Patients with untreated heart failure (HF) exhibit a blunted hemodynamic and neuroendocrine response to a high sodium intake, leading to excessive sodium and water retention. However, it is not known whether this is the case for patients with compensated HF receiving angiotensin-converting enzyme inhibitors and β-adrenoreceptor blockers. Therefore, we determined the hemodynamic and neuroendocrine responses to 1 wk of a low-sodium diet (70 mmol/day) and 1 wk of a high-sodium diet (250 mmol/day) in 12 HF patients and 12 age-matched controls in a randomized, balanced fashion. During steady-state conditions, hemodynamic and neuroendocrine examinations were performed at rest and during bicycle exercise. In seated HF patients, high sodium intake increased body weight (1.6 ± 0.4%), plasma volume (9 ± 2%), cardiac index (14 ± 6%), and stroke volume index (21 ± 5%), whereas mean arterial pressure was unchanged. Therefore, the total peripheral resistance decreased by 10 ± 4%. Similar hemodynamic changes were observed during an incremental bicycle exercise test. Plasma concentrations of angiotensin II and norepinephrine were suppressed, whereas plasma pro-B-type natriuretic peptide remained unchanged. In conclusion, high sodium intake was tolerated without any excessive sodium and water retention in medically treated patients with compensated HF. The observation that high sodium intake improves cardiac performance, induces peripheral vasodilatation, and suppresses the release of vasoconstrictor hormones does not support the advice for HF patients to restrict dietary sodium.
- dietary sodium
- plasma volume
the inability to excrete sodium in excess is well characterized in untreated heart failure (HF), and it is therefore recommended that these patients should reduce dietary salt intake (16). Throughout the past two decades, medical treatment of HF has improved, and today most patients receive β-adrenoreceptor blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS). In such patients it has recently been demonstrated that acute central intravascular volume expansion elicits a hemodynamic, neuroendocrine, and renal response similar to that of normal controls (7, 8). Thus the intact baroreflex-mediated response to increased cardiac and arterial filling leads to decreased systemic vascular resistance and suppressed neuroendocrine mediators, thereby promoting renal sodium excretion.
High sodium intake augments intravascular filling, decreases vascular resistance, improves cardiac performance, and suppresses vasoconstrictor hormones in healthy subjects (5). Hence, it is conceivable that patients with medically treated compensated HF would exhibit similar beneficial effects.
Therefore, we examined 12 patients with medically treated compensated HF and 12 healthy controls after 1 wk of high and 1 wk of low sodium intake. Our aim was to investigate whether the hemodynamic and neuroendocrine responses to variations in sodium intake would be different between the two groups.
Fifteen male patients with compensated HF and 14 age-matched controls were included. Three patients and two controls were excluded because of vasovagal episodes or lack of compliance to the diet. Baseline characteristics of the remaining HF patients [New York Heart Association (NYHA) functional class II, n = 6; NYHA III, n = 6] are presented in Table 1.
The HF diagnosis (ischemic, n = 8; idiopathic, n = 4) was based on clinical and radiological evaluation in combination with evidence of impaired left ventricular ejection fraction (<40%). All patients were in sinus rhythm, had normal blood glucose and creatinine levels and normal spirometry, and performed an exercise test to exclude symptomatic ischemic disease. There was no recent history of acute myocardial infarction, angina pectoris, or cardiac decompensation (<2 mo). The patients received angiotensin-converting enzyme (ACE) inhibitors (n = 11), angiotensin receptor blockers (n = 1), α/β-adrenoreceptor blockers (n = 5), β-adrenoreceptor blockers (n = 7), diuretics (n = 10), spironolactone (n = 4), digoxin (n = 1), long-acting nitrates (n = 2), statins (n = 10), and low-dose aspirin (n = 10). Pharmacological treatment remained unchanged 2 wk before the study.
All control subjects were healthy according to medical history and routine clinical evaluation including spirometry and echocardiography. Baseline 48-h urinary sodium excretion was determined for all participants. Written informed consent was obtained from all subjects. The study was approved by the Ethics Committee of Copenhagen (KF 01-063/02).
The study consisted of two consecutive 7-day periods, between which the participants shifted from a low (70 mmol/day)- to a high (250 mmol/day)-sodium isocaloric diet or vice versa in a balanced, randomized fashion. Water intake was free. Twenty-four-hour urine collections for determination of renal sodium excretion were performed during the final 10 days of the 14-day study period.
The participants were examined after overnight fasting on the final day of each dietary period (the HF patients took their habitual morning medication). After voiding, all subjects were weighed and instrumented. The subjects drank 200 ml of water while resting in an armchair for 30 min. Thereafter, measurements were performed under conditions of seated rest, supine rest, and during bicycle exercise.
The experimental session consisted of two consecutive 90-min periods in the seated and supine position, respectively. During the initial 60 min of each session, the patients rested, and measurements were performed in the remaining 30 min. Ambient temperature and humidity were 23.5 ± 0.1°C (mean ± SE) and 40.0 ± 0.3%, respectively.
Cardiac output was derived from three measurements of pulmonary capillary blood flow by inert gas rebreathing as previously described in detail (9). Briefly, a closed system containing a rebreathing gas mixture (0.5% N2O, 0.1% SF6, and 28% O2 in N2) connected to an infrared photoacoustic gas analyzer was used (Innocor; Innovision, Odense, Denmark). Rebreathings were performed for 25 s with a gas volume of 30% of the subject's vital capacity and a breathing rate of 20 breaths/min. Pulmonary blood flow was determined from the gas concentration traces. Heart rate (HR) was obtained from ECG recordings. Arterial pressures were measured by sphygmomanometry between the rebreathings. All measurements were performed with the brachial cuff at the level of the fourth intercostal space while the patient was seated and at the level of the midaxillary line while the patient was supine. Cardiac index (CI), stroke volume index (SVI), pulse pressure (PP), mean arterial pressure (MAP), and total peripheral resistance (TPR) were calculated using conventional formulas.
Left atrial diameter was measured by echocardiography using M-mode recordings obtained from the parasternal long-axis view (6). Printouts of the recordings were analyzed by the same investigator in a blinded fashion.
Plasma volume (PV) was determined in patients after 1 h in the seated and supine positions by using human serum albumin labeled with radioactive iodine ([125I]HSA) (17). In brief, after an initial blood draw, 200 kBq of [125I]HSA were injected through a peripheral cubital venous catheter. From the opposite venous catheter, blood samples were collected at 10, 20, and 30 min after injection, and PV was calculated from the radioactivity of the samples. All subjects received a thyoride blocking dose of 400 mg of potassium iodide per os 2 h before the injections. The radiation exposure for the entire study was 0.24 mSv.
Blood samples were drawn from patients after 1 h in each position and immediately centrifuged at 3,700 rpm for 10 min and transferred to a freezer. Plasma concentrations of norepinephrine (NE) and epinephrine (Epi) were measured using radioenzymatic assay, whereas angiotensin II (ANG II) and pro-B-type natriuretic peptide (pro-BNP) were measured using radioimmunoassays (10, 19, 20).
Hematocrit was determined on fresh blood samples by centrifugation of microhematocrit tubes for 5 min at 12,600 g. Plasma concentrations of sodium, potassium, and albumin, blood urea nitrogen (BUN), hemoglobin, urine osmolality, and sodium concentration were analyzed using conventional methods.
After a 3-h break, an incremental exercise test (30 W/3 min, start 40 W) was performed on an upright electromagnetically braked bicycle (Technogym, Gambettola, Italy). The patients exercised until exhaustion (dyspnea or fatigue). HR was continuously recorded, and arterial blood pressures were determined using the sphygmomanometric method. Cardiac output was measured at each workload by inert gas rebreathing (gas volume similar to the voluntary ventilation with a composition of 1% N2O, 0.2% SF6, and 36% O2 in N2 and a breathing rate of 30 breaths/min). Before the study, the subjects had performed several tests to become familiarized with the rebreathing maneuver. Furthermore, the same protocol had been used to determine oxygen consumption (V̇o2) at each exercise step and maximum V̇o2 (V̇o2 max; AMIS 2001; Innovision).
The hemodynamics variables are presented as differences between the low- and high-sodium sessions at rest, low-intensity exercise (≤70% V̇o2 max), and high-intensity exercise (>70% V̇o2 max).
Data are presented as means ± SE. ANG II and NE were normally distributed after log transformation and are therefore presented as geometric means (95% confidence intervals). Epi and pro-BNP could not be transformed to normality and are therefore presented as medians (interquartile range).
The effect of sodium on hemodynamics and neuroendocrine variables within the groups was evaluated using a paired t-test or Wilcoxon signed-rank test as appropriate. To evaluate differences between the groups, we applied an unpaired t-test or the Mann-Whitney U-test.
A one-way ANOVA for repeated measures followed by post hoc t-tests (Bonferroni correction) was performed within the groups used to detect an effect of time on renal sodium excretion and to evaluate the effect of exercise intensity on the sodium-induced changes in hemodynamics variables. In all statistical analyses, the significance level of 0.05 was chosen. The statistical analyses were performed using SigmaStat for Windows (version 2.03; SPSS).
Sodium intake and excretion.
Sodium balance was achieved during the last 3 days at each level of sodium intake. There were no significant differences in sodium excretion between the groups (Fig. 1).
Body fluid volumes.
In the HF patients, body weight was 90.3 ± 4.1 kg on low sodium intake and 91.7 ± 4.0 kg on high sodium intake; i.e., body weight increased by 1.6 ± 0.4% (P < 0.005). The corresponding values for the controls were 88.4 ± 4.2 and 89.5 ± 4.2 kg (1.2 ± 0.2%, P < 0.005). In the HF patients, the PV expanded by 9 ± 2% when seated (n = 11; P < 0.005) and 8 ± 2% when supine (n = 12; P < 0.01) during high sodium intake (Table 2). The corresponding values for controls were 7 ± 2% (n = 12; P < 0.005) and 7 ± 2% (n = 11; P < 0.005).
In HF patients and controls in the seated position, CI increased by 14 ± 6% (P < 0.05) and 13 ± 3% (P < 0.0005), respectively, during high sodium intake (Table 3). As the result of a trend toward lower HR, SVI increased by 21 ± 5% (P < 0.005) in HF patients and 18 ± 2% (P < 0.0001) in controls. MAP remained unchanged due to a decrease in TPR by 10 ± 4% (P = 0.0501) in HF patients and 12 ± 2% (P < 0.0005) in controls. A higher PP during high sodium intake (seated, P < 0.01) probably reflected the intravascular volume expansion and increased preload; however, only minor changes were detected in left atrial diameter (Table 3).
In control subjects in the supine position, CI, SVI, and TPR were significantly less affected by changes in sodium intake, whereas this was not the case for HF patients (Fig. 2). MAP remained unchanged in the HF patients but increased modestly in the controls (P < 0.05).
Hemoglobin, hematocrit, BUN, and plasma concentrations of albumin and creatinine decreased during high sodium intake (Table 2). In HF patients, plasma sodium concentrations increased (P < 0.0005) during high sodium intake, whereas this was not the case in controls.
Plasma concentrations of NE were higher in HF patients than in controls; however, the NE levels were similarly suppressed in both groups during high sodium intake. Plasma Epi concentrations tended to be higher in HF patients compared with controls (seated, P = 0.12), but there was no effect of changing sodium intake (Table 4). Plasma ANG II concentrations were almost similar in the two groups and were significantly lowered by high sodium intake (Table 4). Plasma pro-BNP concentrations were elevated in HF patients regardless of sodium intake and posture (P < 0.005), but there was no response to changes in sodium intake (Table 4).
HF patients exercised 585 ± 87 s on low and 617 ± 88 s on high sodium intake (no significant difference, NS), whereas respective values for control subjects were 981 ± 88 and 988 ± 94 s (NS). The effect of sodium was significant on CI, SVI, and TPR at rest on the bicycle and during low- and high-intensity exercise, whereas MAP remained unaffected (Fig. 3). The relative response attenuated with increasing workloads, although this was significant only for SVI and HR in HF patients (Fig. 4).
To our knowledge, this is the first investigation to assess the hemodynamic, neuroendocrine, and renal responses to a change in sodium intake in medically treated patients with stable, compensated HF. All patients were studied after 1 wk of a low (70 mmol/day) and 1 wk of a high (250 mmol/day) sodium intake at rest, after a posture shift and during exercise. Our results indicate that the renal, hemodynamic, and neuroendocrine responses to changes in sodium intake are similar in patients and healthy individuals. High sodium intake was tolerated without any excessive sodium and water retention and was associated with improved cardiac performance, peripheral vasodilatation, and suppression of vasoconstrictor hormones.
During steady-state conditions, renal sodium output (Fig. 1) was slightly lower than the sodium intake (70 and 250 mmol/day), reflecting a small loss of sodium through sweat and feces (13). Although renal sodium handling seemed marginally slower in HF patients compared with controls, no difference was observed in cumulated sodium balance or in body weight. The PV expansion and hemodilution were similar in the two groups during high sodium intake. These findings oppose the results of previous studies, in which untreated and conventionally (digoxin) treated patients with HF have been shown to accumulate sodium and water in excess during dietary sodium loading (2, 4, 14, 27, 30). However, it was recently demonstrated that monotherapy with ACE inhibitors restores renal sodium excretion during acute volume expansion in compensated HF (7). Hence, it is conceivable that the neuroendocrine link, which senses the intravascular volume expansion induced by high sodium intake and promotes renal sodium excretion, is preserved in medically treated HF patients.
Altered sodium intake elicited the same absolute and relative hemodynamic response in HF patients as in healthy controls. High sodium intake expanded the intravascular volume and increased cardiac preload as indicated by a higher left atrial diameter. Despite a higher CI, MAP remained unchanged because of compensatory peripheral vasodilatation (Table 3). Our results are in accordance with recent studies of medically treated patients with compensated HF in which acute central intravascular volume expansion elicited a hemodynamic, neuroendocrine, and renal response similar to that of normal controls (7, 8).
In contrast, untreated or conventionally treated patients with moderate to severe HF increase neither CI nor SVI despite higher preload (indicated by increased pulmonary capillary wedge pressure) in response to sodium loading (4). Even in early asymptomatic HF, sodium loading causes higher ventricular end-diastolic volume but unchanged ejection fraction (30). Thus the untreated HF patient is probably unfavorably located on the Frank-Starling curve with a depressed response to increased preload.
In conjunction, these findings demonstrate that the vasodilatation and suppression of the sympathetic nervous system induced by long-term treatment with ACE inhibitors and β-adrenoreceptor blockers probably allows the HF patients to benefit from increased intravascular filling by improved cardiac forward flow. Because multiple interactions between the RAAS and the sympathetic nervous system have been demonstrated (11), it is likely that the combined medical treatment induces synergistic cardiovascular effects. However, this was not tested in the present study.
The diagnosis of HF was confirmed by a twofold higher plasma NE concentration in patients compared with controls. Sodium intake was a major determinant of the sympathetic nervous activity as indicated by plasma NE levels, which confirms previous findings in untreated (4) and treated HF (1).
In early HF, the baseline activity of the RAAS is normal and the response to altered sodium intakes seems intact (29, 30). In later stages of the disease, an increased activity of the RAAS has been observed in a subset of HF patients despite increased sodium intake (3, 4). We found that plasma ANG II concentrations were similar in HF patients and controls, showing that the patients received ACE inhibitors (Table 4). Despite ACE inhibition, the ANG II plasma concentrations were modulated by alterations in sodium intake to the same extend in HF patients and controls. These findings indicate that the effort to reduce the deleterious effect of a high activity of the sympathetic nervous system and RAAS by medical therapy is greatly influenced by the level of sodium intake.
To our knowledge, the effect of sodium intake on pro-BNP plasma concentrations has not been reported previously. Pro-BNP levels were higher in HF patients than in controls, but in contrast to expectations, plasma pro-BNP concentrations remained unchanged despite the intravascular volume expansion during high sodium intake. Previous investigations have shown that the bioactive peptide BNP seems to reflect intravascular volume changes induced by altered sodium intake better in healthy subjects (21, 29) as well as HF patients (1). The low sensitivity for pro-BNP to detect short-term changes in intravascular and cardiac volumes might be explained by a longer half-life in plasma compared with BNP (26). It is possible, however, that an effect of sodium intake on plasma pro-BNP concentrations would have been detected if the power of the study was higher (i.e., more subjects included) or if the sensitivity of the assay was better.
Interaction of posture and sodium intake.
Changes in intravascular volumes and central hemodynamics induced by altered sodium intake might be masked when evaluated in subjects in the supine position because of an a priori central volume expansion (5). We confirmed that the impact of high sodium intake on hemodynamics is attenuated in the supine position in healthy subjects (5). In contrast, the HF patients exhibited a more uniform hemodynamic response in both postures, e.g., SVI increased by 21 and 14% in the seated and supine positions, respectively. This might be explained by a left ventricular volume-pressure relationship (Frank-Starling) that is less steep and shifted toward higher volumes during HF (15). It is therefore conceivable that HF patients in contrast to controls benefit from the additional intravascular volume expansion induced by high sodium intake even in the supine position, where the central vascular volume is already expanded.
Sodium intake and exercise.
The influence of sodium intake on exercise performance remains sparsely described. We used an incremental exercise test to reveal whether hemodynamic changes induced by altered sodium intake at rest would be reflected during exercise, too. The maximal exercise capacity (time) of the HF patients did not improve, although it was evident that CI and SVI increased, whereas HR and TPR decreased during exercise when the sodium intake was high (Fig. 4). More studies should be conducted to analyze whether these effects could improve exercise performance during submaximal workloads.
We found that sodium- and water-retaining hormonal systems were activated and that cardiac forward flow was impaired during sodium restriction. In addition, it has been demonstrated that intravascular volume depletion induced by low sodium intake can compromise renal function, especially if associated with ACE inhibitor or diuretic therapy (24, 28). Thus not only neuroendocrine activation but also a compromised cardiorenal function could result from intravascular volume depletion induced by low sodium intake. Conversely, maintenance of an adequate intravascular volume might serve as adjunctive therapy as recently shown in refractive HF, where dry weight was reached faster and hospital stays were reduced in patients who received a small volume of intravenous hypertonic saline solution in addition to conventional therapy by furosemide (25). Furthermore, in a 3-yr follow-up, morbidity and hospitalization were reduced in patients receiving this therapy in combination with increased (120 vs. 80 mmol/day) sodium intake (22).
In combination, these findings suggest that sodium combined with appropriate drug therapy might be beneficial to maintain the intravascular volume, thereby improving cardiac and renal blood flow. Notably, the high sodium intake in the present investigation approximates the habitual intake of the subjects as well as normal sodium intake in Western countries (18). Thus, if a low-sodium diet should be implemented according to guidelines (16), it would require a continuous effort to avoid salt, which is troublesome, because most of the salt ingested is already in the food before preparation (23).
We assessed systemic hemodynamic variables by using noninvasive techniques, which excluded the possibility of obtaining cardiac filling pressures. Furthermore, direct indexes of diastolic function were not estimated. However, during acute central blood volume expansion induced by water immersion, central venous pressure increases similarly in patients with medically treated compensated HF and in healthy controls (8). Acute immersion constitutes a much greater volumetric stimulus than observed in this study. Nevertheless, the possibility of inappropriate changes of these variables during a long-term increase of sodium intake cannot be excluded.
It might be argued that our patients received inappropriately high doses of diuretics and that the effects of sodium intake could have been obtained simply by reducing the diuretic dosage. Two patients, however, did not receive diuretics, and the mean furosemide-equivalent dose in the remaining patients was modest (65 mg). Moreover, plasma volume and body weight were similar in HF patients and controls during both levels of sodium intake, indicating no overuse of diuretics.
Finally, long-term changes in sodium intake might induce changes in hemodynamic and neuroendocrine function that are not reflected in this investigation of short duration. It has been demonstrated, however, that the increase in sympathetic nervous activity in response to sodium restriction persists for a minimum of 8 wk in hypertensives, which indicates that the neurohormonal responses are not transient (12). Our findings during short-term conditions should be interpreted with caution in relation to the usual clinical practice. In fact, the results should merely serve to draw attention to the dogma that low sodium intake per se is favorable in heart failure.
In conclusion, the renal, hemodynamic, and neuroendocrine responses to alterations in sodium intake are similar in patients with medically treated compensated HF and in healthy individuals. High sodium intake was tolerated without any excessive sodium and water retention. The observation that high sodium intake improves cardiac performance, induces peripheral vasodilatation, and suppresses the release of vasoconstrictor hormones does not support the advice for HF patients to restrict dietary sodium.
This study was supported by Danish Research Councils Grant 2006-01-0012 and by Danish Heart Foundation Grant 02-1-3-40-22986.
We gratefully acknowledge the assistance of B. Larsen, U. Kjærulff-Hansen, L. Vergo, M. Gybel, A. E. Nielsen, and L. Petersen. We thank Prof. M. Kjaer for providing laboratory facilities.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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