Clinical and Molecular Characteristics of Primary Aldosteronism in Blacks

Primary Aldosteronism (PA) is the most common cause of secondary hypertension, accounting for
6-8% of hypertension and 14-25% of resistant hypertension. This prevalence translates to
approximately 1 in 30-50 adults or about 4,000,000 Americans with PA. Until recently, the
deleterious effects of PA were thought to derive solely from aldosterone-mediated sodium
retention and associated blood pressure rise. However, animal studies and clinical trials
demonstrate that mineralocorticoid receptor (MR) blockade has cardio- and reno-protective
effects that clearly exceed those expected from blood pressure reduction alone. Growing
evidence supports the concept that excess aldosterone, in the presence of elevated blood
pressure, initiates a cascade characterized by fibrosis, oxidative stress, and activation of
pro-inflammatory and pro-fibrotic pathways, leading to morbidity via worsened insulin
sensitivity, impaired bone formation, and accelerated cardiovascular remodeling. Recent
studies have identified several new genetic underpinnings of PA, both germline and somatic,
including mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and ARMC5. As the effects of chronic
hyperaldosteronism differ between races, it is not surprising that the relative prevalence of
these mutations differs among cohorts. African Americans (AA) in particular have increased
susceptibility to end-organ damage from aldosterone excess-induced cardiovascular remodeling.
They are more likely to have congestive heart failure, end-stage renal disease, and
atherosclerotic events than age-matched Caucasians. However, to date no comprehensive
analysis of mutations in PA has been performed in AA. (Note: for the purposes of this
protocol, the terms Black or African American incorporate individuals who self-identify as
Black, African American, or the Caribbean diaspora).

The aims of this study are to identify the germline and/or somatic mutations causing PA in
AA, define the effects of these mutations on aldosterone production in AA, and to identify
effective pharmacologic agents that will inhibit inappropriate aldosterone production in
target cells. Aldosterone producing adenoma (APA) and other adrenocortical tumor (ACT)
specimens will be gathered from archival (collected under protocol 00-CH-160 and other
related NIH studies) and prospective research subjects with PA that will be evaluated at the
NIH Clinical Research Center under the proposed protocol. Samples will be analyzed using
state-of-the-art next-generation sequencing (NGS). Human adrenal cell lines (H295R and
others, as appropriate) will be used to study the mutations effect on aldosterone production.
Additionally, this will help identify possible effective pharmacologic therapeutics to treat
PA. Animal models of novel genetic causes of PA may also be created to study the molecular
mechanisms underpinning the disease.

- INCLUSION CRITERIA:

Inclusion criteria for main study:

- Age greater than or equal to 18y.

- Self-described Black race. Those with reported other racial backgrounds may enroll in
protocol 00-CH-0160 instead.

- Evidence supportive of the diagnosis of PA (e.g. HTN, hypokalemia, known adrenal
nodule, elevated ARR, etc).

- Willing and able to return to the NIH for follow-up evaluation.

Inclusion criteria for blood (peripheral) DNA only study:

- Age greater than or equal to 7y.

- Relative of a patient that participates in the main study (above) (i) with family
history of hypertension, ACTs, or both, or (ii) with a genetic mutation identified in
the course of the genetic investigations described in the main study.

EXCLUSION CRITERIA:

Exclusion criteria for main study:

- Individuals over the age of 70 years will be excluded because of the possibility of
comorbidities that may significantly affect appropriate initial work-up and
post-operative management. In addition, research data may be compromised by the
inability to interpret data collected from patients over the age of 70 years that may
be on multiple medications for a variety for reasons.

- Women who are pregnant or nursing will be excluded for safety concerns with
hyperaldosteronism workup.

- Individuals whose medical status will not allow them, for safety reasons, to
participate in the provocative testing (e.g. NYHA Class III or IV heart failure, or
CKD Stage 3b or worse), or who in the opinion of the investigators have unacceptably
high risk for surgical morbidity and mortality (e.g. Revised Cardiac Risk Index Class
IV or above, or American Society of Anesthesiologists Physical Status Class 3 or
above) will be excluded from the protocol, as they will not be able to participate
profitably in the research aspects of this protocol.

- Individuals who have current substance abuse or a psychiatric disorder or any other
condition that in the opinion of the investigators would impede competence,
compliance, or participation in the study.

- Individuals found to have a known inherited syndrome as the cause for hormone
over-secretion will be excluded from participation in this protocol, as the mechanisms
of hormone over-secretion and tumorigenesis is likely to be distinct in these
individuals. Specific examples of syndromes that may be excluded from this protocol
include individuals with Carney complex, McCune-Albright syndrome, and MEN-1. If
inquiries are received from such patients, they will be referred to the appropriate
ongoing protocols, if possible.

- Family members who end up being diagnosed with PA will be referred to the 00-CH-0160
protocol, to avoid selection bias in genetic mutation analyses for PA.

- Patients unwilling or unable to abide by procedures of the protocol.



Exclusion criteria for the DNA only study:

-Patients unwilling or unable to provide peripheral blood for DNA studies.