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Abstract-Chloride (Cl − ) is the major extracellular anion in the body, accompanying sodium (Na + ), and is primarily derived from dietary sources. Data suggest that increased dietary Cl − intake increases blood pressure, yet paradoxically, higher serum Cl − appears associated with lower mortality and cardiovascular risk. This implies that serum Cl − also reflects risk pathways independent of blood pressure, serum Na + , and bicarbonate (HCO 3 − ). We analyzed 12 968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl − was an independent predictor of mortality. To distinguish the effect of Cl − from Na + and HCO 3 − , we adjusted for these electrolytes and also performed the analysis stratified by Na + /HCO 3 − and Cl − levels. Generalized estimating equation was used to determine the effect of baseline Cl − on follow-up blood pressure. The total time at risk was 197 101 person-years. The lowest quintile of serum Cl − (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl − was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na + , K + , and HCO3 − levels. The group with Na + >135 and Cl − >100 had the best survival, and compared with this group, the Na + >135 and Cl − <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl − (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl

Abstract-Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor.

Among the environmental factors that affect blood pressure, dietary sodium chloride has been studied the most, and there is general consensus that increased sodium chloride intake increases blood pressure. There is accruing evidence that chloride may have a role in blood pressure regulation which may perhaps be even more important than that of Na+. Though more than 85 % of Na+ is consumed as sodium chloride, there is evidence that Na+ and Cl− concentrations do not go necessarily hand in hand since they may originate from different sources. Hence, elucidating the role of Cl− as an independent player in blood pressure regulation will have clinical and public health implications in addition to advancing our understanding of electrolyte-mediated blood pressure regulation. In this review, we describe the evidence that support an independent role for Cl− on hypertension and cardiovascular health.

H yperuricemia is associated with incident hypertension, 1 and preclinical studies support a role for hyperuricemia in the development of hypertension. Hyperuricemia has been shown to raise blood pressure (BP) in normotensive rats, and this rise is attenuated by urate-lowering drugs.2 Furthermore, sustained hyperuricemia has been shown to induce a primary renal arteriolopathy and a salt-sensitive rise in BP in experimental models. Recently, randomized placebo-controlled and blinded clinical trials have shown that urate-lowering drugs reduce BP in hyperuricemic, hypertensive adolescents and in obese adolescents with prehypertension. 4,5 In 1 study, both allopurinol (a xanthine oxidase inhibitor that reduces the formation of uric acid) and probenecid (a uricosuric drug) were studied.5 For similar reductions in uric acid, both agents were associated with significant reduction in systolic BP, suggesting that the effect is mediated by uric acid reduction per se.Whether serum uric acid has a direct pathophysiological role in the sequelae of hypertension in older adults is less clear. A recent analysis of 6984 patients undergoing treatment for hypertension showed no relationship between baseline serum uric acid level and long-term BP change, although it did show an association between high uric acid level and decline in renal function.6 Equally, it is less clear whether drugs that lower uric acid also lower BP in adults with hypertension. A meta-analysis of the effect of allopurinol on BP, combining data from 10 clinical studies with 738 participants, found a small reduction in BP in allopurinol-treated patients (3.3 mm Hg; 95% confidence interval [CI], −1.4 to −5.3 mm Hg) for systolic BP. 7 We hypothesized that, similar to in adolescents, the initiation of allopurinol would be associated with a fall in BP in older adults with hypertension and that higher doses would have a greater effect. We extracted data from the UK Clinical Practice Research Datalink (CPRD, formally General Practice Research Database) to test this hypothesis. Materials and MethodsThe CPRD is the world's largest computerized database of anonymized longitudinal clinical records from primary care.8 It contains data on demographic characteristics, diagnoses, prescriptions, referrals to secondary care, and medical history.9 Information is collected from >500 practices giving details of >3.4 million patients, and the Abstract-Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patie...