Correspondence
Uric Acid and Cardiovascular Risk
N Engl J Med 2009; 360:538-541January 29, 2009
- Article
To the Editor:
In their review of uric acid and cardiovascular disease, Feig and colleagues (Oct. 23 issue)1 state that “it is worth noting that humans and apes have higher uric acid levels than most other mammals, since they lack the hepatic enzyme uricase, which degrades uric acid to allantoin.” That is not entirely accurate. The uricase gene underwent mutational silencing during hominoid evolution in the Miocene epoch some 8 million to 24 million years ago, an event that was postulated to confer a selective advantage through blood-pressure homeostasis mediated by uric acid in low-salt environments.2 The original mutation probably occurred when the lineage of the great apes (chimpanzees, gorillas, and orangutans) diverged from that of the lesser apes. Therefore, gibbons and siamangs do not have the uricase mutation linked to hyperuricemia.3 Furthermore, a very recent discovery through positional cloning of the hyperuricemia locus in the Dalmatian dog proved that SLC2A9 splice variants, which encode a combination high-capacity urate transporter and high-affinity glucose–fructose transporter shared by humans,4 contributes to 5 to 10% of serum urate and explains in part why humans have higher uric acid levels than most other mammals.5
5 ReferencesMelvin K. Leow, M.D., Ph.D.
Brenner Center for Molecular Medicine, Singapore 117609, Singapore
mleowsj@massmed.org 1
Feig DI ,Kang D-H ,Johnson RJ . Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-1821
Full Text | Web of Science | Medline2
Watanabe S ,Kang DH ,Feng L , et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 2002;40:355-360
CrossRef | Web of Science | Medline3
Wu XW ,Muzny DM ,Lee CC ,Caskey CT . Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78-84
CrossRef | Web of Science | Medline4
Bannasch D ,Safra N ,Young A ,Karmi N ,Schaible RS ,Ling GV . Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog. PLoS Genet 2008;4:e1000246-e1000246
CrossRef | Web of Science | Medline5
Vitart V ,Rudan I ,Hayward C , et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008;40:437-442
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To the Editor:
Feig et al. mention the association between genetic polymorphism and serum levels of uric acid and several cardiovascular risk factors. I would like to add that other chromosomal locations have been discovered, such as those found on chromosome 15,1 chromosome 2,2 chromosome 4,3 and chromosome 6.4
4 ReferencesCristóbal Bueno, M.D.
Hospital Infanta Cristina, 06010 Badajoz, Spain
cbueno3@hotmail.com 1
Yang Q ,Guo CY ,Cupples LA ,Levy D ,Wilson PW ,Fox CS . Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 2005;54:1435-1441
CrossRef | Web of Science | Medline2
Tang W ,Miller MB ,Rich SS , et al. Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Diabetes 2003;52:2840-2847
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Cheng LS ,Chiang SL ,Tu HP , et al. Genomewide scan for gout in Taiwanese aborigines reveals linkage to chromosome 4q25. Am J Hum Genet 2004;75:498-503
CrossRef | Web of Science | Medline4
Nath SD ,Voruganti VS ,Arar NH , et al. Genome scan for determinants of serum uric acid variability. J Am Soc Nephrol 2007;18:3156-3163
CrossRef | Web of Science | Medline
To the Editor:
On the basis of several studies in humans and animals, Feig et al. speculate that uric acid could be directly responsible for increasing blood pressure. If this is true, should not the blood pressure be elevated in patients with genetic disorders such as some forms of glycogen-storage disease and the Lesch–Nyhan syndrome? In these genetic disorders, the levels of uric acid are markedly elevated, but hypertension is not one of the cardinal manifestations before renal involvement.
Nitin Trivedi, M.D.
Saint Vincent Hospital, Worcester, MA 01608
nitin.trivedi@stvincenthospital. com To the Editor:
Whether uric acid is a marker or a risk factor for cardiovascular disease remains unclear. If uric acid is harmful, then why do the kidneys reclaim more than 90% of the amount filtered? Uric acid is a potent antioxidant and contributes to more than 50% of the antioxidant capacity of blood. In hominids as a means to increase blood pressure, whether in response to maintaining an upright posture or to a low-salt and low-purine diet, mutation of uricase occurred and resulted in higher uric acid levels in humans than in other mammals. Purine metabolism by xanthine oxidase results in the production of uric acid and reactive oxygen species. Since uric acid is an antioxidant, it binds to reactive oxygen species to form stable nitric oxide donors. Xanthine oxidase is up-regulated during oxidative stress and disease states. It seems to me that uric acid is probably a marker for rather than a cause of endothelial dysfunction.1 The inhibition of xanthine oxidase may be more beneficial than just decreasing the uric acid level by other means that do not reduce the production of reactive oxygen species.
1 ReferencesMalvinder S. Parmar, M.B., M.S.
Northern Ontario School of Medicine, Timmins, ON P4N 8P2, Canada
atbeat@ntl.sympatico. ca 1
Tsukimori K ,Yoshitomi T ,Morokuma S ,Fukushima K ,Wake N . Serum uric acid levels correlate with plasma hydrogen peroxide and protein carbonyl levels in preeclampsia. Am J Hypertens 2008;21:1343-1346
CrossRef | Web of Science | Medline
To the Editor:
In their review of the associations between uric acid and cardiovascular diseases (e.g., hypertension, the metabolic syndrome, and chronic kidney disease), Feig et al. missed another important cardiovascular disease: heart failure. The rate of heart failure has gradually increased in developed countries and is known to be closely related to uric acid levels. Thus, we wish there had been a discussion about the relation between uric acid and heart failure in their review article.
Anker et al. reported that the uric acid level was a strong, independent prognostic marker in patients with heart failure.1 In the Seattle Heart Failure Model, uric acid was included for the prediction model of survival in patients with heart failure.2 Recently, the clinical benefits of oxypurinol, a xanthine oxidase inhibitor that is known to decrease the level of uric acid, were suggested in patients with an elevated uric acid level in a manner correlating with the results of the Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) study.3 Therefore, studies that examine whether uric acid might serve as a valuable prognostic biomarker as well as an overlooked drug target in patients with heart failure would seem to be of interest.
3 ReferencesJaewon Oh, M.D.
Ho Youn Won, M.D.
Seok-Min Kang, M.D., Ph.D.
Yonsei University College of Medicine, Seoul 120-752, South Korea1
Anker SD ,Doehner W ,Rauchhaus M , et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107:1991-1997
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Levy WC ,Mozaffarian D ,Linker DT , et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113:1424-1433
CrossRef | Web of Science | Medline3
Hare JM ,Mangal B ,Brown J , et al. Impact of oxypurinol in patients with symptomatic heart failure: results of the OPT-CHF study. J Am Coll Cardiol 2008;51:2301-2309
CrossRef | Web of Science | Medline
To the Editor:
Feig et al. present evidence that an elevated serum level of uric acid is strongly associated with cardiovascular and renal risks and that the lowering of uric acid levels with allopurinol mitigates those risks. Given the strengths of the evidence that uric acid is both a marker and a mechanism of disease, their conclusion that allopurinol therapy “cannot be recommended” for asymptomatic hyperuricemia seems surprising. The authors suggest that their data are the basis for a hypothesis that still requires testing and note that allopurinol can cause “occasional” severe reactions. However, that is a vast overstatement of the risks of allopurinol, a drug that has been used extensively for more than 40 years and has an acceptable side-effect profile. Furthermore, severe reactions can probably be avoided by stopping the drug immediately if a rash or other unexplained illness develops. I would suggest that a more prudent interpretation is that until better evidence becomes available, allopurinol therapy is “not unreasonable” in patients with asymptomatic hyperuricemia whose condition cannot be treated by simple measures, such as avoiding a high intake of meat or excessive diuretic therapy.
Lee A. Hebert, M.D.
Ohio State University Medical Center, Columbus, OH 43210Brad Rovin, M.D.
Ohio State University, Columbus, OH 43210Author/Editor Response
Leow states that the uricase mutation involved only the great apes. Although the greater apes (and humans) lack uricase because of a nonsense mutation in codon 33 of exon 2, the lesser apes (gibbons and siamangs) also have a nonsense mutation involving uricase (i.e., in codon 18 of exon 2).1 The loss of uricase makes humans uniquely susceptible to diet-induced alterations in uric acid levels. As both Leow and Bueno indicate, the regulation of uric acid is complex and includes genetic polymorphisms in urate transporters (URAT1 and SLC2A9) and other as-yet-unidentified genes.
Trivedi asks why hypertension is not a cardinal feature of hereditary hyperuricemic conditions, such as the Lesch–Nyhan syndrome and glycogen-storage diseases. In addition to hyperuricemia, the Lesch–Nyhan syndrome has neurologic and other manifestations that could have an effect on blood pressure. In type 1 glycogen-storage disease, both hyperuricemia and hypertension are common.2,3 Regardless, the role of uric acid in blood pressure in these conditions will not be known until studies are performed that evaluate the effects of lowering uric acid levels. Other mechanisms, such as dysfunction of the renal and sympathetic nervous systems and altered production of vasoactive mediators, could also change the relative effect of uric acid on blood pressure.
Parmar questions whether uric acid is a mediator of cardiovascular risk or whether an elevated uric acid level reflects underlying activation of xanthine oxidase. Xanthine oxidase may cause cardiovascular disease through oxidant production rather than through uric acid. Although studies in animals and cell culture largely support a direct role for uric acid in endothelial dysfunction and hypertension, we agree that this question is unresolved in humans. Furthermore, experimental studies suggest that the intracellular uric acid concentration is key in the mediation of its cellular effects.4,5 Thus, it will also be important to determine how clinical interventions act on serum concentrations and intracellular levels of uric acid.
Oh et al. comment on the potential role of uric acid in congestive heart failure. Space was limited for our review, but we agree that more studies are indicated to determine the role of uric acid in this important cardiovascular condition.
Hebert suggests that a more liberal application of hypouricemic therapy would be prudent, given current physiological and epidemiologic data. We agree that “asymptomatic hyperuricemia” may be a misnomer in light of evidence of the link between uric acid and hypertension, insulin resistance, and cardiovascular risk. Additional clinical trials may determine whether the lowering of uric acid may be beneficial not only in the treatment but also in the prevention of some forms of hypertension. All treatments must be evaluated in terms of both efficacy and side effects. Although allopurinol has been used for more than 40 years, side effects may occur in 1 to 3% of patients and rarely can be life-threatening (www.drugs.com/pro/allopurinol.html). Given these concerns, we believe that more clinical trials are needed to assess efficacy and potential adverse events before any general treatment recommendations can be made.
5 ReferencesDaniel I. Feig, M.D., Ph.D.
Baylor College of Medicine, Houston, TX 77030
dfeig@bcm.tmc. edu Richard J. Johnson, M.D.
University of Colorado Health Sciences Center, Denver, CO 802621
Oda M ,Satta Y ,Takenaka O ,Takahata N . Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002;19:640-653
Web of Science | Medline2
Yetman RJ ,Andrew-Casal M ,Hermida RC , et al. Circadian pattern of blood pressure, heart rate, and double product in liver glycogen storage disease. Chronobiol Int 2002;19:765-783
CrossRef | Web of Science | Medline3
Chen YT ,Coleman RA ,Scheinman JI ,Kolbeck PC ,Sidbury JB . Renal disease in type I glycogen storage disease. N Engl J Med 1988;318:7-11
Full Text | Web of Science | Medline4
Kang DH ,Han L ,Ouyang X , et al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol 2005;25:425-433
CrossRef | Web of Science | Medline5
Kang DH ,Park SK ,Lee IK ,Johnson RJ . Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005;16:3553-3562
CrossRef | Web of Science | Medline
- Citing Articles (1)
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1
Sanae Hamaguchi, Tomoo Furumoto, Miyuki Tsuchihashi-Makaya, Kazutomo Goto, Daisuke Goto, Takashi Yokota, Shintaro Kinugawa, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui. (2011) Hyperuricemia predicts adverse outcomes in patients with heart failure. International Journal of Cardiology 151:2, 143-147
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