Abstract
Objective
Sacubitril/valsartan combines the effects of angiotensin receptor blockers (ARBs) with increased atrial natriuretic peptide (ANP) levels through neprilysin inhibition. ANP has vasodilatory and natriuretic effects. ARB efficacy is diminished by high daily salt intake (HDSI) in hypertension; however, it is unclear whether HDSI similarly affects the efficacy of sacubitril/valsartan. We aimed to assess the effect of ANP on blood pressure (BP) in patients with hypertension and HDSI treated with sacubitril/valsartan.
Methods
Fifty consecutive patients with hypertension previously on ARBs were enrolled and switched to sacubitril/valsartan (200 mg). BP and ANP levels were measured at baseline and two weeks after initiation. DSI was calculated from spot urine samples at these time points. Patients were divided into HDSI and low DSI (LDSI) groups based on the median baseline DSI.
Results
All patients had chronic kidney disease. The baseline average systolic/diastolic BP was 151±11/89±16 mmHg. At follow-up, both groups showed significant absolute and percentage BP reductions, with no significant differences between the groups. The DSI levels obtained by urine tests were significantly higher in the HDSI group than in the LDSI group. ANP levels increased in both groups at follow-up and more significantly in the HDSI group than in the LDSI group (573±585 vs. 84±78 pg/mL, p＜0.001; 144±98% vs. 35±28%, p＜0.001).
Conclusion
Sacubitril/valsartan was effective in lowering BP not only in patients with lower salt intake but also in patients with higher salt intake. The notable medication-induced increase in ANP levels may contribute to BP reduction through vasodilatory and natriuretic actions.
Keywords: angiotensin receptors, atrial natriuretic peptide, dietary sodium chloride, neprilysin
Introduction
Hypertension is one of the most prevalent modifiable risk factors for cardiovascular diseases, including stroke and congestive heart failure (1). The global prevalence of hypertension is increasing owing to the aging of the population and increased exposure to lifestyle risk factors, including unhealthy diets and cigarette smoking (i.e., high sodium and low potassium intake and lack of physical activity) (2). Antihypertensives such as angiotensin receptor blockers (ARBs) have been proven to lower morbidity and mortality related to cardiovascular diseases (3). However, in patients with high sodium intake or salt-sensitive hypertension, the antihypertensive efficacy of ARBs is diminished (4,5). Sacubitril/valsartan (also known as LCZ696) is a first-in-class angiotensin receptor/neprilysin inhibitor that offers highly selective inhibition of both neprilysin and angiotensin receptors (6,7). In response to this treatment, the levels of atrial natriuretic peptide (ANP), which has vasodilatory and natriuretic effects, have been reported to increase (8-10). Considering these effects, increased ANP levels may lead to reduced blood pressure. However, whether these ANP functions are affected by high sodium intake remains unclear.
Hence, this study aimed to investigate the effects of ANP on blood pressure in patients with hypertension and high sodium intake who were treated with sacubitril/valsartan.
Materials and Methods
Study population
The clinical outcomes of 50 patients with essential hypertension treated with ARBs at our affiliated centers (Niigata, Japan) between September 2023 and September 2024 were prospectively assessed. We calculated the required sample size based on a previous study that enrolled patients with high salt intake in both ARB and ARB plus diuretic groups (11). In that study, the mean ± SD difference in systolic blood pressure was approximately 15±17 mmHg. Based on these values, the estimated sample size was 21 patients per group (Î ± =0.05; power =80%). The definition of essential hypertension in the present study was as follows: the inclusion criteria were a systolic pressure of ≥140 mmHg or diastolic pressure of ≥90 mmHg irrespective of the treatment with antihypertensive drugs; and the exclusion criteria were a history or evidence of a secondary form of hypertension, a transient ischemic cerebral attack during the 6 months before enrollment, a history of percutaneous coronary intervention during the 6 months before enrollment, non-compensated heart failure, chronic kidney disease with an estimated glomerular filtration rate of ＜30 mL/min/1.73 m2, or a history of change in medical therapy during the 6 months before enrollment.
The study protocol was approved by the Institutional Ethics Committee of Toyosaka Hospital, and written informed consent was obtained from all patients.
Timings of biomarker and blood pressure measurements
Blood pressure measurements and blood and urine tests were performed at baseline and at the 2-week follow-up after starting the sacubitril/valsartan treatment. Blood pressure was measured in the sitting position after 5 min of rest using either an automated, validated device (e.g., OMRON, Kyoto, Japan) or a standard sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Blood pressure was measured three times, and the average was used. The patients were instructed to avoid caffeine and smoking for at least 30 min before the measurement. The measurement was conducted in a quiet room with the patient comfortably seated and their back supported by a chair.
ANP levels were measured at SRL (Tokyo, Japan). Blood tests for ANP were performed after resting for at least 20 min. ANP levels were measured before and two weeks after the start of sacubitril/valsartan therapy.
Additionally, to evaluate daily salt intake (DSI), urinary tests were performed three times on different days during the week prior to both baseline and follow-up assessments. The average value is used as the DSI. According to the Japanese hypertensive guidelines, Tanaka's formula was used to evaluate the DSI in patients (12).
Administration of antihypertensive medication
Sacubitril/valsartan (200 mg) was administered in accordance with the manufacturer's recommendations. During the 2-week period, no change in antihypertensive medication was permitted unless the patient experienced severe hypertension or side effects of sacubitril/valsartan, such as hyperkalemia. In addition, sacubitril/valsartan is not recommended as a first-line antihypertensive drug in Japan. No combination of sacubitril/valsartan with other antihypertensive drugs, including calcium channel blockers, was allowed, except in combination with ARBs or angiotensin-converting enzyme inhibitors. Therefore, only patients who were prescribed ARBs were enrolled to prevent confounding factors, especially in terms of antihypertensive effects. Additionally, patients were encouraged to maintain their pretreatment lifestyle, including salt intake.
Statistical analyses
Based on the median DSI value of 9.2 g/day, as determined at baseline, the patients were divided into two groups: a high DSI (HDSI; n=25) and a low DSI (LDSI) group (n=25).
Normally distributed continuous variables are reported as mean ± standard deviation and were compared between the HDSI and LDSI groups using the unpaired t-test. Non-normally distributed continuous variables were reported as medians with first and third quartiles and compared between groups using the Mann-Whitney U-test. Categorical variables were reported as frequencies and were compared using the chi-square (χ2) or Fisher's exact tests.
All tests were two-tailed with a significance level of 0.05. Statistical analyses were performed using EZR (ver. 4.0.3, R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics
Fifty patients with essential hypertension were enrolled between September 2023 and September 2024. The baseline characteristics are summarized in Table 1. The mean age of the patients was 70±8 years, and approximately half were males (52%). All patients had chronic kidney disease, defined as estimated glomerular filtration rate ＜60 mL/min/1.73 m2, and approximately 25% had a history of heart failure or ischemia. The laboratory test results of the patients are summarized in Table 2. The average and median DSIs were 9.5±1.3 g/day and 9.2 g/day [8.7-9.9], respectively. All patients switched from ARBs to sacubitril/valsartan (Table 2).
Table 1.
Baseline Characteristics.
| All (n=50) | HDSI (n=25) | LDSI (n=25) | p value | |
|---|---|---|---|---|
| Age (years) | 70±8 | 71±7 | 69±7 | 0.26 |
| Male | 26 (52.0) | 14 (56.0) | 12 (48.0) | 0.78 |
| Height (cm) | 164±7 | 165±6 | 162±10 | 0.41 |
| Body weight (kg) | 55±11 | 56±12 | 54±10 | 0.52 |
| Smoking (ever) | 8 (16.0) | 5 (20.0) | 3 (12.0) | 0.70 |
| Comorbidity | ||||
| Heart disease | 0.99 | |||
| IHD | 3 (6.0) | 2 (8.0) | 1 (4.0) | |
| HFpEF | 6 (12.0) | 3 (12.0) | 3 (12.0) | |
| HFrEF | 4 (8.0) | 2 (8.0) | 2 (8.0) | |
| Diabetes mellitus | 12 (24.0) | 5 (20.0) | 7 (28.0) | 0.52 |
| Dyslipidemia | 14 (28.0) | 6 (24.0) | 8 (32.0) | 0.75 |
Values are expressed as the mean±standard deviation or % (n). HFpEF: heart failure with preserved ejection fraction, HFrEF: heart failure with reduced ejection fraction, IHD: ischemic heart disease
Table 2.
Laboratory and Blood Pressure Data at Baseline.
| All (n=50) | HDSI (n=25) | LDSI (n=25) | p value | |
|---|---|---|---|---|
| Initial dose of sacubitril/valsartan (mg) | 200 | 200 | 200 | - |
| Systolic blood pressure (mmHg) | 151±11 | 150±10 | 151±11 | 0.64 |
| Diastolic blood pressure (mmHg) | 87±23 | 87±24 | 89±22 | 0.83 |
| eGFR (mL/min/1.73 m2) | 41.1±10.1 | 39.9±11.1 | 42.3±9.1 | 0.31 |
| Estimated daily salt intake (g/day) | 9.5±1.3 9.2 (8.7-9.9) |
10.4±1.2 9.9 (9.6, 10.8) |
8.6±0.6 8.7 (8.5, 9.0) |
<0.001 <0.001 |
| ANP (pg/mL) | 410±380 212 (135, 733) |
392±352 235(135, 685) |
426±400 198(154, 750) |
0.75 0.74 |
| Medication before sacubitril/valsartan | ||||
| ARB | 0.40 | |||
| Olmesaltan 20 mg | 28 (56.0) | 16 (64.0) | 12 (48.0) | |
| Azilsartan 20 mg | 22 (44.0) | 9 (36.0) | 13 (52.0) |
Values are expressed as the mean ± standard deviation, median (Q1-Q3), or % (n). ANP: atrial natriuretic peptide, ARB: angiotensin receptor blocker, eGFR: estimated glomerular filtration rate
Comparison between the HDSI and LDSI groups
No differences were observed in the baseline characteristics, including a history of heart failure or ischemia (Table 2). In the HDSI group, the DSI was 10.4±1.2 g/day, while in the LDSI group, it was 8.6±0.6 g/day. Changes in medications, including switch rates from ARBs to sacubitril/valsartan, were comparable between the HDSI and LDSI groups. Additionally, two weeks after starting sacubitril/valsartan, the percentage and absolute changes in blood pressure significantly decreased in both groups, with no significant differences between them (Fig. 1). Notably, as shown in Fig. 2, the DSI obtained by urine tests especially increased in the HDSI group relative to the baseline values. Additionally, ANP levels increased at follow-up in both groups, with a significantly greater increase in the HDSI group than in the LDSI group (573±585 vs. 84±78 pg/mL, p＜0.001; 144±98 vs. 35±28%, p＜0.001, respectively) (Fig. 3).
Figure 1.
Comparison of the change in blood pressure in the high daily salt intake (HDSI) and low DSI (LDSI) groups. No differences were observed in the percentage and absolute changes in systolic blood pressure between the HDSI and LDSI groups.
Figure 2.
Comparison of the absolute changes in the daily salt intake (DSI) value in the high DSI (HDSI) and low DSI (LDSI) groups. The change in DSI levels was found to be increased at follow-up in both groups, with a significantly greater increase in the HDSI group than in the LDSI group.
Figure 3.
Comparison of the percentage and absolute changes in the atrial natriuretic peptide (ANP) level in the high daily salt intake (HDSI) and low DSI (LDSI) groups. The rate of change in the ANP level was significantly greater in the HDSI group than in the LDSI group.
Discussion
The main findings of this study are as follows. First, in patients with essential hypertension, sacubitril/valsartan caused a significant decrease in blood pressure relative to baseline, with no significant difference between the HDSI and LDSI groups. Second, ANP levels were significantly higher in patients with HDSI than in those with LDSI at follow-up. To the best of our knowledge, no previous study has investigated the relationships among blood pressure, DSI, and changes in ANP levels.
Evidence of antihypertensive effects of sacubitril/valsartan
Sacubitril/valsartan is superior to other antihypertensive drugs (13,14). Additionally, in cases of apparently resistant hypertension where valsartan, an ARB, and a diuretic were administered, switching from valsartan to sacubitril/valsartan led to acceptable blood pressure control (15). However, in clinical settings, salt-sensitive hypertension or hypertension due to HDSI is often refractory to antihypertensive therapy (16). In particular, the antihypertensive effects of ARBs have been reported to be diminished under these high sodium intake conditions, resulting in decreased plasma renin and angiotensinogen concentrations (4,5). In such cases, diuretic drugs such as thiazides have been reported to be beneficial (17). A previous study showed that high sodium intake caused non-dipping of blood pressure, even in patients treated with angiotensin II receptor blockers, and diuretics restored the decrease in nocturnal blood pressure (11). However, their adverse metabolic effects, including diabetes, hyperuricemia, and hypertriglyceridemia, must be considered. Another study in which the patients were switched from ARBs to sacubitril/valsartan showed a readily reduced blood pressure in cases with low plasma renin activity, reflecting salt sensitivity and high salt intake (18,19). Additionally, according to a previous report, blood pressure in mice lacking the guanylyl cyclase A receptor for ANP remained unchanged (20), and the antihypertensive effects of ANP have been reported (21,22). Therefore, ANP appears to play a crucial role in decreasing salt sensitivity and promoting salt excretion. Therefore, it has been proposed that combining valsartan (an ARB) with neprilysin inhibition (i.e., sacubitril/valsartan) would be beneficial for salt-associated hypertension, such as salt-sensitive hypertension (14).
Insights from renal pathophysiology, including renal blood flow
Renal blood flow is autoregulated within a certain blood pressure range (23). However, the relationship between renal perfusion pressure and blood flow appears to differ in different regions of the kidney, including the cortex and medulla (23). The autoregulation of blood flow is maintained in the cortical region but not in the medullary region (23), where an increase in blood flow was observed when renal perfusion pressure was elevated. Differences in these mechanisms may lead to natriuresis. A previous report indicated that increased blood flow in the medullary region but not in the cortical region leads to natriuresis (sodium excretion) in the kidneys (24). Furthermore, ANP increases blood flow in the vasa recta of the medullary region (25), likely by promoting natriuresis through enhanced medullary blood flow. This process may contribute to a decrease in blood pressure. In the present study, the change in the DSI value derived from urine tests was significantly greater in the HDSI group than in the LDSI group, suggesting that significant natriuresis occurred in the HDSI group. A previous study reported that sacubitril/valsartan increased natriuresis in the early phase after initiation, although this effect was not observed one month after starting treatment (14). Thus, during the 2-week period of the present study, natriuresis probably contributed to the reduction in blood pressure through enhanced medullary blood flow, which may have been mediated by an increase in ANP levels. However, a human study employing continuous intravenous ANP administration reported that increased urine volume did not affect blood pressure (26).
Beyond its natriuretic action, ANP also exerts pleiotropic effects, including vasodilation through activation of natriuretic peptide receptor 1 in the vascular system (8,9,27), suppression of the renin-angiotensin-aldosterone system, and attenuation of sympathetic nervous system activity (28). Thus, sacubitril/valsartan increases ANP levels, thereby modulating renal pathophysiology, enhancing vasodilation, and influencing endocrine secretion, all of which contribute to antihypertensive efficacy.
Study limitations
The present study has some limitations. First, although this was a prospective study, its sample size was relatively small. Second, no patient had extreme salt intake, which is consistent with the average salt intake level reported in Japan (29). Therefore, whether sacubitril/valsartan is truly effective against salt-sensitive hypertension or extreme salt intake remains unknown. Third, this study did not include a washout period. Fourth, ANP clearance is accelerated in patients with heart failure (30,31). It remains unclear how a previous history of heart failure affects ANP activity. Fifth, a switch was made from ARBs to sacubitril/valsartan in all cases. However, in Japan, the use of sacubitril/valsartan as a first-choice treatment for hypertension is not recommended. Therefore, it remains unclear whether similar findings would occur when sacubitril/valsartan is used as the first-line antihypertensive drug. Sixth, we did not evaluate the data in terms of endocrine secretion, such as renin and aldosterone activity, because ANP might inhibit aldosterone production. Finally, information on proteinuria and the causes of chronic kidney disease is lacking. Thus, a large, randomized trial is warranted to elucidate the influence of sacubitril/valsartan-induced increase in ANP levels on its antihypertensive effects.
Conclusion
Our study showed that, unlike ARBs, sacubitril/valsartan was effective in lowering blood pressure not only in patients with lower salt intake but also in those with higher salt intake. The notable medication-induced increase in ANP levels may contribute to the reduction in blood pressure through vasodilatory and natriuretic actions.
The authors state that they have no Conflict of Interest (COI).
Acknowledgments
The authors acknowledge Yutaka Iguchi (Laboratory of Biology, Nagano, Japan) for his help with the statistical analysis.
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