Application Note - Magnetic Resonance

Investigating links between urinary excretion and cardiovascular disease*

*published as a Nature Communications article by Pazoki R, et al. Nature Communications 2019;10:3653.

Investigating links between urinary excretion and cardiovascular disease


Poor cardiovascular health is a major cause of morbidity arising from heart attacks, strokes, heart failure, chronic kidney disease, and the onset of vascular dementia. Furthermore, cardiovascular disease is the leading cause of death worldwide, accounting for 17.5 million annual deaths each year1. There is consequently much interest in reducing risk factors for cardiovascular disease.

One of the many risk factors for developing cardiovascular disease is high dietary intake of sodium. Excretion in the urine of both sodium and potassium has been shown to be associated with high blood pressure and cardiovascular disease2,3. Indeed, high sodium consumption was estimated to have caused 1.65 million deaths as a result of cardiovascular disease in 20104.

These findings are supported by research in animal models, epidemiological studies, and clinical trials that report sodium to be the leading modifiable cause of morbidity and mortality from cardiovascular disease, and hypertension4,5.

However, the underlying biological mechanisms that link sodium intake with cardiovascular risk have yet to be elucidated.

The link between sodium excretion and cardiovascular disease

Sodium is an essential nutrient, required for normal cellular and physiological function. Its levels are therefore tightly regulated within a narrow range. This is achieved by the exchange of sodium ions between intracellular and extracellular spaces by means of specialized transmembrane pumps that require energy in the form of ATP. These ATP-dependent sodium pumps actively transport sodium into the cell in exchange for potassium out of the cell6.

Salt (sodium chloride) is the main source of sodium intake, accounting for around 95% of daily intake with the vast majority being excreted by the kidneys. However, if blood levels of sodium become too high, this can lead to an increased risk of developing hypertension and a greater cardiovascular risk.

Being a readily managed factor, sodium consumption is a prime target for reducing the incidence of cardiovascular disease. Indeed, limiting sodium intake has been shown to effectively reduce the risk of cardiovascular disease in the general population7. The observed reduction was particularly marked among more susceptible individuals, such as those with underlying elevated blood pressure, and those with higher body mass index.

Evidence from prospective cohort studies including more than 300,000 people suggests that the risk of cardiovascular events is lowest in populations consuming an average sodium intake of 3–5 grams per day8. Increased risk of cardiovascular events was associated with sodium intake of more than 5 grams per day, and this was most prominent among individuals with hypertension.

The link between sodium intake and cardiovascular disease is supported by data from epidemiological studies, research in animal models, and randomized clinical trials that showed a significant, direct association of sodium, and inverse association of potassium intakes with blood pressure9,10. Furthermore, data from recent functional research provide evidence of a direct effect of sodium on lipid accumulation in adipocytes11. Since lipid metabolism is already known to influence cardiovascular risk, this suggests that sodium may increase the risk of developing cardiovascular disease directly as well as indirectly through the development of hypertension.

Although the relationship between sodium intake and blood pressure is well-established, the relationship of sodium level with the risk of cardiovascular disease is less clear.

Identifying common pathways for sodium excretion and cardiovascular disease

Further insight into the genetic and physiological pathways underlying the link between sodium intake and cardiovascular disease has recently been obtained in a genome-wide association study (GWAS) on urinary sodium and potassium excretion12.

Genomic and metabolomic analyses were conducted on over 2,000 serum samples. This included quantification of 105 lipoprotein subclasses using the Bruker IVDr LIpoprotein Subclass Analysis solution on the Avance IVDr platform.

The genetic basis of urinary sodium and potassium excretion was shown to be highly pleiotropic, reflecting the involvement of numerous pathways. A total of 63 novel sodium and potassium loci were identified, most of which were already associated with cardiovascular risk factors, such as lipid levels, dietary intake, smoking, and alcohol consumption12. Of the sodium and potassium loci identified, 12 were associated with metabolites known to be major components of lipid and lipoprotein fractions, including vitamin A and various amino acids12. The strongest urinary sodium locus was in the MLIP gene.

The data indicate a shared genetic component between urinary sodium and potassium expression and cardiovascular traits. Enrichment in functions related to behavioral response to stimuli was reported, and this might indicate that the heritable component of urinary sodium and potassium excretion could be driven by the behavioral response.

The numerous urinary traits identified in this research confirmed that there is a complex network of interplay between dietary intake, homeostatic mechanisms that tightly control intra- and extracellular concentrations of sodium and potassium excretion via the kidney, and other behavioral pathways.

Although several potential genetic mechanisms were identified, the complexity of the relationship, with numerous inter-dependencies, makes the unraveling of causal pathways between urinary excretion and other variables, such as BMI extremely challenging.


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3. Mente A, et al. New Engl. J. Med. 2014;371:601–611.

4. Mozaffarian D, et al. New Engl. J. Med. 2014;371:624–634.

5. Gao S, et al. Arterioscler. Thromb. Vasc. Biol. 2017;37:598–606.

6. Skou JC. Chem. Int. Ed. Engl. 1998;37:2320–2328.

7. Morrison AC, Ness RB. Annual Review of Public Health 2011;32:71-90.

8. O'Donnell M, et al. Circulation Research 2015;116:

9. Dyer AR, et al. Am. J. Epidemiol. 1994;139:940–951.

10. Alderman M. N. Engl. J. Med. 2001;344:1716–1719.

11. Gao S, et al. Arterioscler. Thromb. Vasc. Biol. 2017;37:598–606.

12. Pazoki R, et al. Nature Communications 2019;10:3653.

* Bruker NMR Instruments are for research Use Only. Not for Use in Clinical Diagnostic Procedures.