An unsavory truth: sugar, more than salt, predisposes to hypertension and chronic disease.

Ferdinand et al have written a very important and insightful review article summarizing strong evidence recommending combined isosorbide dinitrate and hydralazine therapy to reduce mortality and morbidity for AfricanAmericans with heart failure and reduced ejection fraction. The investigators have correctly pointed out that more genetic information is necessary to assess the impact of many other polymorphisms that may affect drug response.Wewould like to add important information that is relevant to nitric oxide (NO) biology and may help to explain mechanisms possibly involved in racial differences observed when patients receive isosorbide dinitrate and hydralazine, which are drugs that directly or indirectly affect NO activity. There is now evidence that combinations of genetic polymorphisms (haplotypes) in the gene encoding endothelial NO synthase (eNOS) may be more informative than single eNOS polymorphisms with respect to endogenous NO formation and bioavailability. Importantly, a specific eNOS gene haplotype combining particular eNOS gene variants (C-Glu-b) is associatedwith lower levels of both nitrate and nitrite, which are products of NO metabolism and reflect endogenous NO formation. This association has been reported in both white and black subjects, although major differences exist in the distribution of haplotype frequency when whites and blacks are compared. This eNOS haplotype apparently predisposes to hypertension in obese children and adolescents, although different eNOS haplotypes have been associated with hypertension in adults. In line with the suggestion byFerdinand et al, it remains to be determined which eNOS haplotypes may predict the responses to isosorbide dinitrate and hydralazine therapy, particularly in African-Americans. In addition, there is evidence that black subjects have higher circulating concentrations of an endogenous NOS inhibitor, the asymmetric dimethylarginine, and therefore, black subjects may be exposed to additional factors impairing endogenous NO formation that are counteracted