To the Editor: The study of tilarginine (L-NG-monomethylarginine [L-NMMA])by the Tilarginine Acetate Injection in a Randomized InternationalStudy in Unstable MI Patients With Cardiogenic Shock (TRIUMPH) investigators1 indicates that nonspecific inhibition of nitric oxide synthase (NOS) using L-NMMA does not improve 30-day survival or 6-month mortality rate in patients with myocardial infarction (MI) complicated by cardiogenic shock. Of note is that when renal function was assessed as a continuous variable, patients with higher creatinine levels tended to have worse outcomes with L-NMMA.
Elevated plasma concentration of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) leads to the development of endothelial dysfunction and represents a novel cardiovascular risk factor and a predictor for all-cause and cardiovascular mortality.2 Even minor impairment of renal function is associated with increased ADMA levels.3 Elevated levels of ADMA have also been observed in critically ill patients, in whom they are inversely associated with survival. Moreover, short-term administration of ADMA to healthy men reduces renal perfusion and cardiac output.4 This seems to be important because in the TRIUMPH trial the group treated with L-NMMA showed no change of renal function while the placebo group had improved serum creatinine levels. Therefore, elevated endogenous levels of the NOS inhibitor ADMA due to underlying renal dysfunction and critical illness might predispose to impairment of microcirculation in several crucial organ systems when an additional, external nonselective NOS inhibitor (L-NMMA) is administered.
It would be important to reassess the results of this study by using estimated glomerular filtration rates, as recently suggested by an American Heart Association scientific statement for patients at increased risk for cardiovascular disease,5 as well as by measuring plasma levels of ADMA. Adjusting for underlying differences in glomerular filtration rate and ADMA levels, as well as assessing a possible deleterious effect of L-NMMA on renal function, may help to interpret the results of the TRIUMPH study.
Another mechanism not considered by the authors is the possible deleterious effects of NOS inhibition on cardiovascular regenerative processes. Bone marrow–derived endothelial progenitor cells (EPCs) participate in neovascularization of ischemic tissues and vascular homeostasis.6 Patients with coronary artery disease with low amounts of circulating EPCs are at increased risk for cardiovascular events.6 Endothelial NOS is of paramount importance for mobilization and function of EPCs. Increased levels of ADMA impair mobilization, differentiation, and function of EPCs in patients with coronary artery disease.6 Therefore, interfering with NO production by non–isoform-specific inhibition of NOS might impair endogenous repair processes after MI and contribute to a detrimental cardiovascular outcome.
Financial Disclosures: None reported.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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