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Dietary Salt Restriction in Heart Failure: Where Is the Evidence?
Dietary Salt restriction in Heart Failure: Where is the Evidence? James J. DiNicolantonio, Subhankar Chatterjee, James H. O’Keefe PII: DOI: Reference:
S0033-0620(15)30030-X doi: 10.1016/j.pcad.2015.12.002 YPCAD 702
To appear in:
Progress in Cardiovascular Diseases
Please cite this article as: DiNicolantonio James J., Chatterjee Subhankar, O’Keefe James H., Dietary Salt restriction in Heart Failure: Where is the Evidence?, Progress in Cardiovascular Diseases (2015), doi: 10.1016/j.pcad.2015.12.002
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ACCEPTED MANUSCRIPT Dietary Salt restriction in Heart Failure: Where is the Evidence?
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James J. DiNicolantonio, PharmD1, Subhankar Chatterjee, MBBS2, and James H. O‘Keefe, MD1
Affiliations:
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1- Mid-America Heart Institute at Saint Luke‘s Hospital, Kansas City, Missouri, USA
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([email protected])
2- R. G. Kar Medical College & Hospital, Kolkata, India Correspondence: Dr. James J. DiNicolantonio, PharmD, Saint Luke‘s Mid America Heart
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Word count: 2515
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Conflict of Interest: None
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Institute, Tel: 607-738-8853 Email: [email protected]
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ACCEPTED MANUSCRIPT Abbreviations ACM - all-cause mortality
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AVP - arginine vasopressin BP – blood pressure
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CO – cardiac output
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CV - cardiovascular CVD – cardiovascular disease HF - heart failure
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HTN- hypertension
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HR – hazard ratio
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MAP - mean arterial pressure
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NYHA – New York Heart Association RAAS - renin angiotensin aldosterone system SNS - sympathetic nervous system
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Abstract
Several dietary guidelines, health organizations and government policies recommend
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population-wide sodium restriction to prevent hypertension and related comorbidities like heart failure (HF). The current European Society of Cardiology and American College of
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Cardiology/American Heart Association Heart Failure guidelines recommend restricting sodium in HF patients. However, these recommendations are based on expert opinion (level C), leading to wide variability in application and lack of consensus among providers
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pertaining to dietary salt restriction. To evaluate the strength of current evidences to recommend dietary salt restriction among HF patients, we performed a comprehensive
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literature review and explored the safety and efficacy of such recommendations.
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Key words: chloride, heart failure, hypertension, salt, sodium
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ACCEPTED MANUSCRIPT Introduction Notwithstanding substantial progress in the pharmacology and technology related to
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cardiovascular (CV) care, heart failure (HF) remains the most frequent cause of hospital
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admission and readmission.1 Along with the wide pharmaceutical armamentarium and availability of devices, such as cardiac resynchronization therapy, physical exercise and
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dietary salt and fluid restriction remain essential steps in the management of HF and are
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recommended by nearly all HF guidelines.2-6 The current 2013 ACCF/AHA guideline recommends sodium restriction to 1.5 gm/day for patients with stage A and B HF, while for stage C and D HF AHA advises salt restriction < 3 gm/day7, which is much lower than what an average American diet contains (approximately 3.7g/day)8. Yet the recommendation for
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drastic reductions in the consumption of salt is still an unresolved issue in patients with HF. To evaluate the strength of the current evidence to recommend dietary salt restriction among
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HF patients, we performed a comprehensive literature review to explore the safety and
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efficacy of such recommendations.
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Pathophysiology of HF
HF is defined as a decreased ability of the heart to fill (diastolic HF) and/or eject blood (systolic HF) due to structural and/or functional defects in the myocardium leading to a reduced cardiac output (CO).2 The structural (as in dilated cardiomyopathy) or functional (as in myocardial infarction) insult to the heart is viewed as the index event. Following an index event, although pumping capacity of the heart starts to progressively decline, the patient remains largely asymptomatic or minimally symptomatic due to various compensatory mechanisms—that are orchestrated predominantly through
activation of neurohormonal
systems both within the heart and systemically. Reduced CO and the subsequently decreased
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ACCEPTED MANUSCRIPT effective intravascular volume lead to unloading of high pressure baroreceptors in left ventricle, aortic arch and carotid sinus. This results in loss of parasympathetic output with
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increased sympathetic discharge and non-osmotic secretion of arginine vasopressin (AVP)
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(also known as antidiuretic hormone). Activation of sympathetic nervous system (SNS) and/or reduced renal blood flow and/or a decrease in sodium delivery, results in the release of
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renin from the macula densa in the kidney, and leads to activation of the renin angiotensin aldosterone system (RAAS). Both RAAS and AVP act as powerful vasoconstrictors that
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increase the permeability of renal collecting ducts leading to increased salt and water reabsorption. On the other hand, in HF the natriuretic peptide system, which can modulate the effects of peptides such as angiotensin II and AVP, becomes inadequate to counteract the maladaptive effects of neurohormonal activation because of reduced efficacy and inadequate
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cleaving of natriuretic peptides9,10 downregulation of renal natriuretic peptide receptors and
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degradation of natriuretic peptides by endopeptidases present in the renal tubule.11 Therefore, although these compensatory mechanisms try to maintain homeostasis even in the face of the
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failing heart, they ultimately cause end-organ damage by various mechanisms such as
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remodelling of the heart and excessive water retention (predisposing to hyponatremia, pulmonary congestion, and increased morbidity/mortality).12
Dietary Sodium Restriction: Current Practices and Evidence The Heart Failure Society of America Clinical Practice Guidelines state: ―dietary sodium restriction (2000-3000 mg daily) is recommended for patients with the clinical syndrome of HF and preserved or depressed left ventricular ejection fraction. Further restriction (< 2,000 mg daily) may be considered in moderate to severe HF (Strength of Evidence = C).‖13 In this section we explore that lack of existing evidence that lowering sodium in HF patients
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ACCEPTED MANUSCRIPT improves morbidity/mortality and where the recommendations for a lower sodium diet stem
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from.
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The concept of restricting salt among the general population (to prevent the emergence of hypertension (HTN) as well as HTN-induced HF) and the associated comorbidities originated the
noted
observational
cross-sectional
study
INTER-SALT.14
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from
Across
52
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―INTERSALT‖ centres, the median 24-hour urinary sodium excretion ranged from 0.2 to 242.1 mmol. When the relation between blood pressure (BP) and salt intake (assessed by the 24-hour urinary sodium excretion) was studied within each of the 52 INTERSALT centres (with adjustments for sex and age applied), a positive association was found in 39 of the 52
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centres (significant in 15) and a negative association was revealed in 13 centres (significant in 2). Analyses across centres of median BP and the prevalence of HTN in relation to median
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sodium excretion showed a positive association when all 52 centres were included but not
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when 4 populations with low sodium values were excluded. In another prospective study15 a group of 1499 participants were followed for more than 6 years and their BP and sodium
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excretion were measured. The annual increases in mean BP were 0.37 mm Hg systolic and 0.47 mm Hg diastolic (p < 0.001), but on average the 24-hour urinary sodium excretion did not change over time. However, in multivariable-adjusted analyses of individual participants, a 100-mmol increment in 24-hour sodium excretion was associated with a significant 1.71 mm Hg increase in systolic BP (p < 0.001), without concomitant change in diastolic BP. What this tells us is that among and within various populations, sodium intake appears to only weakly track with BP.
As described earlier, in HF the reduced CO and renal perfusion causes RAAS activation that causes salt and water retention, which in turn may cause or worsen the congestive symptoms 6
ACCEPTED MANUSCRIPT in HF. In this regard, the recommendation of a low salt diet for HF patients seems appealing as water is thought to follow salt (more salt ingested leads to increased thirst and greater fluid
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retention). However, experimental evidence shows that for subjects who are not sodium
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deprived, sodium intake expands intravascular volume via fluid shift from the interstitial space into the blood vessels without increasing total body water.16 In a study of 24 patients
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(12 compensated HF patients and 12 controls) randomized to 1 week of a low-sodium diet (70 mmol/day i.e., 1.575 mg/day) and 1 week of a high-sodium diet (250 mmol/day i.e.,
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5.625 mg/day); the high sodium group had a 9% increase in plasma volume, 14% increase in cardiac index, a 21% increase in stroke volume index, and a 10% decrease in total peripheral resistance. 17 The authors concluded that a high sodium intake did not cause excessive sodium
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and water retention in medically treated compensated HF patients and thus, the improvements in cardiac status caused by a high sodium intake do not support the advice for a sodium-
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restricted diet in HF patients. Lennie et al showed that 3 g dietary sodium restriction might be appropriate for patients in NYHA functional Classes III and IV, but harmful for NYHA
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Classes I and II patients (HR for event-free survival for 24-hour Urinary Na > 3 g in NYHA
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Class I/II was 0.44 (95% CI=0.20-0.97) and 2.54 (95% CI=1.10-5.84) for NYHA III/IV).18 A meta-analysis of 58 studies looking at sodium restriction showed that in normotensive individuals, mean arterial BP (MAP) was reduced by only by 0.6 mmHg and in HTN by 3 mmHg.19 Yet this small reduction of BP needs to be weighed against the activation of the SNS and RAAS. A recent Cochrane review performed by Adler et al failed to demonstrate any benefit of salt restriction among normotensive and HTN individuals with respect to CV disease (CVD) morbidity and mortality.20 The PURE investigators showed sodium intake between 3 gm/day to 6 gm/day was associated with lower risk of CVD events and mortality than was either a higher or lower level of intake.21 These data challenge the extrapolation between lower salt intake and BP over to a reduction in hard clinical events. Therefore, BP
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ACCEPTED MANUSCRIPT reduction alone is not enough to recommend dietary salt restriction in the general population to prevent HTN and the subsequent related pathophysiological consequences (e.g., HF for
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example).
Unintended Consequences of Dietary Sodium Restriction
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Lack of changes in urinary sodium excretion in 38 US studies conducted over 46 years (1957
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to 2003)22 and in 13 surveys carried out in the United Kingdom over 25 years (1984 to 2008)23 support the concept that sodium intake is difficult to manipulate chronically. Regardless, a 14-year follow up study has shown that lower serum sodium levels <135 mEq/L is an independent variable that predicts shorter survival time among elderly HF
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hospitalized patients (HR 1.67; 95% CI, 1.19-2.32).24 Other data in unselected groups of patients, non-dialysis dependent chronic kidney disease, congestive HF, CVD, or liver
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disease support this notion.25 Thus, sodium restriction may make the clinical situation worse
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in these patients not better.
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Low Sodium and CVD Events A retrospective analysis of participants in two earlier HTN treatment trials revealed a ‗J‘ shaped relation of sodium intake to CVD outcomes with the lowest risk between 4.0 and 5.99 grams/day, with continuous increases in risk with sodium levels above and below this range.26 Graudal et al investigated the incidence of all-cause mortality (ACM) and CVD events in populations exposed to different level of dietary sodium. Their study found that the risks of ACM and CVD events were decreased with a usual sodium intake (2.6 grams/day to 5 grams/day) vs. a low sodium intake (<2.6 grams/day) (ACM: HR=0.91, 95% CI; CVDE: HR=0.90, 95% CI) and increased with a high sodium vs. a usual sodium intake (ACM: HR=1.16, 95% CI; CVDE: HR=1.12, 95% CI), thus producing a U- shaped curve between 8
ACCEPTED MANUSCRIPT sodium intake and health outcome.27 This may be due to activation of RAAS and SNS at both higher and lower sodium intakes. Patients with HF may be at a similar increased risk with
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sodium restriction. Indeed, a low sodium diet (2 grams/day vs. 6 grams/day) has also been
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found to increase plasma norepinephrine and serum aldosterone levels, in 50 stable
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outpatients with mild to moderate HF and this was associated with HF progression.28
Salt restriction leads to an increased SNS tone and increased heart rate, which needs to be
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weighed against the comparative meagre decrement in BP. This generally results in an increased net product of heart rate and MAP, which ultimately leads to an increased load on the left ventricle and systemic arteries.29 Importantly, increased heart rate causes increased myocardial oxygen consumption which has detrimental effects on the prognosis of HF
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patients.29
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A study among streptozocin-induced diabetic rats has shown that low sodium intake accelerates atherogenic plaque formation and increases CVD mortality in Type 1 diabetics,
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probably through activation of RAAS.30 Another study among apolipoprotein E knock-out mice indicated that a low-salt diet (containing 0.03% sodium) for 6 weeks results in a 4-fold increase in plaque accumulation compared to mice receiving diet containing 0.30% sodium. Again the finding links a low-salt intake with activation of the RAAS, increased expression of vascular adhesion molecules, inflammatory cytokines and increased adhesion of leukocytes to blood vessels.31 Low-sodium intake also decreases bradykinin and increases angiotensin-I and angioteinsin-II.32 Thus, a low salt intake may decrease endothelial function/increase endothelial apoptosis, as bradykinin actually acts by producing endothelial nitric oxide.33 On the other hand, as bradykinin plays a pivotal role in the kinin system, such as the promotion of fibrinolysis, a low-salt intake may increase the propensity of thrombosis 9
ACCEPTED MANUSCRIPT and CV morbidity/mortality.34 All these factors ultimately increase the risk of myocardial
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infarction which is a leading cause of HF.
Hyponatremia: Lethal in HF
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HF patients are at high risk for developing hyponatremia, the most frequent electrolyte imbalance among hospitalized HF patients.35-37 In HF, multiple synergistic mechanisms
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contribute to the development of hyponatremia. 1.) Reduced cardiac output leads to decreased renal blood flow and glomerular filtration. This leads to a compensatory increased salt and water reabsorption in the proximal tubules to try and improve renal blood flow. The reduction in renal blood flow leads to reduced delivery of solute and water to the distal collecting
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tubules and collecting ducts. Thus, the kidney‘s ability to excrete dilute urine is impaired.38 2) HF activates SNS and RAAS, and also increases secretion of AVP resulting in enhanced
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sodium resorption but preferential water retention.39 3) Hyponatremic patients with advanced
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HF often have inappropriately elevated plasma AVP that fails to diminish, even with acute water loading.40 4) The standard HF regimens include diuretics, which commonly cause
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hyponatremia.41 Restriction of dietary sodium may foster the development of hyponatremia, which is itself a potent indicator of poor outcome42-44 and associated with longer hospital stay45 and increased rehospitalizsation.46 Research shows that correcting hyponatremia is associated with better outcomes.47 In a study recruiting 1000 patients with chronic HF, mortality was lowest when sodium levels were in the range between 140-145 mmol/l; however both below and above these values mortality increased.48
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ACCEPTED MANUSCRIPT Salt Is More than Just Sodium In the regulation of serum osmolality, BP and CVD events, we pay much attention to sodium
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while chloride remains a neglected and less researched electrolyte. However, salt is
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composed of more than just sodium.49 Two studies have shown that a low chloride (serum concentration < 100 mmol/L) as compared to higher levels is an independent predictor of all
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cause and CV mortality.50, 51 Moreover, a 1 mmol/L increase in serum Cl was associated with
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a 1.5% reduction (HR=0.985, 95% CI=0.98-0.99) in all-cause mortality.51 Although the issue of how a low serum chloride increases mortality is still poorly understood, potential explanations include propagation of atherosclerosis52, generation of arrythmogenic foci53 and
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increased activation of RAAS54.
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Normal Sodium Diets and Prognosis in Patients with HF
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In patients with systolic HF, maintaining a normal sodium diet has been shown to prevent RAAS activation and progression of HF when compared with a low sodium diet.55,
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A
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prospective cohort study57 looking at 10-year-follow up data among 2642 older adults (age range, 71-80 years) showed that ten-year CV mortality was non-significantly lower in the group receiving 1500 to 2300 mg/day (30.7%) sodium than in the group receiving less than 1500 mg/d (33.8%) and the group receiving greater than 2300 mg/day (35.2%) (p = .07). Sodium intake of greater than 2300 mg/day was associated with non-significantly higher mortality even in adjusted models (HR vs 1500-2300 mg/day, 1.15; 95% CI, 0.99-1.35; p = 0.07).
A normal sodium diet has been shown to improve renal blood flow in patients with systolic HF.57-61 An improvement in renal blood flow allows the kidneys to be perfused better with a 11
ACCEPTED MANUSCRIPT subsequent improvement in glomerular filtration which allows loop diuretics to better access their site of action. Normal-sodium diets (around 2.8 grams/day of sodium) have been shown
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to decrease aldosterone, renin, norepinephrine, brain natriuretic peptide, plasma renin
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activity, angiotensin II, interleukin-6, tumor necrosis factor-alpha in numerous randomized controlled trials compared to a low-sodium diet (around 1.8 grams/day of sodium).57-62
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Furthermore, a normal-sodium diet probably helps to prevent the compensatory RAAS system activation due to loop diuretics and a limited fluid intake thereby improving cardiac
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function.
Despite HF being a ―fluid-overload‖ state, when these patients are placed on loop diuretics and a limited fluid intake, a state of ―extracellular volume depletion‖ occurs, i.e. a decrease in
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body hydration status.57-61 As compared to a low-sodium diet, a normal-sodium diet has been
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shown to increase serum sodium levels, body hydration status by improving this extracellular volume depletion and reduce rehospitalization in patients who are in acutely decompensated
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as well as compensated systolic HF.57-61 Trials using a low-sodium diet have shown
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approximately twice the mortality and hospitalizations for HF compared with a normalsodium diet.57-61 Of course with any study, there are limitations. Since these trials are from the same group of authors, who also used fairly large doses of loop diuretics, these results may not be generalizable to the systolic HF population. Moreover, the validity of these studies has been questioned, and thus further randomized trials should be performed in HF patients. Despite current controversies,62 these aforementioned studies clearly suggest the need for more evidence before recommending sodium restriction in HF patients. Table 1 highlights reasons for and against salt restriction in HF patients.
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ACCEPTED MANUSCRIPT Conclusion Considering the available evidence and weighing the documented benefits versus risks,
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recommendation for lowering salt intake, both for the general population (to reduce the risk
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of HTN and subsequent HF) and in patients with established HF, is questionable. The intake of sodium should be individualized, and further studies are needed to clarify this important
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issue.
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Table 1: Reasons for and against dietary salt restriction in heart failure patients
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For
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May reduce dyspnea and improve edema May reduce blood pressure
Against
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May improve walking distance/NYHA functional class
May increase the risk of hyponatremia (and thus hospitalizations, falls, and premature death) Activates the RAAS Activates the SNS May worsen renal function May increase inflammatory cytokines May increase heart rate May worsen stroke volume, cardiac index, and total peripheral vascular resistance
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46. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A
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multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 333:1190–5.
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47. Rossi J, Bayram M, Udelson JE, et al. Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights
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from tha Acute anc Chronic Therapeutic Impact of v Vasopressin Antagonist ic Chronic
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Heart Failure (ACTIV in CHF) trial. Acute Cardiac Care 2007;9:82-6. 48. Deubner N, Berliner D, Brenner S, Podolskaya A, Gueder G, Fenske W et al. Differential impact of sodium levels on mortality risk in heart failure. Eu Heart J. 2010; 49. Gasowski J, Cwynar M. There is more to salt than just a pinch of sodium. Hypertens. 2013;62:829-30. 50. De Bacquer D, De Backer G, De Buyzere M, Kornitzer M. Is low serum chloride level a risk factor for cardiovascular mortality? J Cardiovasc Risk. 1998;5:177–84. 51. McCallum L, Jeemon P, Hastie CE, Patel RK, Williamson C, Redzuan AM et al. Serum chloride is an independent predictor of mortality in hypertensive patients. Hypertens. 2013;62:836–843.
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ACCEPTED MANUSCRIPT 52. Yang H, Huang LY, Zeng DY, Huang EW, Liang SJ, Tang YB et al. Decrease of intracellular chloride concentration promotes endothelial cel inflammation by activating
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nuclear factor-κB pathway. Hypertens. 2012;60:1287–93.
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53. Hiraoka M, Kawano S, Hirano Y, Furukawa T. Role of cardiac chloride currents in changes in action potential characteristics and arrhythmias. Cardiovasc Res. 1998;40:23–
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33.
54. Berend K, van Hulsteijn LH, Gans RO. Chloride: the queen of electrolytes? Eur J Intern
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Med. 2012;23:203–11.
55. Nakasato M, Strunk CM, Guimara˜es G, et al. Is the low-sodium diet actually indicated for all patients with stable heart failure? Arq Bras Cardiol. 2010;94:92-101.
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56. Damgaard M, Norsk P, Gustafsson F, et al. Hemodynamic and neuroendocrine responses to changes in sodium intake in compensated heart failure. Am J Physiol Regul Integr
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Comp Physiol 2006;290:R1294-301.
57. Licata G, Di Pasquale P, Parrinello G, et al. Effects of high-dose furosemide and small-
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volume hypertonic saline solution infusion in comparison with a high dose of furosemide
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as bolus in refractory congestive heart failure: long-term effects. Am Heart J 2003;145:459e66.
58. Paterna S, Di Pasquale P, Parrinello G, et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide Alone in refractory congestive heart failure. J Am Coll Cardiol 2005;45:1997e2003. 59. Paterna S, Parrinello G, Cannizzaro S, et al. Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure Am J Cardiol 2009;103:93e102Paterna S, Fasullo S,
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ACCEPTED MANUSCRIPT 60. Parrinello G, et al. Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restrictionin patients with compensated heart
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failure with new York heart Association Class III (Class C) (SMAC-HF study). Am J
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Med Sci 2011;342:27e37.
61. Paterna S, Gaspare P, Fasullo S, et al. Normal-sodium diet compared with low sodium
Clin Sci (London) 2008;114:221e30
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diet in compensated congestive heart failure: is sodium an old enemy or a new friend?
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62. Van Horn L. Dietary Sodium and Blood Pressure: How Low Should We Go? Prog Cardiovasc Dis. 2015 Jul-Aug;58(1):61-8. doi: 10.1016/j.pcad.2015.05.008. Epub 2015
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May 21.
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To appear in:
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Please cite this article as: DiNicolantonio James J., Chatterjee Subhankar, O’Keefe James H., Dietary Salt restriction in Heart Failure: Where is the Evidence?, Progress in Cardiovascular Diseases (2015), doi: 10.1016/j.pcad.2015.12.002
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ACCEPTED MANUSCRIPT Dietary Salt restriction in Heart Failure: Where is the Evidence?
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James J. DiNicolantonio, PharmD1, Subhankar Chatterjee, MBBS2, and James H. O‘Keefe, MD1
Affiliations:
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1- Mid-America Heart Institute at Saint Luke‘s Hospital, Kansas City, Missouri, USA
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([email protected])
2- R. G. Kar Medical College & Hospital, Kolkata, India Correspondence: Dr. James J. DiNicolantonio, PharmD, Saint Luke‘s Mid America Heart
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Word count: 2515
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Conflict of Interest: None
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Institute, Tel: 607-738-8853 Email: [email protected]
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ACCEPTED MANUSCRIPT Abbreviations ACM - all-cause mortality
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AVP - arginine vasopressin BP – blood pressure
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CO – cardiac output
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CV - cardiovascular CVD – cardiovascular disease HF - heart failure
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HTN- hypertension
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HR – hazard ratio
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MAP - mean arterial pressure
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NYHA – New York Heart Association RAAS - renin angiotensin aldosterone system SNS - sympathetic nervous system
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Abstract
Several dietary guidelines, health organizations and government policies recommend
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population-wide sodium restriction to prevent hypertension and related comorbidities like heart failure (HF). The current European Society of Cardiology and American College of
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Cardiology/American Heart Association Heart Failure guidelines recommend restricting sodium in HF patients. However, these recommendations are based on expert opinion (level C), leading to wide variability in application and lack of consensus among providers
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pertaining to dietary salt restriction. To evaluate the strength of current evidences to recommend dietary salt restriction among HF patients, we performed a comprehensive
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literature review and explored the safety and efficacy of such recommendations.
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Key words: chloride, heart failure, hypertension, salt, sodium
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ACCEPTED MANUSCRIPT Introduction Notwithstanding substantial progress in the pharmacology and technology related to
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cardiovascular (CV) care, heart failure (HF) remains the most frequent cause of hospital
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admission and readmission.1 Along with the wide pharmaceutical armamentarium and availability of devices, such as cardiac resynchronization therapy, physical exercise and
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dietary salt and fluid restriction remain essential steps in the management of HF and are
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recommended by nearly all HF guidelines.2-6 The current 2013 ACCF/AHA guideline recommends sodium restriction to 1.5 gm/day for patients with stage A and B HF, while for stage C and D HF AHA advises salt restriction < 3 gm/day7, which is much lower than what an average American diet contains (approximately 3.7g/day)8. Yet the recommendation for
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drastic reductions in the consumption of salt is still an unresolved issue in patients with HF. To evaluate the strength of the current evidence to recommend dietary salt restriction among
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HF patients, we performed a comprehensive literature review to explore the safety and
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efficacy of such recommendations.
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Pathophysiology of HF
HF is defined as a decreased ability of the heart to fill (diastolic HF) and/or eject blood (systolic HF) due to structural and/or functional defects in the myocardium leading to a reduced cardiac output (CO).2 The structural (as in dilated cardiomyopathy) or functional (as in myocardial infarction) insult to the heart is viewed as the index event. Following an index event, although pumping capacity of the heart starts to progressively decline, the patient remains largely asymptomatic or minimally symptomatic due to various compensatory mechanisms—that are orchestrated predominantly through
activation of neurohormonal
systems both within the heart and systemically. Reduced CO and the subsequently decreased
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ACCEPTED MANUSCRIPT effective intravascular volume lead to unloading of high pressure baroreceptors in left ventricle, aortic arch and carotid sinus. This results in loss of parasympathetic output with
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increased sympathetic discharge and non-osmotic secretion of arginine vasopressin (AVP)
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(also known as antidiuretic hormone). Activation of sympathetic nervous system (SNS) and/or reduced renal blood flow and/or a decrease in sodium delivery, results in the release of
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renin from the macula densa in the kidney, and leads to activation of the renin angiotensin aldosterone system (RAAS). Both RAAS and AVP act as powerful vasoconstrictors that
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increase the permeability of renal collecting ducts leading to increased salt and water reabsorption. On the other hand, in HF the natriuretic peptide system, which can modulate the effects of peptides such as angiotensin II and AVP, becomes inadequate to counteract the maladaptive effects of neurohormonal activation because of reduced efficacy and inadequate
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cleaving of natriuretic peptides9,10 downregulation of renal natriuretic peptide receptors and
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degradation of natriuretic peptides by endopeptidases present in the renal tubule.11 Therefore, although these compensatory mechanisms try to maintain homeostasis even in the face of the
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failing heart, they ultimately cause end-organ damage by various mechanisms such as
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remodelling of the heart and excessive water retention (predisposing to hyponatremia, pulmonary congestion, and increased morbidity/mortality).12
Dietary Sodium Restriction: Current Practices and Evidence The Heart Failure Society of America Clinical Practice Guidelines state: ―dietary sodium restriction (2000-3000 mg daily) is recommended for patients with the clinical syndrome of HF and preserved or depressed left ventricular ejection fraction. Further restriction (< 2,000 mg daily) may be considered in moderate to severe HF (Strength of Evidence = C).‖13 In this section we explore that lack of existing evidence that lowering sodium in HF patients
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ACCEPTED MANUSCRIPT improves morbidity/mortality and where the recommendations for a lower sodium diet stem
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from.
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The concept of restricting salt among the general population (to prevent the emergence of hypertension (HTN) as well as HTN-induced HF) and the associated comorbidities originated the
noted
observational
cross-sectional
study
INTER-SALT.14
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from
Across
52
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―INTERSALT‖ centres, the median 24-hour urinary sodium excretion ranged from 0.2 to 242.1 mmol. When the relation between blood pressure (BP) and salt intake (assessed by the 24-hour urinary sodium excretion) was studied within each of the 52 INTERSALT centres (with adjustments for sex and age applied), a positive association was found in 39 of the 52
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centres (significant in 15) and a negative association was revealed in 13 centres (significant in 2). Analyses across centres of median BP and the prevalence of HTN in relation to median
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sodium excretion showed a positive association when all 52 centres were included but not
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when 4 populations with low sodium values were excluded. In another prospective study15 a group of 1499 participants were followed for more than 6 years and their BP and sodium
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excretion were measured. The annual increases in mean BP were 0.37 mm Hg systolic and 0.47 mm Hg diastolic (p < 0.001), but on average the 24-hour urinary sodium excretion did not change over time. However, in multivariable-adjusted analyses of individual participants, a 100-mmol increment in 24-hour sodium excretion was associated with a significant 1.71 mm Hg increase in systolic BP (p < 0.001), without concomitant change in diastolic BP. What this tells us is that among and within various populations, sodium intake appears to only weakly track with BP.
As described earlier, in HF the reduced CO and renal perfusion causes RAAS activation that causes salt and water retention, which in turn may cause or worsen the congestive symptoms 6
ACCEPTED MANUSCRIPT in HF. In this regard, the recommendation of a low salt diet for HF patients seems appealing as water is thought to follow salt (more salt ingested leads to increased thirst and greater fluid
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retention). However, experimental evidence shows that for subjects who are not sodium
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deprived, sodium intake expands intravascular volume via fluid shift from the interstitial space into the blood vessels without increasing total body water.16 In a study of 24 patients
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(12 compensated HF patients and 12 controls) randomized to 1 week of a low-sodium diet (70 mmol/day i.e., 1.575 mg/day) and 1 week of a high-sodium diet (250 mmol/day i.e.,
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5.625 mg/day); the high sodium group had a 9% increase in plasma volume, 14% increase in cardiac index, a 21% increase in stroke volume index, and a 10% decrease in total peripheral resistance. 17 The authors concluded that a high sodium intake did not cause excessive sodium
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and water retention in medically treated compensated HF patients and thus, the improvements in cardiac status caused by a high sodium intake do not support the advice for a sodium-
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restricted diet in HF patients. Lennie et al showed that 3 g dietary sodium restriction might be appropriate for patients in NYHA functional Classes III and IV, but harmful for NYHA
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Classes I and II patients (HR for event-free survival for 24-hour Urinary Na > 3 g in NYHA
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Class I/II was 0.44 (95% CI=0.20-0.97) and 2.54 (95% CI=1.10-5.84) for NYHA III/IV).18 A meta-analysis of 58 studies looking at sodium restriction showed that in normotensive individuals, mean arterial BP (MAP) was reduced by only by 0.6 mmHg and in HTN by 3 mmHg.19 Yet this small reduction of BP needs to be weighed against the activation of the SNS and RAAS. A recent Cochrane review performed by Adler et al failed to demonstrate any benefit of salt restriction among normotensive and HTN individuals with respect to CV disease (CVD) morbidity and mortality.20 The PURE investigators showed sodium intake between 3 gm/day to 6 gm/day was associated with lower risk of CVD events and mortality than was either a higher or lower level of intake.21 These data challenge the extrapolation between lower salt intake and BP over to a reduction in hard clinical events. Therefore, BP
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ACCEPTED MANUSCRIPT reduction alone is not enough to recommend dietary salt restriction in the general population to prevent HTN and the subsequent related pathophysiological consequences (e.g., HF for
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example).
Unintended Consequences of Dietary Sodium Restriction
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Lack of changes in urinary sodium excretion in 38 US studies conducted over 46 years (1957
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to 2003)22 and in 13 surveys carried out in the United Kingdom over 25 years (1984 to 2008)23 support the concept that sodium intake is difficult to manipulate chronically. Regardless, a 14-year follow up study has shown that lower serum sodium levels <135 mEq/L is an independent variable that predicts shorter survival time among elderly HF
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hospitalized patients (HR 1.67; 95% CI, 1.19-2.32).24 Other data in unselected groups of patients, non-dialysis dependent chronic kidney disease, congestive HF, CVD, or liver
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disease support this notion.25 Thus, sodium restriction may make the clinical situation worse
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in these patients not better.
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Low Sodium and CVD Events A retrospective analysis of participants in two earlier HTN treatment trials revealed a ‗J‘ shaped relation of sodium intake to CVD outcomes with the lowest risk between 4.0 and 5.99 grams/day, with continuous increases in risk with sodium levels above and below this range.26 Graudal et al investigated the incidence of all-cause mortality (ACM) and CVD events in populations exposed to different level of dietary sodium. Their study found that the risks of ACM and CVD events were decreased with a usual sodium intake (2.6 grams/day to 5 grams/day) vs. a low sodium intake (<2.6 grams/day) (ACM: HR=0.91, 95% CI; CVDE: HR=0.90, 95% CI) and increased with a high sodium vs. a usual sodium intake (ACM: HR=1.16, 95% CI; CVDE: HR=1.12, 95% CI), thus producing a U- shaped curve between 8
ACCEPTED MANUSCRIPT sodium intake and health outcome.27 This may be due to activation of RAAS and SNS at both higher and lower sodium intakes. Patients with HF may be at a similar increased risk with
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sodium restriction. Indeed, a low sodium diet (2 grams/day vs. 6 grams/day) has also been
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found to increase plasma norepinephrine and serum aldosterone levels, in 50 stable
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outpatients with mild to moderate HF and this was associated with HF progression.28
Salt restriction leads to an increased SNS tone and increased heart rate, which needs to be
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weighed against the comparative meagre decrement in BP. This generally results in an increased net product of heart rate and MAP, which ultimately leads to an increased load on the left ventricle and systemic arteries.29 Importantly, increased heart rate causes increased myocardial oxygen consumption which has detrimental effects on the prognosis of HF
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patients.29
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A study among streptozocin-induced diabetic rats has shown that low sodium intake accelerates atherogenic plaque formation and increases CVD mortality in Type 1 diabetics,
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probably through activation of RAAS.30 Another study among apolipoprotein E knock-out mice indicated that a low-salt diet (containing 0.03% sodium) for 6 weeks results in a 4-fold increase in plaque accumulation compared to mice receiving diet containing 0.30% sodium. Again the finding links a low-salt intake with activation of the RAAS, increased expression of vascular adhesion molecules, inflammatory cytokines and increased adhesion of leukocytes to blood vessels.31 Low-sodium intake also decreases bradykinin and increases angiotensin-I and angioteinsin-II.32 Thus, a low salt intake may decrease endothelial function/increase endothelial apoptosis, as bradykinin actually acts by producing endothelial nitric oxide.33 On the other hand, as bradykinin plays a pivotal role in the kinin system, such as the promotion of fibrinolysis, a low-salt intake may increase the propensity of thrombosis 9
ACCEPTED MANUSCRIPT and CV morbidity/mortality.34 All these factors ultimately increase the risk of myocardial
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infarction which is a leading cause of HF.
Hyponatremia: Lethal in HF
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HF patients are at high risk for developing hyponatremia, the most frequent electrolyte imbalance among hospitalized HF patients.35-37 In HF, multiple synergistic mechanisms
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contribute to the development of hyponatremia. 1.) Reduced cardiac output leads to decreased renal blood flow and glomerular filtration. This leads to a compensatory increased salt and water reabsorption in the proximal tubules to try and improve renal blood flow. The reduction in renal blood flow leads to reduced delivery of solute and water to the distal collecting
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tubules and collecting ducts. Thus, the kidney‘s ability to excrete dilute urine is impaired.38 2) HF activates SNS and RAAS, and also increases secretion of AVP resulting in enhanced
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sodium resorption but preferential water retention.39 3) Hyponatremic patients with advanced
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HF often have inappropriately elevated plasma AVP that fails to diminish, even with acute water loading.40 4) The standard HF regimens include diuretics, which commonly cause
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hyponatremia.41 Restriction of dietary sodium may foster the development of hyponatremia, which is itself a potent indicator of poor outcome42-44 and associated with longer hospital stay45 and increased rehospitalizsation.46 Research shows that correcting hyponatremia is associated with better outcomes.47 In a study recruiting 1000 patients with chronic HF, mortality was lowest when sodium levels were in the range between 140-145 mmol/l; however both below and above these values mortality increased.48
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ACCEPTED MANUSCRIPT Salt Is More than Just Sodium In the regulation of serum osmolality, BP and CVD events, we pay much attention to sodium
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while chloride remains a neglected and less researched electrolyte. However, salt is
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composed of more than just sodium.49 Two studies have shown that a low chloride (serum concentration < 100 mmol/L) as compared to higher levels is an independent predictor of all
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cause and CV mortality.50, 51 Moreover, a 1 mmol/L increase in serum Cl was associated with
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a 1.5% reduction (HR=0.985, 95% CI=0.98-0.99) in all-cause mortality.51 Although the issue of how a low serum chloride increases mortality is still poorly understood, potential explanations include propagation of atherosclerosis52, generation of arrythmogenic foci53 and
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increased activation of RAAS54.
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Normal Sodium Diets and Prognosis in Patients with HF
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In patients with systolic HF, maintaining a normal sodium diet has been shown to prevent RAAS activation and progression of HF when compared with a low sodium diet.55,
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A
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prospective cohort study57 looking at 10-year-follow up data among 2642 older adults (age range, 71-80 years) showed that ten-year CV mortality was non-significantly lower in the group receiving 1500 to 2300 mg/day (30.7%) sodium than in the group receiving less than 1500 mg/d (33.8%) and the group receiving greater than 2300 mg/day (35.2%) (p = .07). Sodium intake of greater than 2300 mg/day was associated with non-significantly higher mortality even in adjusted models (HR vs 1500-2300 mg/day, 1.15; 95% CI, 0.99-1.35; p = 0.07).
A normal sodium diet has been shown to improve renal blood flow in patients with systolic HF.57-61 An improvement in renal blood flow allows the kidneys to be perfused better with a 11
ACCEPTED MANUSCRIPT subsequent improvement in glomerular filtration which allows loop diuretics to better access their site of action. Normal-sodium diets (around 2.8 grams/day of sodium) have been shown
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to decrease aldosterone, renin, norepinephrine, brain natriuretic peptide, plasma renin
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activity, angiotensin II, interleukin-6, tumor necrosis factor-alpha in numerous randomized controlled trials compared to a low-sodium diet (around 1.8 grams/day of sodium).57-62
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Furthermore, a normal-sodium diet probably helps to prevent the compensatory RAAS system activation due to loop diuretics and a limited fluid intake thereby improving cardiac
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function.
Despite HF being a ―fluid-overload‖ state, when these patients are placed on loop diuretics and a limited fluid intake, a state of ―extracellular volume depletion‖ occurs, i.e. a decrease in
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body hydration status.57-61 As compared to a low-sodium diet, a normal-sodium diet has been
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shown to increase serum sodium levels, body hydration status by improving this extracellular volume depletion and reduce rehospitalization in patients who are in acutely decompensated
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as well as compensated systolic HF.57-61 Trials using a low-sodium diet have shown
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approximately twice the mortality and hospitalizations for HF compared with a normalsodium diet.57-61 Of course with any study, there are limitations. Since these trials are from the same group of authors, who also used fairly large doses of loop diuretics, these results may not be generalizable to the systolic HF population. Moreover, the validity of these studies has been questioned, and thus further randomized trials should be performed in HF patients. Despite current controversies,62 these aforementioned studies clearly suggest the need for more evidence before recommending sodium restriction in HF patients. Table 1 highlights reasons for and against salt restriction in HF patients.
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ACCEPTED MANUSCRIPT Conclusion Considering the available evidence and weighing the documented benefits versus risks,
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recommendation for lowering salt intake, both for the general population (to reduce the risk
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of HTN and subsequent HF) and in patients with established HF, is questionable. The intake of sodium should be individualized, and further studies are needed to clarify this important
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issue.
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Table 1: Reasons for and against dietary salt restriction in heart failure patients
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For
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May reduce dyspnea and improve edema May reduce blood pressure
Against
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May improve walking distance/NYHA functional class
May increase the risk of hyponatremia (and thus hospitalizations, falls, and premature death) Activates the RAAS Activates the SNS May worsen renal function May increase inflammatory cytokines May increase heart rate May worsen stroke volume, cardiac index, and total peripheral vascular resistance
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