Eligibility Details:
The subjects evaluated in this protocol are hypertensive and carry the Striatin rs254093
risk allele. Most will be recruited from the HyperPATH cohort. The HyperPATH cohort was
developed under a SCOR in Hypertension program. This program has demographic data and DNA
on more than 4000 subjects. Currently, nearly 2000 of them have undergone an extensive
phenotyping protocol. All hypertensive medications have been stopped for 3 weeks before
study except agents that interfere with the renin-angiotensin-aldosterone system (RAAS) are
stopped for three months and amlodipine and/or hydrochlorothiazide is added if necessary
for blood pressure control until one month before study initiation. Then each subject is
studied twice on a diet consisting of 100 mmol potassium, 800 mg calcium, isocaloric, 2500
ml. The two times they are studied are after one week of a liberal sodium diet (200 mmol)
and after one week of a low sodium diet (10 mmol). Blood is obtained supine, upright and
after a 3 ng Ang II infusion and a norepinephrine dose response curve. BP and renal plasma
flow are assessed in response to the diet and the Ang II infusion and 24 hour urines are
collected on each diet. An oral glucose tolerance test is performed on each subject and
blood is obtained for DNA. In addition to hypertensives, the nearly 2000 intensively
studied cohort consists of 75 individuals in 10 families, 225 sibling pairs with
hypertension, 525 normotensive individuals without a family history of hypertension or
diabetes before the age of 60, and 250 type II diabetic subjects with or without
hypertension. On most of the 4000 subjects serum, plasma, urine and DNA is available for
measurements and analyses. Currently the data set consists of approximately 2100 data
points of demographic data, family history, biomarkers, and genotypes. The subjects have
been recruited from Boston MA, Salt Lake City UT, Paris France, Rome Italy and Nashville
TN. The demographics consists of the following: 52% male, 18% of African descent, 3% Asian
descent, age 17-66, hypertension stage 1-2, diet or oral medication controlled diabetes
(80% of the total diabetics). A few subjects will be recruited from advertisements on the
Internet and in local newspapers, from fliers and postings in the hospital, through
mailings to households located in the Boston areas and through patient registries at
Brigham and Womens Hospital. As an example of the richness of these sources is the Research
Patient Data Registry (RPDR). RPDR is a centralized clinical data registry of 2.8 million
Brigham and Womens Hospital and Massachusetts General Hospital patients. With approval of
the Institutional Review Board, investigators may use the RPDR Data Acquisition Engine to
obtain medical record information for patients with a specific diagnosis. Patients who meet
inclusion criteria for a specific study can be identified. Potential research subjects may
be contacted by his/her physician to inform the patient of the possibility of participating
in a research study and to provide the patient with the information for contacting the
study personnel. Investigators from Brigham and Womens Hospital may apply to use the RPDR.
RPDR contains over 90,000 hypertensives, ages 17-65 years with 13.5 % of African descent
and 52.8 % women.
We reported in our studies using the HyperPATH cohort that there was no racial, age or
ethnic differences in the salt sensitive blood pressure responses related to Striatin
allele variants. Thus, an equal number of females and males and the same proportion of
Africans as in the HyperPATH cohort will be studied. Subjects in HyperPATH and those
recruited for the new study in this project will have the similar characteristics. The
range in age is >17; however, it is anticipated that the clear majority will be between the
ages of 40 and 60 years.
Hypertensive patients previously treated will be weaned off medications for two-three weeks
except agents that interfere with the renin-angiotensin-aldosterone system (RAAS) are
stopped for three months and amlodipine and/or hydrochlorothiazide is added if necessary
for blood pressure control until one month before study initiation. Thus, these subjects
will match the characteristics of subjects recruited in HyperPATH. They must have a
diastolic blood pressure between 95 and 105 mm Hg off medication in each of three screening
visits. Subjects with diastolic blood pressures greater than 105 mm Hg or systolic blood
pressures greater than 180 mm Hg will be excluded. Subjects with only elevated systolic
blood pressure (but diastolic less than 95 mm Hg) will be excluded because such subjects
were not in the HyperPATH cohort.
Based on individual statements, subjects with current excessive alcohol use (greater than
12 oz/ETOH/week) or recreational drug use will be excluded. Subjects taking other
medications (except thyroid supplements) or weighing more than 150% of an ideal body weight
will be excluded. Subjects with other major cardiovascular diseases, diabetes, asthma, or
other major medical illness will be excluded. Subjects who smoke will be excluded. In
addition, subjects must have normal values for the following screening tests: CBC, serum
electrolytes, liver enzymes, TSH, urinalysis, 24-hour urine excretion of catecholamines and
cortisol, and ECG. Specifically, estimated GFR must be > 60 ml/min and serum potassium <
5.0 mmol/l. Subjects with hypokalemia while on diuretics will be evaluated for
hyperaldosteronism before inclusion in this study. Cushings syndrome will be ruled out
clinically, and with a 24-hour urine cortisol if there is clinical uncertainty. For the
more difficult question of renal artery stenosis, we will perform renal artery digital
subtraction angiogram in patients with hypertension and a two-component abdominal bruit.
Patients with greater than 50% renal artery stenosis will be further evaluated, but
excluded from this study. Subjects with a known sensitivity to any of the agents, such as
amlodipine or eplerenone will be excluded. Women who are pregnant will be excluded and will
be dropped from the study if they become pregnant during the study because eplerenone has
not been approved for use in pregnancy and the activity of the RAAS is dramatically altered
by pregnancy.
The screened, eligible hypertensives will enter a two-week single blind placebo washout
phase. Pill count will be used to determine compliance. Those with BP between
145-170/90-109 mmHg and pill count between 80-100% will enter the randomized phase,
counseled regarding salt intake, and randomized double blindly into one of our two
treatment arms. We will recruit approximately 105 individuals to have 45 individuals in
each drug group for analyses. This assumes that we will have 10-15% non-completers.
INCLUSION CRITERIA:
1. rs2540923A allele carrier
2. ages >17 years;
3. hypertension as defined by primary physician;
4. not on more than two anti-hypertensives;
5. normal renal, metabolic, electrolyte, complete blood cell count, and lipid profile
laboratory tests;
6. if on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker or
mineralocorticoid receptor antagonist, needs to be washed out for 3 months.
EXCLUSION CRITERIA:
1. known cardiac disease other than hypertension
2. renal, circulatory or neurologic diseases
3. diabetes; smoking
4. secondary hypertension as indicated by history, physical examination or screening
blood and urine tests; any drug therapy, except for anti-hypertensives and replacement
thyroid medication.
common.study.methods.has-drugs-yes
common.study.methods.is-healthy-no
