This is the first study to assess the effects of low dietary salt ingestion in subjects with resistant hypertension. Dietary salt restriction substantially reduced both office and 24-hr ambulatory BP. The degree of BP reduction induced by dietary salt restriction in this group of subjects with resistant hypertension is considerably larger than reductions observed in normotensive populations or in cohorts of general hypertensive subjects. These results demonstrate that excessive dietary salt ingestion contributes importantly to elevated BP levels in patients with resistant hypertension.
Observational studies of large, unselected cohorts indicate a positive correlation between dietary salt intake and BP. In the INTERSALT Cooperative Research study, urinary sodium was related to the slope of BP increases with age, but not to median BP or prevalence of hypertension.1
In this study, increases in 100 mmol per day of dietary sodium were associated with increases in systolic BP of 2.2 mm Hg. Similarly, intervention studies indicate that reductions in dietary salt intake by 50 mmol per day reduce mean systolic BP in normotensive subjects by approximately 1.7–2.9 mm Hg.[15
Studies of hypertensive populations suggest a stronger relation between dietary salt and severity of hypertension than observed in normotensive subjects. In evaluations of hypertensive cohorts, dietary salt restriction lowers systolic BP by 2–10 mm Hg and diastolic BP by 1–6 mm Hg.[17
]For example, in the Dietary Approaches to Stop Hypertension (DASH) trial, 412 patients with mild-moderate hypertension (range 120–159/80–95 mm Hg) were randomized to the DASH diet (which is rich in vegetables, fruits, and low-fat dairy products) or control diet.[17
] Each group received increasing levels of dietary sodium (50, 100, 150 mmol/24-hr) for 30 consecutive days in a cross-over design. As compared with the control diet during high dietary sodium intake, the DASH diet and low dietary sodium intake lowered systolic BP by 11.5 mm Hg in participants with hypertension (12.6 mm Hg for blacks; 9.5 mm Hg for others).
In an evaluation of subjects with severe hypertension, Fotherby et al. assessed the BP effects of low dietary salt ingestion in 17 untreated hypertensive subjects with a mean office BP of 176±17/96±11 mm Hg.[20
]After 5 weeks of low-salt diet (80–100 mmol/day), 24-hr systolic and diastolic BP decreased by 5 and 2 mm Hg, respectively. In a study by Gavras et al, a much greater BP reduction was achieved with extreme dietary salt restriction in combination with intense diuretic therapy in subjects with uncontrolled BP on maximal doses of at least 2 agents (a diuretic and a sympatholytic agent).[34
]In this study, BP decreased on average by 21/7 mm Hg during ingestion of a diet limited to 10 mmol of sodium with concurrent administration of either hydrochlorothiazide 100 mg or furosemide 80 to 200 mg daily. In the current study, we observe a similar degree of BP reduction with less severe sodium restriction (50 mmol/day) and with continuation of hydrochlorothiazide as conventionally dosed.
The current results suggest that patients with resistant hypertension are exquisitely salt sensitive, manifesting a mean reduction in office BP of 22.7/9.1 mm Hg in response to a low-salt diet. The magnitude of BP reduction was confirmed with the demonstration of a 20.7/9.6 mm Hg reduction in daytime BP by ABPM. This degree of BP reduction is much larger than reductions previously observed in unselected hypertensive subjects. It suggests that patients with resistant hypertension are particularly salt sensitive and emphasizes the importance of low dietary salt intake in the clinical management of resistant hypertension. Treatment with renin-angiotensin system blockers could partially explain the enhanced salt-sensitivity of these subjects. Animal studies demonstrate that long-term administration of angiotensin converting enzyme inhibitors heightens the hypertensive response to high-dietary salt.[35
In the present study, the increases in PRA and the decreases in BNP, creatinine clearance, and body weight during dietary salt restriction are consistent with reduction in intravascular volume. Overall, these findings provide support for the hypothesis that persistent fluid retention contributes to resistance to antihypertensive treatment.[37
]The current results suggest that this persistent fluid retention is attributable, at least in part, to excess dietary salt. Importantly from a clinical perspective, the intravascular fluid retention observed during consumption of the high-salt diet occurred in spite of all subjects receiving hydrochlorothiazide 25 mg daily. This suggests that conventional doses of hydrochlorothiazide, the most commonly used diuretic in the United States, may not be sufficient to overcome sodium-induced fluid retention, at least in this very salt sensitive cohort.
In the current study, we also demonstrate a tendency toward reduction in vascular stiffness with low dietary salt intake as indicated by reductions in PWV and AIx. The lack of significance of changes in AIx and PWV may have occurred due to measurement errors or to the small sample size. If the vascular changes are confirmed in subsequent studies, it would suggest that during reduced dietary salt ingestion improvements in vascular stiffness combine with reductions in intravascular volume to lower BP.
In prior studies we have reported a very high prevalence of aldosterone excess, including classical primary aldosteronism, in patients with resistant hypertension.[37
]Accordingly, aldosterone excess, in causing sodium and fluid retention, likely contributed to salt sensitivity in these patients. In addition, subtle chronic kidney disease may also have exacerbated sodium retention, although this effect should have been minimized as patients with overt renal dysfunction, i.e., creatinine clearance <60 ml/min, were excluded from enrollment.
Stimulation of the renin-angiotensin-aldosterone system with low-salt ingestion, as observed in the current study, has raised concerns about potentially accelerating target-organ damage.[41
]We think this unlikely, at least in the current cohort, as the sizable decrease in BP observed with salt restriction would be expected to substantially reduce cardiovascular risk. Further, we have previously shown that renal deterioration in patients with resistant hypertension, as indicated by the degree of proteinuria, is, in part, volume dependent.[42
] In addition, Siragy and coworkers have shown that salt restriction in rats activates the kalikrein kinin system with release of bradykinin, prostaglandin E2
, and cGMP in the kidney, most likely via activation of AT2
receptors, which should have favorable effects on vascular function.[44
] Taken together, the reduction in intravascular volume that occurs during low dietary salt ingestion should protect against target-organ damage separate from improvements in blood pressure.
Strengths of the present study include its cross-over, randomized design, use of ABPM, and confirmation of dietary adherence by measurement of 24-hr urinary sodium excretion. Weaknesses include evaluation of a relatively small number of subjects, unblinded administration of the salt diets, and the short duration of the dietary treatment periods. Analysis of data from trials of salt reduction suggest that even greater BP reduction would be achieved with a longer intervention period.[4
] Although the sample size is small, the crossover design provided sufficient power to assess the primary endpoints. Bias from unblinded administration of the 2 dietary was minimized by use of ABPM to quantify change in BP.[46
There was slightly higher urinary potassium excretion during the low- compared to the high-salt diet (difference of 11.4 mmol/day). The difference may have been related to upregulation of the renin-angiotensin-aldosterone system during low-salt intake. While higher potassium intake may have contributed to the reduction in BP observed during low-salt intake, the effect would be anticipated to be modest as trials of potassium supplementation indicate that on average an additional intake of 75 mmol/day lowers BP by 3.1/2.0 mm Hg.[48
An important clinical consideration to be addressed in a separate study is whether or not the current degree of dietary sodium restriction can be accomplished and maintained by patients absent home delivery of specially prepared meals. Taking in consideration that 75% of the daily intake of sodium in Westernized countries is from salt inserted during commercial processing of foods and/or during food preparation by restaurants [49
], reductions in the sodium content in the food supply would be a critical component to achieve lower levels of sodium intake.
All of the subjects enrolled into the current study reported having been previously advised to lower their dietary salt intake and all reported having done so. However, the baseline 24-hr sodium excretion in these subjects averaged 195 mmol/24-hr corresponding to ingestion of 11.6 grams of salt per day. While the current analysis was limited to a small number of subjects, this amount of salt ingestion is similar to that observed in an analysis of 274 patients with resistant hypertension, in whom urinary sodium excretion during ingestion their normal diet averaged 187 mmol/24-hr or 11 grams of salt.[37
]These findings indicate that in spite of reporting a salt restricted diet, these patients were continuing to ingest a diet very high in salt content.
In summary, the current study demonstrates that high dietary salt ingestion is an important cause of resistant hypertension. This effect is related to excess intravascular fluid retention that persists in spite of conventional thiazide diuretic use. These data emphasize that the clinical management of patients with resistant hypertension should include intensive dietary salt restriction. The degree of salt restriction needed to overcome resistance to pharmacologic therapies needs to be defined, but is unlikely to be accomplished without expert dietary consultation.