Mineralocorticoid Receptor (MR) Antagonist (Eplerenone) vs Amlodipine and STRIATIN

Summary

Salt sensitivity of blood pressure is a substantial risk factor for cardiovascular morbidity and mortality. Inappropriate increases in renal sodium reabsorption lead to volume expansion, hypertension and salt sensitive blood pressure. Key homeostatic mechanisms that regulate renal sodium reabsorption are: first, hormonal, e.g., renin-angiotensin-aldosterone system and second, vascular, e.g., renal vasculature. Dysfunction in one or both mechanisms leads to hypertension and salt sensitive blood pressure. The investigators recently documented that striatin plays a novel role in the development of salt sensitive blood pressure. However, the mechanisms that lead to striatin-mediated salt sensitive blood pressure are not clear; defining these mechanisms is the overall goal of this proposal.

Striatin is a calmodulin- and caveolin-binding protein that can function as either a scaffolding and/or signaling protein, specifically in relation to the mechanism of action of steroids. In a large study of well characterized subjects from the International Hypertensive Pathotype (HyperPATH) cohort, the investigators documented that hypertensive and normotensive humans who are striatin risk allele carriers have salt sensitive blood pressure.

The investigators then developed a striatin heterozygous knockout mouse as a tool to identify potential mechanisms for the salt sensitive blood pressure. The investigators documented that these mice also have salt sensitive blood pressure with higher blood pressure levels and inappropriately increased aldosterone levels on a liberal salt diet.

Conditions

• Hypertension
• Genetics Hypertension

Interventions

DRUG

Eplerenone vs Amlodipine

We posit that decreases in striatin activity/levels increases aldosterone secretion resulting in hypertension and salt sensitive blood pressure. Thus, our mechanistic clinical study will assess whether hypertensive striatin risk allele carriers will show significantly greater reductions in blood pressure with a specific aldosterone mediated treatment approach (mineralocorticoid receptor blockade) than with a non-specific approach (amlodipine). To test this hypothesis, we will perform a randomized, double-blind, active controlled study in hypertensive carriers of the striatin risk allele using a novel two-limb, proof-of-principle study. Our primary outcome will be a liberal salt diet systolic blood pressure with a secondary outcome of salt sensitive blood pressure. Therefore, this mechanistic trial will provide support for using a genetic marker that identifies individuals who are uniquely responsive to mineralocorticoid receptor blockade--personalized, precision medicine.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

  collaborator NIH

• Brigham and Women's Hospital

  lead OTHER

Principal Investigators

• Gordon H Williams · Brigham and Women's Hospital

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-01-15

Primary Completion

2023-08-28

Completion

2024-01-31

FDA Drug

Yes

Countries

• United States

Study Locations