spectrometry and evaluated its association with all‐cause mortality and incident CVD . On follow‐up (median 17.3 years), 775 participants died and 522 developed new‐onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log‐nitrate 1.21; 95% confidence interval, 1.04–1.40 [ P =0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00–1.35 [ P =0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable‐adjusted hazard ratio per unit increase log‐nitrate 1.08; 95% confidence interval, 0.89–1.31 [ P =0.42]). Conclusions: In our prospective community‐based investigation, a higher plasma nitrate concentration was associated with all‐cause mortality but not with incident CVD . The association of nitrate with mortality may at least in part be attributable to its association with renal function.

Drug-related problems (DRP, defined as adverse drug events/reactions and medication errors) are a common threat for patient safety. With the aim to aid improved allocation of specialist resources and to improve detection and prevention of DRP, numerous predictive scoring tools have been proposed. The external validation and evidence for the transferability of these tools still faces limitations. However, the proposed scoring tools include partly overlapping sets of similar factors, which may allow a new approach to estimate the external usability and validity of individual risk factors. Therefore, we conducted this systematic review and analysis. We identified 14 key studies that assessed 844 candidate risk factors for inclusion into predictive scoring tools. After consolidation to account for overlapping terminology and variable definitions, we assessed each risk factor in the number of studies it was assessed, and, if it was found to be a significant predictor of DRP, whether it was included in a final scoring tool. The latter included intake of ≥ 8 drugs, drugs of the Anatomical Therapeutic Chemical (ATC) class N, ≥1 comorbidity, an estimated glomerular filtration rate (eGFR) <30 mL/min and age ≥60 years. The methodological approach and the individual risk factors presented in this review may provide a new starting point for improved risk assessment.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

Several lists of potentially inappropriate medication (PIM) for elderly patients have been developed worldwide in recent years. Those lists intend to reduce prescriptions of drugs that carry an unnecessarily high risk of adverse drug events in elderly patients. In 2010, an expert panel published the PRISCUS list for the German drug market. This study calculates the amount of drug reimbursement for PIM in Germany and potential cost effects from the perspective of statutory health insurance when these are replaced by the substitutes recommended by the PRISCUS list. Register-based data for the 30 top-selling drugs on the PRISCUS list in 2009 for patients greater than or equal to 65 years of age were provided by the Scientific Institute of the German Local Health Care Fund. We calculated the percentage of sales and defined daily doses for patients greater than or equal to 65 years of age compared with the total statutory health insurance population. Reimbursement costs for the recommended substitutions were estimated by considering different scenarios. In 2009, drug reimbursement for the 30 top-selling PIM prescribed to patients greater than or equal to 65 years of age were calculated to be €305.7 million. Prescribing the recommended substitution medication instead of PIM would lead to an increased total reimbursement cost for the German health care system ranging between from €325.9 million to €810.0 million. The results show that the substitution of PIM by medication deemed to be more appropriate for the elderly comes along with additional costs. Consequently, there is no short-term incentive for doing so from a payer perspective. Future studies have to consider the long-term effects and other sectors.