Abstract
Studies aiming to associate the sodium/potassium (Na/K) ratio with hypertension use 24‐hour urinary excretion as a daily marker of ingestion. The objective of this study was to evaluate the association between urinary Na/K ratio and structural and functional vascular alterations in non‐diabetic hypertensive patients. In hypertensive patients (n = 72), aged between 40 and 70 years, both sexes (61% women), in use of hydrochlorothiazide, we measured blood pressure, 24‐hour urine sample collection, assessment of carotid‐femoral pulse wave velocity (cf‐PWV, Complior), central hemodynamic parameters (SphygmoCor), and post‐occlusive reactive hyperemia (PORH). The participants were divided according to the tertile of 24‐hour urinary Na/K ratio. Each group contained 24 patients. Systolic blood pressure was higher in T2 (133 ± 9 vs 140 ± 9 mmHg, P = .029). C‐reactive protein (CRP) presented higher values in T3 as compared to T1 [0.20(0.10‐0.34) vs 1.19 (0.96‐1.42) mg/dL, P < .001]. Higher values in T3 were also observed for aortic systolic pressure (aoSP) [119(114‐130) vs 135(125‐147) mmHg, P = .002] and cf‐PWV (9.2 ± 1.6 vs 11.1 ± 1.5 m/s, P < .001). The urinary Na/K ratio presented significant correlations with proteinuria (r = .27, P = .023), CRP (r = .77, P < .001), cf‐PWV (r = .41, P < .001), and post‐occlusive reactive hyperemia on cutaneous vascular conductance (PORH CVC) (r = −.23, P = .047). By multivariate linear regression, it was detected an independent and significant association of cf‐PWV with urinary Na/K ratio (R 2 = 0.17, P < .001) and PORH CVC with CRP (R 2 = 0.30, P = .010). Our data indicated that increased urinary Na/K ratio in non‐diabetic hypertensive patients was associated with higher degree of inflammation, raised peripheral and central pressure levels, and changes suggestive of endothelial dysfunction and arterial stiffness.
Keywords: arterial Stiffness, endothelium, hypertension, potassium, sodium
1. INTRODUCTION
Systemic arterial hypertension has been associated with insulin resistance and cardiovascular disease (CVD) events such as sudden death, stroke, acute myocardial infarction, heart failure, peripheral arterial disease, and chronic kidney disease.1 High incidence and mortality due to CVD and hypertension all over the world can be explained in part by the change in dietary habits with the adoption of the western diet with increased consumption of refined and ultra‐processed foods, providing high amounts of sodium and reduced potassium intake.2, 3 The control of salt consumption is important since its excess has adverse effects on health, such as thickening of the arterial wall, inhibition of nitric oxide (NO) production, and sympathetic stimulation, leading to an increase in blood pressure (BP) and worsening in the long‐term hypertension control.4
Sodium and potassium intake are vital for human life, but excess sodium and potassium insufficiency are associated with adverse health outcomes.5 Measuring these electrolytes through 24‐hour urinary excretion is the gold standard method, since under normal conditions, 95% of sodium and 77% of potassium ingested are eliminated by urine for 24 hours, showing good correlation with dietary intake.6, 7
Most epidemiological studies have shown that sodium/potassium (Na/K) ratio in 24‐hour urine is a higher metric than isolated sodium or potassium, and strongly associated with BP and hypertension.8 Recent studies have reported that central BP has a better predictive power for future cardiovascular events compared with brachial BP.9 However, the relationship between urinary Na/K ratio and central BP is not well known, and it is not clear whether the central pressure is influenced not only by the high sodium intake but also by the low intake of potassium.
Increased arterial stiffness is an important marker of CVD risk and an independent predictor of cardiovascular and all‐cause mortality.10 Aortic stiffening increases the aortic pulse wave velocity (PWV), and the early return of reflected waves to the heart leads to increased left ventricular afterload, reducing diastolic coronary flow, and causing damage to important organs.11, 12 Studies have suggested that a sodium‐rich diet in hypertensive patients produces a significant elevation in PWV through independent and dependent effects of BP.13 Nevertheless, there is no evidence about the association between arterial stiffness and urinary Na/K ratio.
Sodium and potassium homeostasis play an important role in endothelial function through endothelium‐dependent vasodilation, which is deficient in primary hypertension.14 Sodium retention decreases NO synthesis, whereas a potassium‐rich diet causes endothelium‐dependent vasodilation.14 Besides the effects on vascular tone, a potassium‐rich diet seems to reduce cardiovascular risk by inhibiting arterial thrombosis, atherosclerosis, and arterial wall hypertrophy.15
Studies with hypertensives subjects have detected increased levels of ultra‐sensitive C‐reactive protein (CRP), suggesting an association between vascular inflammation and hypertension. Patients with high salt intake present increased levels of serum CRP even at normal blood pressure levels.16 These findings suggest that high dietary salt intake can contribute directly to this process through arterial injury, or indirectly through the increase of inflammation effects17 but the link between dietary potassium intake and vascular inflammation is not known.
Inadequate eating habits are among the modifiable environmental factors of hypertension. As dietary survey methods are influenced by memory and accuracy of information given by patients, 24‐hour urine is the gold standard method for the evaluation of sodium and potassium consumption. Thus, is extremely important to evaluate the association of the urinary relation of these electrolytes with pressure, vascular, and inflammation parameters. The present study aimed to evaluate the association between urinary Na/K ratio and structural and functional vascular changes in non‐diabetic hypertensive patients.
2. METHODS
2.1. Study population
Hypertensive patients aged between 40 and 70 years, both sexes, in use of hydrochlorothiazide for at least four weeks, were selected from our outpatient clinic and admitted to a cross‐sectional study. The exclusion criteria were body mass index (BMI) ≥ 35 kg/m2, diabetes mellitus, hormone replacement therapy, use of betablocker or statin, and an estimated glomerular filtration rate (GFR) of <60 ml/min/1.73 m2. The protocol was approved by the local Ethics Committee and all the participants read and signed the informed consent form.
2.2. Nutritional and biochemical evaluation
The nutritional status assessment was obtained by measuring body weight and height using electronic scales with a stadiometer, and BMI was calculated as weight (in kg) divided by squared height (in meters). Venous blood samples were collected after 8‐hour fasting. Serum glucose, creatinine, sodium, potassium, total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, and triglycerides (TG) were measured with an autoanalyzer technique (Technicon DAX96, Miles Inc). Low‐density lipoprotein (LDL)‐cholesterol concentrations were calculated using Friedewald´s equation, when TG concentrations < 400 mg/dL. C‐reactive protein was measured by turbidimetry method. The evaluation of renal function was performed using the estimated GFR using the Chronic Kidney Disease —Epidemiology Collaboration (CKD‐EPI) equation. Insulin was measured by radioimmunoassay, and the Homeostatic Model Assessment‐Insulin Resistance (HOMA‐IR) index [fasting glucose (mmol/L) × fasting insulin (mUI/mL)/22.5] was used for estimating insulin sensitivity.
2.3. Urine collection
The urine collection started immediately after the first spot urine voided by the patients in the morning. The participants received two plastic containers, with a capacity of two liters each, and were asked to return to the clinic in the following day. All of the 24‐h urine samples were refrigerated at or below 4°C within 24 hour of collection. Samples were then transported to the central laboratory for analysis of urinary sodium, potassium, magnesium, and protein. Urinary sodium and potassium concentrations were measured by using ion‐selective electrode.
2.4. Blood pressure and cardiovascular risk assessment
Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained with a calibrated electronic device (model HEM‐705CP, OMRON Healthcare Inc). The measurements were performed in the office with the patient in a seated position after 5‐minutes resting. After three readings with one‐minute interval, the mean was calculated and considered for study analysis. If there is a difference greater than 7 mmHg in SBP, a new measurement was made. Pulse pressure (PP) was determined from the difference between SBP and DBP. The mean arterial pressure (MAP) was determined by the equation: MAP = DBP + PP/3.
The estimation of vascular age was based on D'Agostino study, which evaluated the risk of CVD in the Framingham Heart Study.18 This assessment considers the risk of developing fatal or nonfatal coronary disease, ischemic or hemorrhagic stroke, transient cerebral ischemia, peripheral arterial disease, or heart failure over a 10‐year period. The predictors considered are sex, age, treated or non‐treated SBP, total cholesterol, HDL‐cholesterol, presence or absence of diabetes, and smoking or non‐smoker status.
2.5. Post‐Occlusive reactive hyperemia (PORH)
Microvascular reactivity was evaluated using a Laser Speckle Contrast Image (LSCI) system with a 785‐mm laser wavelength (Pericam PSI System), in combination with PORH for continuous reduction in microvascular endothelium‐dependent cutaneous perfusion changes expressed in arbitrary perfusion units (APU). The examination was performed in the morning by the same experiment researcher, and the patient underwent a period of acclimatization for 10 minutes in a room with a temperature around 22 ± 1°C. A sphygmomanometer was used on the brachial artery to apply a pressure of 50 mmHg above the SBP for three minutes. After rapid decompression, flow changes were recorded to evaluate PORH. The flow was recorded before, during the three minutes of occlusion and three minutes after the period of reactive hyperemia. Through the analyzes, we obtained mean 1‐min baseline results, mean PORH peak, and cutaneous vascular conductance (CVC) was obtained by the following formula: CVC = baseline perfusion (or PORH)/ peripheral MAP.
2.6. Central Hemodynamic Parameters
The assessment of arterial wave reflection was performed non‐invasively using a commercially available tonometry device (SphygmoCor, AtCor Medical). The SphygmoCor systems utilize a Medical Electronics Module Model EM3, an AtCor Medical/Millar tipped pressure tonometer (Millar Instruments) and a validated generalized mathematical transfer function to synthesize a central aortic pressure waveform. Participants rested quietly in a supine position in a temperature‐controlled room for five minutes prior to initial radial artery pulse pressure waveform analysis. After 10 sequential waveforms were acquired, a validated generalized transfer function was used to generate the corresponding central aortic pressures and pressure waveforms.12 Aortic systolic pressure (aoSP), aortic PP (aoPP), augmentation pressure (AP), and augmentation index (AIx) were derived from pulse waveform analysis. AP was the difference between the second and the first systolic peak pressure, and AIx was defined as the ratio of AP to aoPP, expressed as a percentage [Aix = (AP/ PP) × 100]. In addition, a normalized AIx for a heart rate of 75 beats/min has been derived.19 Amplification of PP was calculated by the formula: 1 + (peripheral PP − aoPP)/ aoPP.
2.7. Pulse wave velocity (PWV)
The pulse waves of all patients were obtained transcutaneously by COMPLIOR‐SP (Alam Medical), using transducers placed on the right carotid and on the right femoral artery at the same time. Carotid‐femoral PWV was calculated by dividing the distance travelled (in meters) by the time travelled (in seconds). The time travelled was obtained by measuring the time difference between the arrival of the pulse wave at the femoral and carotid arteries. The distance travelled was estimated as 80% of the direct tape measure distance between carotid and femoral artery. The mean of two measurements was calculated and when the difference between them was more than 0.5 m/s, a third measurement was obtained and the median was considered as the final value.20 All PWV values were adjusted by mean arterial pressure (MAP) to obtain normalized PWV (PWV‐N) = 100 × (PWV/MAP).21
2.8. Statistical analysis
The results were expressed as mean ± standard deviation (SD) for continuous variables with normal distribution or median (interquartile range) for non‐Gaussian variables. The Shapiro‐Wilk test was used to assess normal distribution. The urinary Na/K ratio tertiles were compared by the one‐way ANOVA test followed by Tukey's post‐test, and Kruskal‐Wallis as non‐parametric test for non‐normal variables. The categorical variables were presented as frequency and percentage, and compared by the chi‐square test. The Pearson (normal distribution) or Spearman (non‐normal variables) coefficient was obtained in correlation tests among the continuous variables. Multivariate linear regression was performed considering cf‐PWV, aoSP and PORH CVC separately as dependent variables, and adjusted for gender and age. In the sample size calculation, to obtain a difference of 1 m/s in PWV, 1.6 in SD, 80% study power and 5% significance, a minimum of 62 participants would be necessary. Statistical analyzes were performed by the Statistical Package for the Social Sciences (SPSS) version 20 for Windows (SPSS).
3. RESULTS
We selected 78 patients for this study, but four were excluded for glycemia ≥ 126 mg/dL, one for presenting TG of 600 mg/dL, and one patient for cardiac arrhythmia, identified during vascular tests. Therefore, the results presented below refer to the 72 patients included in the study, 61% female (n = 44) and mean age 58 years for women (47‐70 yo) and men (40‐70 yo). Patients were divided according to the tertile of the Na/K ratio excreted in the urine for 24 hours. The first tertile was defined as urinary Na/K ratio < 2.69 (7 male, 17 female); the third tertile ≥ 4.39 (12 male, 12 female); and the second tertile (nine male, 15 female) between the previous values.
The clinical characteristics of study population are presented in Table 1. There was no significant difference in mean age, sex, and anthropometric data between the groups. The CV risk and vascular age were higher in the last tertile without reaching statistical significance. The 2nd tertile presented significantly higher SBP (133 ± 9 vs 140 ± 9 mmHg, P = .029) and MAP (98 ± 8 vs 104 ± 8 mmHg, P = .028) when compared to the 1st tertile. The biochemical data were similar between the groups showing no significant difference in renal function and lipid profile. The median CRP was significantly and increasingly higher in the 2nd and 3rd tertiles (0.20 vs 1.00 vs 1.19 mg/dL, P < .001). There was no statistical difference regarding the use of antihypertensive drugs.
Table 1.
Clinical, pressure and laboratory parameters divided by the tertile of the urinary sodium/potassium ratio
| Parameters | Urinary Na/K ratio | |||
|---|---|---|---|---|
| 1st Tertile < 2.69 (n = 24) | 2nd Tertile ≥ 2.69 e < 4.39 (n = 24) | 3rd Tertile ≥ 4.39 (n = 24) | P value | |
| Age, years | 60 (53‐65) | 57 (50‐64) | 61 (54‐65) | .272 |
| Female, n (%) | 17 (71) | 12 (50) | 15 (63) | .329 |
| CVR, % | 9.8 (8.5‐17.5) | 14.2 (8.6‐23.8) | 18.1 (8.4‐29.4) | .229 |
| Vascular age, years | 70 (67‐79) | 71 (62‐86) | 80 (65‐86) | .347 |
| BMI, kg/m2 | 28.9 ± 2.6 | 28.9 ± 4.2 | 29.2 ± 4.3 | .940 |
| SBP, mmHg | 133 ± 9 | 140 ± 9* | 139 ± 12 | .029 |
| DBP, mmHg | 81 ± 9 | 85 ± 8 | 86 ± 8 | .065 |
| PP, mmHg | 52 ± 8 | 55 ± 8 | 53 ± 8 | .475 |
| MAP, mmHg | 98 ± 8 | 104 ± 8* | 104 ± 9* | .028 |
| HR, bpm | 70 (62‐75) | 69 (62‐75) | 66 (63‐74) | .904 |
| Na, mEq/L | 140.5 ± 2.5 | 139.2 ± 2.1 | 140.1 ± 2.8 | .134 |
| K, mEq/L | 4.1 ± 0.4 | 4.3 ± 0.4 | 4.3 ± 0.4 | .170 |
| Creatinine, mg/dL | 0.75 (0.70‐0.92) | 0.86 (0.74‐1.13) | 0.80 (0.73‐1.0) | .243 |
| CKD‐EPI, mL/min/1.73 m2 | 88 ± 17 | 85 ± 15 | 83 ± 15 | .471 |
| Total cholesterol, mg/dL | 213 ± 43 | 202 ± 40 | 210 ± 37 | .603 |
| HDL‐cholesterol ♂, mg/dL | 41 ± 12 | 44 ± 12 | 45 ± 13 | .833 |
| HDL‐cholesterol, mg/dL | 65 ± 22 | 57 ± 15 | 65 ± 16 | .424 |
| LDL‐cholesterol, mg/dL | 115 (92‐158) | 113 (95‐140) | 126 (99‐152) | .708 |
| Triglycerides, mg/dL | 126 (108‐170) | 120 (87‐180) | 121 (78‐139) | .331 |
| Glucose, mg/dL | 94 (86‐105) | 93 (83‐100) | 92 (86‐99) | .822 |
| Insulin, mcU/mL | 12.8 ± 6.8 | 16.4 ± 4.9 | 13.8 ± 5.4 | .095 |
| HOMA‐IR | 3.0 ± 1.7 | 3.7 ± 1.2 | 3.2 ± 1.3 | .220 |
| CRP, mg/dL | 0.20 (0.10‐0.34) | 1.00 (0.54‐1.12)*** | 1.19 (0.96‐1.42)*** , †† | <.001 |
| Antihypertensive treatment, n (%) | ||||
| IRAS | 18 (75) | 23 (96) | 22 (92) | .069 |
| CCA | 5 (21) | 8 (33) | 4 (17) | .367 |
| Monotherapy | 5 (21) | 1 (4) | 1 (4) | .079 |
| 2 drugs | 15 (63) | 15 (63) | 20 (83) | |
| 3 drugs | 4 (17) | 8 (33) | 3 (12) | |
Data expressed as mean ± SD or median (interquartile range) when appropriate or in proportions when indicated. P value is related to OneWay ANOVA test. The symbols are related to Tukey's post‐test.
Abbreviations: BMI, Body Mass Index; BP, blood pressure; CCA, calcium channel antagonist; CKD‐EPI, Chronic Kidney Disease—Epidemiology Collaboration; CRP, C‐reactive protein; CVR, cardiovascular risk; HDL, high‐density lipoprotein; HOMA‐IR, Homeostatic Model Assessment—Insulin Resistance; IRAS, inhibitors of renin‐angiotensin system; K, potassium; LDL, low‐density lipoprotein; MAP, mean arterial pressure; HR, heart rate; Na, sodium; PP, pulse pressure.
P < .05.
P < .01.
P < .001 vs 1st tertile.
P < .05.
P < .01.
P < .001 vs 2nd tertile.
In the 24‐h urine, no significant differences were found in urinary volume, magnesium and calcium between groups. The 2nd and 3rd tertiles presented significantly higher proteinuria values and urinary sodium, and lower urinary potassium compared with the first (Table 2).
Table 2.
24‐hour urine parameters divided by the tertile of the urinary Na/K ratio
| Parameters | Urinary Na/K ratio | |||
|---|---|---|---|---|
| 1st Tertile (n = 24) | 2nd Tertile (n = 24) | 3rd Tertile (n = 24) | P value | |
| Volume, mL | 1800 (1230‐2888) | 2032 (1422‐2500) | 2093 (1435‐3020) | .545 |
| Proteinuria, mg/24 h | 95 (82‐113) | 117 (99‐143)* | 139 (94‐177)** | .036 |
| Na, mEq/24 h | 131 ± 60 | 188 ± 59** | 247 ± 74*** , †† | <.001 |
| K, mEq/24 h | 70 ± 25 | 55 ± 17* | 45 ± 16*** | <.001 |
| Mg, mg/24 h | 74 ± 29 | 76 ± 34 | 101 ± 92 | .229 |
| Ca, mg/24 h | 89 ± 52 | 116 ± 94 | 122 ± 91 | .330 |
| Na/K ratio | 1.89 ± 0.58 | 3.52 ± 0.53*** | 5.76 ± 1.26*** , ††† | <.001 |
Data expressed as mean ± SD or median (interquartile range) where appropriate. P value is related to OneWay ANOVA test. The symbols are related to Tukey's post‐test.
Abbreviations: Ca, calcium; K, potassium; Mg, magnesium; Na, Sodium.
P < .05.
P < .01.
P < .001 vs 1st tertile.
P < .05.
P < .01.
P < .001 vs 2nd tertile.
In relation to vascular tests, aortic systolic pressure was higher in the 2nd and 3rd tertiles, and aortic PP was significantly higher only in the 3rd tertile when compared to the first one. PP amplification was significantly lower in the last tertile. There was no significant difference in AP and AIx. Carotid‐femoral PWV and PWV‐N were significantly higher in the 2nd and 3rd tertiles when compared to the first one. All the parameters obtained by LSCI showed no significant difference between the groups. PORH CVC was progressively lower in the 2nd and 3rd tertile (Figure 1) but did not reach statistical significance (Table 3).
Figure 1.
Demonstration of baseline perfusion and PORH peak in a 1st tertile (superior) and 3rd tertile (inferior) patient. POHR, post‐occlusive reactive hyperemia; CVC, cutaneous vascular conductance; APU, arbitrary perfusion unit
Table 3.
Vascular tests of the groups according to the tertile of the urinary Na/K ratio
| Parameters | Urinary Na/K ratio | |||
|---|---|---|---|---|
| 1st Tertile (n = 24) | 2nd Tertile (n = 24) | 3rd Tertile (n = 24) | P value | |
| SphygmoCor | ||||
| aoSP, mmHg | 119 (114‐130) | 133 (124‐143)* | 135 (125‐147)** | .002 |
| aoPP, mmHg | 42 (35‐49) | 44 (38‐53) | 46 (43‐59)* | .042 |
| AP, mmHg | 14 (10‐17) | 17 (8‐19) | 17 (14‐21) | .059 |
| AIx, % | 31 ± 10 | 31 ± 13 | 35 ± 8 | .238 |
| AIx@75, % | 26 ± 9 | 27 ± 10 | 30 ± 8 | .302 |
| PP amplification | 1.27 ± 0.23 | 1.21 ± 0.23 | 1.09 ± 0.18* | .018 |
| Complior | ||||
| cf‐PWV, m/s | 9.2 ± 1.6 | 10.8 ± 1.6** | 11.1 ± 1.5* | <.001 |
| cf‐PWV‐N, m/s | 9.5 ± 1.9 | 10.5 ± 1.6* | 10.7 ± 1.2* | <.027 |
| LSCI | ||||
| Baseline perfusion, APU | 30.6 ± 12.1 | 29.7 ± 10.3 | 30.2 ± 12.1 | .958 |
| Perfusion PORH, APU | 92.4 ± 19.5 | 89.2 ± 24.9 | 80.8 ± 24.7 | .206 |
| Increased perfusion, % | 218 ± 81 | 221 ± 93 | 191 ± 104 | .478 |
| Baseline CVC, APU/mmHg | 0.31 ± 0.10 | 0.28 ± 0.10 | 0.29 ± 0.11 | .659 |
| PORH CVC, APU/mmHg | 0.94 ± 0.21 | 0.86 ± 0.24 | 0.78 ± 0.25 | .067 |
| CVC increase, % | 218 ± 81 | 221 ± 93 | 190 ± 104 | .453 |
Data expressed as mean ± SD or median (interquartile range) when appropriate or in proportions when indicated. P value is related to OneWay ANOVA test. The symbols are related to Tukey's post‐test.
Abbreviations: AIx, Augmentation Index; Aix@75, Augmentation Index corrected for heart rate of 75 beats per minute; aoPP, aortic pulse pressure; aoSP, aortic systolic pressure; AP, augmentation pressure; APU, arbitrary perfusion unit; CF, carotid‐femoral; LSCI, Laser Speckle Contrast Imaging; N, normalized; PORH CVC, post‐occlusive reactive hyperemia on cutaneous vascular conductance; PWV, pulse wave velocity.
P < .05.
P < .01 vs 1st tertile.
The urinary Na/K ratio was positively correlated with aoSP (r = .41, P < .001), proteinuria (r = .27, P = .023), CRP (r = .77, P < .001), cf‐PWV (r = .41, P < .001), and inversely with PORH CVC (r = −.23, P = .047) (Figure 2). In the multivariate linear regression, an independent and significant association between cf‐PWV and urinary Na/K ratio were observed, and PORH CVC with CRP (Table 4).
Figure 2.
Correlation between urinary Na/K ratio and cf‐PWV (A), C‐reactive protein (B), POHR CVC (C), and proteinuria (D). Na, sodium; K, potassium; cf‐PWV, carotid‐femoral pulse wave velocity; PORH CVC, post‐occlusive reactive hyperemia on cutaneous vascular conductance
Table 4.
Multivariate linear regression of dependent variables carotid‐femoral pulse wave velocity, aortic systolic pressure, and cutaneous vascular conductance of post‐occlusion reactive hyperemia after adjustments for age and sex
| Dependent variables | Independent variables | Non‐standardized B coefficient | CI 95% | Standardized Beta coefficient | P value | R 2 |
|---|---|---|---|---|---|---|
| cf‐PWV | Urinary Na/K | 0.42 |
0.19 0.61 |
0.41 | <.001 | 0.17 |
| aoSP | cf‐PWV | 3.87 |
1.91 5.83 |
0.42 | <.001 | 0.42 |
| aoSP | CRP | 7.33 |
0.29 14.37 |
0.23 | <.001 | 0.48 |
| PORH CVC | CRP | −0.14 |
−0.26 −0.037 |
−0.30 | .010 | 0.30 |
Abbreviations: aoSP, aortic systolic pressure; cf‐PWV, carotid‐femoral pulse wave velocity; CRP, C‐Reactive Protein; K, potassium; Na, sodium; PORH CVC, post‐occlusive reactive hyperemia on cutaneous vascular conductance.
4. DISCUSSION
In this cross‐sectional study, the 24‐h urinary Na/K ratio was associated with clinical, hemodynamic, and vascular variables in hypertensive patients. Parameters of inflammation, peripheral and central BP, arterial stiffness, endothelial dysfunction, and proteinuria were significantly associated with the urinary Na/K ratio.
In the present study, patients were divided according to the urinary Na/K ratio, since some studies have shown that this is the best index related to BP levels and cardiovascular risk, compared with the isolated evaluation of sodium or potassium.8, 22 Urinary magnesium, calcium, and volume were similar among the groups, indicating that there was no influence of these variables on the results and the consistency of urine collection. Recent studies have indicated that a high urinary Na/K ratio may be an independent risk factor for CVD, and that potassium intake is inversely related to cardiovascular events.22, 23 In fact, measurement of the urinary Na/K ratio may better represent the salt loading than the isolated measurement of urinary sodium.24
Several studies have reported a positive association between high urinary Na/K ratio and higher SBP and DBP, while higher K excretion has been inversely associated with BP and risk of hypertension.25, 26 In a multiethnic study, Hedayati et al (2012) observed a positive and strong correlation between urinary Na/K ratio, prevalence of hypertension and BP levels, regardless of clinical covariates. The authors support the hypothesis that dietary sodium excess and potassium deficiency may play an important role in the pathogenesis of hypertension, extending its findings for both sexes and different ethnicities.8 According to a recent study, the urinary Na/K ratio is more closely associated with BP levels than these isolated urine electrolytes, reinforcing that the sodium restriction and potassium addition may be more effective in controlling BP.22
The present study demonstrated higher values of central pressure in the groups with higher urinary Na/K ratio. The same groups presented a lower PP amplification, evidencing a smaller difference between the peripheral and central pressures. These findings could indicate an association between higher urinary Na/K ratio and reduced vessel compliance, but prospective studies are necessary to prove this hypothesis.
Park et al27 has previously reported that urinary Na/K ratio was independently associated with central hemodynamic parameters in hypertensive individuals. That study was the first to demonstrate a significant association of urinary sodium excretion and urinary Na/K ratio with aoSP and PP amplification in a hypertensive population. A positive association between urinary Na/K ratio and aoSP has been documented by other authors, indicating a stronger effect of sodium and potassium intake on central pressure. These results point out the reduction in the urinary Na/K ratio as an important strategy to prevent elevation of aoSP and, eventually, future cardiovascular events.11 Indeed, several studies have demonstrated stronger relationship of central aortic pressure with carotid hypertrophy and atherosclerosis than brachial pressure, supporting the hypothesis that central pressures more accurately reflect the load in the cerebral vasculature.18, 28, 29 Roman et al (2007) also presented the greater association of aoPP with cardiovascular outcome than brachial pressure, emphasizing the greater importance of central PP on SBP,29 which was also evaluated in the present study.
PWV is a direct measure of arterial stiffness and independent predictor of mortality.10 In the present study, the mean values of cf‐PWV suggested arterial stiffness in the highest tertiles. Our results also indicated PWV values partially independent of BP, since the association between arterial stiffness and urinary Na/K ratio was maintained even after correction by MAP. For the first time, at least to our knowledge, a direct correlation was observed between arterial stiffness and urinary Na/K ratio. Some studies have described an independent and positive association between urinary sodium excretion and ankle‐brachial (ab)‐PWV, a different method from that used in the present study. The authors have also noted that few studies have shown a significant association between urinary sodium excretion and ab‐PWV in hypertensive patients. Lastly, they concluded that excessive salt intake is important in the development of arterial stiffness and dysfunction in hypertensive individuals.30
Low sodium diet has been already associated with an improved brachial flow‐mediated dilation (FMD) and enhanced forearm blood flow response to acetylcholine.31 Jablonski et al reported that urinary sodium excretion was 50% lower in dietary restriction, resulting in a 68% increase in brachial FMD and 42% increase in forearm blood flow peak. These findings indicated that an endothelium‐dependent dilation, mediated by NO, was increased in sodium restriction. The authors emphasized that this sodium restriction effect was independent of SBP variation, population characteristics, and other dietary factors.31 Accordingly, the present study demonstrated a relationship between high urinary Na/K and endothelial dysfunction evaluated by PORH. Indeed, PORH CVC was inversely correlated with urinary Na/K ratio and CRP, suggesting that the connection between salt overload and endothelial disfunction could be mediated by an inflammatory mechanism.
The present study also observed that proteinuria was higher in the last tertiles, and directly correlated with urinary Na/K ratio. Considering that proteinuria may be the result of a reduction in the glomerular endothelial function, these findings indicate a possible endothelial dysfunction associated with high sodium and low potassium intake. Some studies have shown a relationship between salt intake, inflammation, and proteinuria in non‐diabetic hypertensive patients, independent of BP, similar to the present study.32, 33 Yilmaz et al demonstrated a positive correlation between proteinuria and serum levels of CRP in treated hypertensive patients, noting that this marker of systemic inflammation and proteinuria is often high in hypertension and predict cardiovascular prognosis regardless of conventional risk factors. In fact, cross‐sectional studies have shown increased plasma and vascular levels of CRP in hypertensive patients pointing out a potential link between vascular inflammation and hypertension. However, it is not clear whether the inflammation causes structural and functional changes in the vessel wall and leads to hypertension, or if it is only a consequence of this.34
Some limitations of this study should be considered, such as the number of enrolled patients. Nevertheless, the sample size was greater than the calculated number and enough to reach statistical significance in the main analyzes. There were inherent difficulties in 24‐hour urine collection, but volume samples lower than one liter were not accepted in order to minimize the possible errors. The inflammation process was only evaluated by CRP levels. Other inflammatory markers could be helpful in verifying the role of inflammation linking urinary Na/K ratio and vascular changes. Like any cross‐sectional study, the causal relationship cannot be determined. Therefore, the findings of the present study should be confirmed in prospective studies with larger sample size.
In conclusion, the results of the present study indicate that higher values of the urinary Na/K ratio were associated with structural and functional vascular changes, characterized by increased peripheral and central systolic pressure, arterial stiffness, proteinuria, and endothelial dysfunction. Higher CRP levels in hypertensive patients with raised urinary Na/K ratio point out the role of inflammation as pathogenic mechanism for vascular damage related to overload of salt intake. Thus, the dietary approach for hypertensive patients should stimulate a lower sodium and higher potassium intake in order to improve blood pressure control and vascular function.
CONFLICTS OF INTEREST
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHORS CONTRIBUTIONS
MRC and MFN conceived and started this cross‐sectional study. MFN coordinated the study. MRC, ARC, WO, and MFN designed the study. WO and MFN supervised the study. MRC, BCAAM, SSM, JDR, and NMF collected the data. MRC and MFN did the statistical analysis. MRC and MFN wrote the first draft of the manuscript. WO and MFN supervised the study conduct and data analysis and provided critical comments on all drafts of the manuscript. All authors reviewed and provided critical comments on drafts. All authors have approved the submitted version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
ACKNOWLEDGMENTS
We thank Mrs Claudia Deolinda Lopes Alves Madureira for the blood sample collection and all the support for this study.
Cunha MR, Cunha AR, Marques BCAA, et al. Association of urinary sodium/potassium ratio with structural and functional vascular changes in non‐diabetic hypertensive patients. J Clin Hypertens. 2019;21:1360–1369. 10.1111/jch.13660
Funding information
This work was supported by grants from the Carlos Chagas Filho Foundation for Research Support at the State of Rio de Janeiro (FAPERJ) and from the National Council for Scientific and Technological Development (CNPq).
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