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Salt and obesity revisited

Jordan, Jens

doi: 10.1097/HJH.0b013e328365d09d
Editorial Commentaries

Medical School Hannover, Institute of Clinical Pharmacology, Germany

Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Medical School Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Tel: +49 511 532 2821; fax: +49 511 532 162821; e-mail:

Approximately 75% of the hypertensive patients seen by general practitioners are overweight or obese [1]. In addition to causing or exacerbating arterial hypertension, obesity makes it more difficult to attain blood pressure control, an issue that has been recently highlighted in a joint statement of the European Society of Hypertension and the European Association for the Study of Obesity [2]. Indeed, the presence of obesity was the strongest predictor for lack of DBP control below 90 mmHg and the second strongest predictor for lack of SBP control below 140 mmHg among participants of the Framingham Heart Study [3]. Finally, obesity adds cardiovascular risk to hypertension. For example, in the Framingham Heart Study, heart failure risk increased 5% in men and 7% in women with each 1 kg/m2 increment in BMI in such a way that heart failure risk was doubled in obese individuals [4].

Understanding the mechanisms driving the increase in blood pressure while raising heart failure risk may provide guidance for future research and eventually for preventive and therapeutic measures. Basic and clinical studies provided novel mechanisms on how obesity burdens the cardiovascular system. Among other mechanisms, obesity is associated with excessive release of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1, and interleukin-6, which have been implicated in myocardial hypertrophy, fibrosis, and apoptosis [5]. Adipose tissue derived molecules, such as fatty acid binding protein 4, may directly depress myocardial function [6,7]. Furthermore, obesity, particularly in the setting of impaired insulin sensitivity, may predispose to excessive myocardial fat storage [8,9]. In experimental studies, excessive myocardial fat fosters production of lipotoxic intermediates [10]. Thus, altered cardiac metabolism and diminished efficiency are already evident in otherwise healthy obese individuals [11]. Work by Bonfils et al. [12] in this issue of the Journal reminds us that, in addition to all these exciting new mechanisms and molecules, we should not forget about the good old sodium ion and its accompanying anion, chloride.

The study by Bonfils et al. [12] is a prime example of how carefully conducted human studies can serve to elucidate pathophysiology. The investigators assessed blood pressure and systemic hemodynamics in morbidly obese patients with and without arterial hypertension and in a normal weight control group. Patients and control individuals were tested after they had received a low sodium (90 mmol/day) or a high sodium (250 mmol/day) diet each for 5 days. Diets were tested in a randomized and cross-over fashion with 2 weeks washout between interventions. The low sodium diet reflects a sodium intake that could be reasonably attained in a real life therapeutic setting. The high sodium diet corresponds to the upper range of sodium ingestion in many Western countries. Because changes in energy balance profoundly affect blood pressure regulation, caloric intake was kept constant throughout the study. The authors applied state-of-the-art methodology to assess blood pressure, systemic hemodynamics, renal function, and plasma volume at the end of the dietary phase. Compared with the low sodium diet, plasma volume was approximately 5–10% higher on the high sodium diet. Remarkably, the response did not differ between groups. The plasma volume expansion on the high sodium diet was associated with a consistent increase in cardiac stroke volume and cardiac output. Indeed, cardiac output increased around 15% in obese hypertensive patients, 20% in obese normotensive patients, and 12% in control individuals. Yet, the substantial increase in cardiac output did not translate into a pressor response of a parallel magnitude. On average, 24-h SBP changed only 1.5% in obese hypertensive patients, 1% in obese normotensive patients, and 1.5% in control individuals. One-quarter or less in each group was classified as being salt sensitive.

One important limitation of the study by Bonfils et al. [12] is the short duration of the change in sodium intake and the relatively low number of individuals in each group, thus, limiting the statistical power. In a much larger study in a Chinese population, blood pressure in participants meeting metabolic syndrome criteria responded more to changes in sodium intake compared with individuals without the metabolic syndrome, and sodium sensitivity was directly related to the number of metabolic syndrome criteria [13]. Yet, in approximately half of the individuals meeting four or five of the metabolic syndrome criteria, blood pressure was not particularly sodium sensitive [13]. Perhaps, sole reliance on blood pressure measurements makes it difficult to assess the true impact of sodium intake on the cardiovascular system. The idea is supported by the observation that substantial increases in plasma volume and cardiac output on a high sodium diet can be attenuated by concomitant reductions in systemic vascular resistance [12]. Thus, even in the absence of blood pressure changes, increased sodium intake may impose an additional burden on the heart facilitating left ventricular hypertrophy, a hypothesis that deserves to be studied in more detail. Perhaps, volume load influences on blood pressure are unmasked when compensatory mechanisms, such as baroreflex blood pressure buffering [14], fail. In the event, baroreflex regulation of heart rate and sympathetic vasomotor tone is disturbed in obese normotensive patients, and more so in obese hypertensive patients [15].

As a young physician, my teacher in nephrology insisted that ‘what comes in must come out or it will stay there forever’. No doubt, this mnemonic holds true when it comes to sodium balance. Abnormalities in renal sodium excretion (‘what comes out’) have been recognized as an important mechanism driving obesity-associated hypertension [16]. Intrarenal abnormalities, excessive neurohumoral activation, and natriuretic peptide deficiency appear to be involved [15,17–20]. Recent studies suggest additional mechanisms affecting sodium homeostasis and volume regulation. Apparently, sodium can be sequestered in the skin interstitial space [21,22]. Remarkably, the interstitial sodium compartment is regulated by immune cells [22]. It is tempting to speculate that impaired sodium sequestration in the skin interstitial space or other hitherto unrecognized compartments could contribute to sodium-sensitivity in some obese individuals.

Although much of the research focused on mechanisms regulating sodium excretion, the fact that increased sodium intake (‘what comes in’) may be equally important was somewhat neglected. In earlier studies showing plasma volume expansion and increased cardiac output in obese individuals, obese individuals also exhibited increased urinary sodium excretion [23]. Obese individuals and those with the metabolic syndrome also excreted more sodium in more recent studies [13,17]. Finally, children and adolescents show a positive correlation between adiposity and urinary sodium excretion [24]. The increase in sodium excretion in obese individuals could result from an increase in food quantity or a larger likelihood of choosing unhealthy foods with higher sodium content. As neurobiological abnormalities in the regulation of energy balance predispose to obesity, there could also be a neurobiological correlate for excess sodium intake. For example, angiotensin II in the brain promotes water and sodium ingestion through separate cell signaling pathways in animals [25].

Overall, sodium remains important in the search for mechanisms and potential new treatments for obesity-associated cardiovascular disorders. Meanwhile, we might apply some of the findings in patient care. It is known for many years that weight loss, which is difficult to achieve and even more difficult to maintain, can reduce plasma volume, cardiac output, and blood pressure [19,26]. We should pay more attention to sodium intake, particularly in obese patients with difficult to control arterial hypertension being aware that many patients will not respond. Others may simply refuse a low sodium diet. Recent studies suggested that a sequential nephron blockade, which augments sodium excretion, is particularly efficacious in attaining blood pressure control in patients with treatment-resistant arterial hypertension [27], who are often obese.

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Conflicts of interest

There are no conflicts of interest.

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