Abstract P163: Prevention Of Cardiac Fibrosis By Dietary Sodium Restriction During Metabolic Syndrome: Involvement Of Endothelial To Mesenchymal Transition

In a rat model of metabolic syndrome (MS), our previous studies have shown that dietary sodium restriction prevents both metabolic and cardiac damages associated with MS. Our aim is now to investigate whether the beneficial effects of sodium restriction could be mediated by endothelial to mesenchymal (EndoMT) transition in the myocardium thereby preventing cardiac fibrosis.High fructose (60%) Sprague Dawley rats were divided into 2 groups: low sodium (<0.01% NaCl, N=20) or normal sodium (0.65% NaCl, N=20) diet for 8 weeks. EndoMT was investigated by q-PCR, WB, and IF on the left ventricles. Transcriptomic analysis was performed using Agilent Rat Gene Expression Microarray. After 8 weeks, fructose-fed rats on normal sodium diet were insulin-resistant and hypertensive, both abnormalities being significantly prevented by sodium restriction. In left ventricles, two mesenchymal proteins, α-smooth muscle actin (αSMA) and vimentin were found significantly reduced using qPCR and WB by sodium restriction (P<0.05), as compared to normal sodium diet. At the opposite, we observed a significant increase in Pecam-1, a specific protein of vascular endothelial cells (P<0.05). Using IF, we detected a co-expression of αSMA and Pecam-1 in 67.3%±4.9 (54 of 88) of cardiac vessels of rats fed normal sodium diet, as compared to 42.3%±3.8 (37 of 88) in rats fed low sodium diet (P<0.05). The transcriptomic study showed that 22 genes, involved in fibrosis, were down-regulated in left ventricles of sodium-restricted rats (P<0.05). By q-PCR, we confirmed that 17 of them were significantly reduced by the low sodium diet (P<0.05). Finally, we established an in vitro model of EndoMT, using primary human aortic endothelial (HAoE) cells that were transdifferentiated with TGF-β2 (10ng/ml). We evidenced in HAoE cells the co-expression of Pecam-1 and collagen-1, as a signature of EndoMT. Especially, fibulin 5, one of the genes identified by transcriptomics was found upregulated (13 folds) in the presence of TGF-β2, confirming its potential role in EndoMT. Our study shows that EndoMT is involved in the prevention of cardiac fibrosis by sodium restriction in our rat model of MS. We also confirmed the involvement of ew genes that could be of interest to improve the management of cardiac fibrosis.

The Effects of Short-Term Changes in Sodium Intake on Plasma Marinobufagenin Levels in Patients with Primary Salt-Sensitive and Salt-Insensitive Hypertension

Increased marinobufagenin (MBG) synthesis has been suggested in response to high dietary salt intake. The aim of this study was to determine the effects of short-term changes in sodium intake on plasma MBG levels in patients with primary salt-sensitive and salt-insensitive hypertension. In total, 51 patients with primary hypertension were evaluated during acute sodium restriction and sodium loading. Plasma or serum concentrations of MBG, natriuretic pro-peptides, aldosterone, sodium, potassium, as well as hematocrit (Hct) value, plasma renin activity (PRA) and urinary sodium and potassium excretion were measured. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed at baseline. In salt-sensitive patients with primary hypertension plasma MBG correlated positively with diastolic blood pressure (ABPM) and serum NT-proANP concentration at baseline and with serum NT-proANP concentration after dietary sodium restriction. In this subgroup plasma MBG concentration decreased during sodium restriction, and a parallel increase of PRA was observed. Acute salt loading further decreased plasma MBG concentration in salt-sensitive subjects in contrast to salt insensitive patients. No correlation was found between plasma MBG concentration and left ventricular mass index. In conclusion, in salt-sensitive hypertensive patients plasma MBG concentration correlates with 24-h diastolic blood pressure and dietary sodium restriction reduces plasma MBG levels. Decreased MBG secretion in response to acute salt loading may play an important role in the pathogenesis of salt sensitivity.

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease

BackgroundDistal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited.MethodsTo investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics.ResultsA total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m2) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and β2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia.ConclusionsDistal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance.Clinical Trial registry name and registration numberDD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886

Interventions for Dietary Sodium Restriction Among Patients with Heart Failure: A Mismatch in the Evidence and Intervention Design (OR22-05-19)

Objectives Dietary sodium restriction guidelines are controversial due to a lack of studies assessing their effect on heart failure outcomes. An important aspect of this problem is the effectiveness of behavioral nutrition interventions to reduce patients’ sodium intake. We systematically reviewed randomized controlled trials (RCTs) of sodium restricted diets and descriptive studies relating mediators of behavior to successful adherence to sodium restricted diets in patients with heart failure. Methods We queried PubMed, CINAHL, and Cochrane databases with relevant search terms for studies published in English January 2000-December 2018. Included were RCTs of interventions for heart failure patients, with sodium restriction as a primary or secondary outcome, and quantitative and qualitative descriptive studies of adherence to sodium restricted diets. Included studies may or may not have reported clinical outcomes (health events, quality of life, etc.). Reviewers noted setting, methods, and outcomes as well as theoretical mediators of dietary behavior change in included studies. We then compared behavioral mediators addressed by the RCTs and behavioral mediators identified in the descriptive studies. Results Of 638 studies identified, 445 were excluded by title. 2 reviewers assessed 60 abstracts and included 36 studies in this analysis: 10 RCTs and 26 descriptive studies. 6 of 10 intervention RCTs were successful, but no interventions achieved the recommended 1500 mg/day sodium intake (mean for all studies 3271 mg/day). Interventions that reduced sodium intake were behaviorally focused, were delivered by an RN and/or RD, and included individual feedback and counseling. RCTs intervened only through knowledge, skills, and social support. Behavioral mediators identified in descriptive studies included perceived risk, perceived benefits, outcome expectations, cultural norms, social norms, social support, taste preferences, determinism, self-efficacy, knowledge, skills, and habits. These were not included in the RCTs, which signifies a mismatch between evidence-based moderators of behavior and intervention designs. Conclusions RCTs have been unable to achieve the recommended goal of 1500 mg/day of sodium. More effective interventions should consider evidence-based mediators, rather than focusing on knowledge and skills. Funding Sources Dr. Burgermaster received funding from NHLBI T32 training grant.