Striatin

Overview

Status: Not yet recruiting
Keywords: Hypertension , Striatin
IRB Number: 00071044
Specialty: Cardiology
Sub Specialties:

Brief Summary

            This study is a logical extension of our previous project entitled “The Genetics of Human Hypertension” which was previously an IRB-approved study utilizing the CCTS (Center for Clinical and Translational Science).  That project has been remarkably productive with many published findings regarding various aspects of hypertension and metabolic syndrome.  This project is a continuation of that study and will focus on one of the findings, but we will continue to collect data in a similar, standardized manner in order to provide additional data to address and extend other findings together with the focused hypothesis detailed in this project.

            In preliminary results, we found that, compared to non-carriers, carriers of a common variant of the striatin gene had a significantly larger increase in systolic pressure when going from a low salt to a generous salt diet.  These results were confirmed in a separate cohort.  This represents one of the few gene variants identified in humans that associate with salt sensitivity (other than certain rare monogenic forms of hypertension).  In other preliminary results, heterozygous knock-out of striatin in mice resulted in increased blood pressure sensitivity to salt.  In vitro cell studies have shown that striatin acts as a scaffold or adapter protein which interacts with the mineralocorticoid receptor (MR) among other cellular proteins and helps mediate some of the rapid, non-genomic effects of aldosterone both in renal tubular cells and in endothelial cells.1,2  Striatin has a similar role in mediating rapid, non-genomic effects of estrogen.3

            The overall objective of this study is to further characterize the vascular, renal, and molecular consequences of the human striatin variant.  Specifically we will test the hypothesis that striatin genotype status identifies subsets of hypertensive subjects that differ in:  1) vascular function, 2) vascular and renal responses to changes in sodium intake and 3) aldosterone responses to acute and chronic stimuli.

 

Detailed Description

This study is a logical extension of our previous project entitled “The Genetics of Human Hypertension” which was previously an IRB-approved study utilizing the CCTS (Center for Clinical and Translational Science). That project has been remarkably productive with many published findings regarding various aspects of hypertension and metabolic syndrome. This project is a continuation of that study and will focus on one of the findings, but we will continue to collect data in a similar, standardized manner in order to provide additional data to address and extend other findings together with the focused hypothesis detailed in this project. In preliminary results, we found that, compared to non-carriers, carriers of a common variant of the striatin gene had a significantly larger increase in systolic pressure when going from a low salt to a generous salt diet. These results were confirmed in a separate cohort. This represents one of the few gene variants identified in humans that associate with salt sensitivity (other than certain rare monogenic forms of hypertension). In other preliminary results, heterozygous knock-out of striatin in mice resulted in increased blood pressure sensitivity to salt. In vitro cell studies have shown that striatin acts as a scaffold or adapter protein which interacts with the mineralocorticoid receptor (MR) among other cellular proteins and helps mediate some of the rapid, non-genomic effects of aldosterone both in renal tubular cells and in endothelial cells.1,2 Striatin has a similar role in mediating rapid, non-genomic effects of estrogen.

Principal Investigator: Paul Hopkins
Department: Cardiovascular Genetics
Co Investigator:

Contact Information

Name:Sally Ibrahim-Hill
Phone: 801-585-7950
Email: sally.ibrahim@utah.edu

Inclusion Criteria

Inclusion criteria:

·       Prior diagnosis of hypertension

·       Age 18 – 65

Exclusion Criteria

Specific exclusion criteria include the following:

·       diabetes mellitus

·       BMI >45

·       secondary causes of hypertension

·       mean systolic blood pressures greater than 180 mm Hg or mean diastolic blood pressures greater than 110 mm Hg at screening (determined as the average of 3 seated blood pressures)

·       isolated systolic hypertension (defined as untreated systolic blood pressure greater than 160 mm Hg but diastolic less than 90 mm Hg)

·       history of clinically diagnosed coronary artery disease

·       history or presence of congestive heart failure

·       definite LVH (identified on ECG at screening or previously by echocardiography or ECG)

·       abnormal heart rhythm identified on ECG at screening (other than occasional PVCs, or mild bradycardia)

·       history of stroke or transient ischemic attack (TIA)

·       asthma or chronic obstructive pulmonary disease

·       excessive alcohol intake (greater than 12 ounces of ethanol per week).  A “standard drink” is equal to a 12 ounce can of beer, a 5 ounce glass of wine, or a 1.5 ounce shot of vodka, whiskey or other liquor.  A standard drink provides about 14 grams = 0.6 ounces of alcohol.  Thus, 12 ounces of ethanol is equivalent to 20 standard drinks per week.

·       Subjects who smoke who are unwilling to refrain from smoking for 72 hours prior to the start of any inpatient studies.

·       recreational drug use

·       persons unable stop medications which may alter renal function (as determined by the PI).  Stable doses of thyroxine, post-menopausal estrogen replacement hormones, and lipid-lowering drugs are to be continued unchanged.  Medications to be discontinued prior to hospital studies include aspirin (for 2 weeks prior), NSAIDs (for 3 days prior), SSRIs (for 3 days prior after taper for most), and most other drugs (for 3 days prior).

·       clinically significant abnormal values for the following screening tests:

o   CBC (Hct less than 36, WBC greater than 11.0)

o   serum potassium greater than 5.2 mmol/l or other serum electrolyte abnormalities considered clinically significant by the investigator.  Unexpectedly high serum potassium levels may be repeated if the high level is suspected to be spurious due to hemolysis.

o   subjects with hypokalemia while on diuretics will be re-evaluated for normalization of potassium after stopping the diuretic before continuing the study.  Subjects may be evaluated for hyperaldosteronism if indicated.

o   liver enzymes (more than 3 times upper limit of normal)

o   TSH greater than 8.0

o   urinalysis (indicative of renal disease other than bladder infection)

o   estimated GFR less than 60 ml/min

o   ECG abnormalities (if determined by the PI to be clinically significant)

·       prior diagnosis of Cushing's syndrome.  A 24-hour urine cortisol may be obtained if there is clinical uncertainty.

·       patients with greater than 50% renal artery stenosis or prior diagnosis of renal artery stenosis  

·       pregnancy (if a subject becomes pregnant during the study they will be discontinued as well)

·       taking birth control pills or injections (due to potential effects on renin-angiotensin system or other hormones or factors affecting blood pressure)

·       subjects with a known sensitivity to any of the agents used in the study, such as para-aminohippurate

·       other results from screening studies suggesting medical problems which, in the judgement of the principal investigator, would justify exclusion from the protocol (such as severe liver disease, ileostomy, electrolyte abnormalities, or renal disease).