Aldosterone, Microvascular Function and Salt-sensitivity

Aldosterone-induced Microvascular Dysfunction as a Cause of Salt-sensitivity in Obesity?

Currently, the incidence of obesity and obesity-related disorders is reaching epidemic proportions, which entails an increasing burden for health care systems. The association of obesity with other risk factors for type 2 diabetes mellitus and cardiovascular disease, such as insulin resistance and hypertension, is often referred to as the metabolic syndrome. During recent years, salt-sensitivity of blood pressure has emerged as an additional cardiovascular risk factor that is related to obesity and other key components of the metabolic syndrome. The underlying pathophysiological mechanisms of these interrelationships are complex and incompletely elucidated. Microvascular dysfunction has been proposed as a link between insulin resistance and hypertension in obese individuals. In addition, impairment of microvascular function was found to be associated with salt-sensitivity of blood pressure. Increased aldosterone levels, as observed in obese individuals, might be a cause of microvascular dysfunction-induced salt-sensitivity and insulin resistance. Aldosterone not only gives rise to sodium-retention in the distal tubule of the kidney, but was also found to impair endothelial function and thus lower NO-availability, which is characteristic of microvascular dysfunction. In addition, elevated aldosterone levels are associated with both hypertension and insulin resistance, which is illustrated in patients with primary aldosteronism, but also in the general population.

The investigators hypothesize that increased aldosterone levels in obese individuals lead to impairment of microvascular function through reduction of NO-availability. This microvascular dysfunction is suggested to play a central role in the pathogenesis of salt-sensitive hypertension and insulin resistance.

Study Overview

• Status: Completed
• Conditions: Hypertension; Metabolic Syndrome; Insulin Resistance; Abdominal Obesity; Sodium-sensitivity
• Intervention / Treatment: Dietary supplement: Low-sodium diet; Dietary supplement: High-sodium diet

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 ER
      • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Obese individuals

• Age 18-65 years
• Caucasian
• Waist circumference > 102 cm (men)/> 88 cm (women)

Lean individuals

• Age 18-65 years
• Caucasian
• Waist circumference < 94 cm (men)/< 80 cm (women)

Exclusion Criteria:

Obese/lean individuals

• Cardiovascular disease (stroke, coronary artery disease, peripheral vascular disease, congestive heart failure, cardiac shunts, cardiac surgery, pulmonary hypertension, cardiac arrhythmias, family history of cardiac arrhythmias or sudden cardiac death)
• Diabetes mellitus/impaired glucose metabolism (fasting glucose values > 5.6 mmol/L
• Stage 3 hypertension (blood pressure > 180/110 mm Hg)
• Unstable or severe pulmonary disease
• Unstable or severe thyroid disorders
• Inflammatory diseases
• Smoking
• Alcohol use > 2 U/day (women)/> 3 U/day (men)
• Use of antihypertensive, lipid-lowering or glucose-lowering medications
• Use of corticosteroids and regular use of NSAIDs
• eGFR< 60 mL/min
• Impairment of hepatic function
• Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Start with low-sodium diet; One week of low-sodium diet, followed by a two-week wash-out period and subsequently, another week of high-sodium diet	Dietary supplement: Low-sodium diet; 50 mmol NaCl per 24h; Dietary supplement: High-sodium diet; 250 mmol NaCl per 24h
Active Comparator: Start with high-sodium diet; One week of high-sodium diet, followed by a two-week wash-out period and subsequently, another week of low-sodium diet	Dietary supplement: Low-sodium diet; 50 mmol NaCl per 24h; Dietary supplement: High-sodium diet; 250 mmol NaCl per 24h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in capillary recruitment between low- and high sodium diets	One week low-sodium diet; wash-out period of two weeks; one week high-sodium diet; order of respective diets is randomized

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: C.D.A. Stehouwer, MD, PhD, Maastricht University Medical Center

Publications and helpful links

General Publications

• Schutten MT, Kusters YH, Houben AJ, Niessen HE, Op 't Roodt J, Scheijen JL, van de Waardenburg MP, Schalkwijk CG, de Leeuw PW, Stehouwer CD. Glucocorticoids affect metabolic but not muscle microvascular insulin sensitivity following high versus low salt intake. JCI Insight. 2020 Mar 26;5(6):e127530. doi: 10.1172/jci.insight.127530.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: February 19, 2014
• First Submitted That Met QC Criteria: February 19, 2014
• First Posted (Estimate): February 21, 2014

Study Record Updates

• Last Update Posted (Actual): May 19, 2017
• Last Update Submitted That Met QC Criteria: May 18, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Hypersensitivity; Obesity; Metabolic Syndrome; Insulin Resistance; Obesity, Abdominal
• Other Study ID Numbers: 47438/IMP10124