In observational analyses of average excretion over a 1½ to 3 year period, we found a suggested positive relation of sodium excretion and an inverse relation of potassium excretion with risk of CVD, but neither were statistically significant when considered separately. Both measures strengthened when modeled jointly, with opposite but similar effects on risk. However, the sodium-potassium ratio displayed the strongest and most statistically significant association, with a 24% increase in risk per sodium/potassium unit that was similar for CHD and stroke and consistent within subgroups.
Few epidemiologic studies have jointly examined the relation of sodium and potassium or their ratio to CVD. Most large longitudinal studies of potassium intake have used food frequency questionnaires,31, 32
which have difficulty fully capturing sodium intake. The sodium-potassium ratio has, however, been found to be a somewhat stronger predictor of BP than sodium alone in data from TOHP I,15
and Southern California.16
Also, in a meta-analysis of trials of potassium supplementation, the effect on blood pressure was modified by average sodium intake.5
We found that the ratio was the strongest of the three measures in predicting CVD, and that the effect of both sodium and potassium were enhanced when the other was included in the model, supporting the notion that the joint activity of these two electrolytes may play an important biologic role.12
Liew et al24
demonstrate that using a ratio makes the implicit assumption that the regression coefficients for the two variables are equal in magnitude but opposite in direction. This was true in our data when sodium and potassium were expressed per SD unit. Further, the ratio provided a better fit to the data, and the addition of a multiplicative interaction term was not statistically significant.23
It is possible that the ratio offers a correction for characteristics of the urine collection, such as completeness over the 24-hour period and correlated measurement errors.27
Whether the improved fit of the ratio is due to a inherent biologic synergism12
or to an artifact of the excretion measurements is unclear.
Previous studies have largely relied on dietary records or recalls for estimating sodium intake, which tend to be less precise than urinary measures, and results have been inconsistent.33-37
Four studies have examined a single measure of urinary sodium excretion and CHD endpoints. One found an inverse relation with MI in hypertensive men but not women,38-40
one found a positive association with CHD in women only,41
and one found a positive relation with CHD and total mortality that appeared stronger in overweight men.42
Most recently, the Rotterdam Study found no effect of sodium, potassium or the ratio on CVD or mortality, except for an effect of the ratio on mortality among those with BMI≥25 kg/m2
That study used a single overnight urine, however, which may have included more measurement error and attenuated any effects. Exposure in TOHP was an average of 3 to 7 24-hour excretions taken over a period of 1 to 3 years, reducing measurement error and within-person variability.15, 18
Fewer studies have examined potassium and cardiovascular disease, with most attention paid to stroke. Higher dietary potassium has generally been associated with decreased stroke incidence or mortality,23, 31, 44-46
although results are sometimes marginal.32, 47
Few studies have examined urinary potassium and risk of CHD.41
We did not find an inverse association with stroke in adjusted analyses, but this was limited by the small number of strokes in our data. A stronger, though non-significant, association was found with total CVD.
Some observational studies have found effects of sodium and potassium on stroke or CVD that may be independent of effects on BP36, 42, 44
or hypertension,31, 32
as in the present study. Urinary sodium excretion has been found to be positively related to urinary albumin excretion,48-50
suggesting that the effect of sodium on CVD may be partially mediated by endothelial damage. Other proposed mechanisms for a cardiovascular effect of sodium independent of BP include a direct effect on left-ventricular mass51
or increased blood flow and vascular reactivity with higher sodium exposure.52, 53
The present study found an effect on CVD outcomes even after controlling for blood pressure. We did not have measured follow-up BP, however, so cannot determine if the sodium observation is fully independent of blood pressure.
Other limitations of the present study include a lack of complete follow-up of trial participants for nonfatal events. Response, however, did not appear to be related to excretion measures. We also did not have a full complement of CVD risk factors, such as lipids, for adjustment. In addition, we used urinary excretion as our exposure, which is assumed to adequately reflect dietary intake. We also had no sodium excretions during follow-up and thus could not account for possible changes during the follow-up period.
The current analysis of the TOHP follow-up data included only those not in an active sodium intervention to better represent long-term usual intake. Previous independent analyses of the TOHP trials found a significant reduction in total CVD as well as a suggested reduction in total mortality among those assigned to the sodium reduction intervention.9
A cluster-randomized trial conducted among elderly residents of a veterans retirement home in Taiwan compared potassium-enriched salt, containing less sodium, to regular salt, and found a significant 41% reduction in CVD mortality in the experimental group.10
Thus, recent randomized trial data support our findings of a reduced risk of CVD among those with lower sodium and/or higher potassium. The 2005 US Dietary Guidelines54
recommend consuming potassium-rich foods, such as fruits and vegetables, as well as consuming little salt. The current totality of evidence suggests that such lowering of dietary sodium intake while increasing potassium consumption at the population level might reduce the incidence of cardiovascular disease.