U.S. patent application number 16/054378 was filed with the patent office on 2018-11-22 for methods for predicting risk of developing hypertension.
The applicant listed for this patent is Critical Care Diagnostics, Inc.. Invention is credited to James V. Snider.
Application Number | 20180335437 16/054378 |
Document ID | / |
Family ID | 50100476 |
Filed Date | 2018-11-22 |
United States Patent
Application |
20180335437 |
Kind Code |
A1 |
Snider; James V. |
November 22, 2018 |
METHODS FOR PREDICTING RISK OF DEVELOPING HYPERTENSION
Abstract
Methods using biomarkers, e.g., serum levels of ST2, to predict
risk of developing hypertension, as well as methods for treating
subjects to reduce the risk of developing hypertension and methods
for selecting and/or stratifying subjects for clinical trials of
treatments to reduce the risk of hypertension.
Inventors: |
Snider; James V.; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Critical Care Diagnostics, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
50100476 |
Appl. No.: |
16/054378 |
Filed: |
August 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15382810 |
Dec 19, 2016 |
10041957 |
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16054378 |
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13969116 |
Aug 16, 2013 |
9523696 |
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15382810 |
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61683956 |
Aug 16, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/6869 20130101;
G01N 2800/50 20130101; A61P 13/00 20180101; A61P 43/00 20180101;
G01N 33/6893 20130101; G01N 2800/321 20130101; A61P 9/08 20180101;
A61P 13/02 20180101; A61P 9/12 20180101; A61P 25/00 20180101 |
International
Class: |
G01N 33/68 20060101
G01N033/68 |
Claims
1. A method for selecting a treatment for a subject, the method
comprising: determining a level of soluble ST2 in a biological
sample from a subject; comparing the level of soluble ST2 in the
biological sample to a reference level of soluble ST2; and
selecting an anti-hypertensive therapy for a subject having an
elevated level of soluble ST2 in the biological sample compared to
the reference level of soluble ST2.
2. The method of claim 1, wherein the reference level of soluble
ST2 is a level of soluble ST2 in a healthy subject.
3. The method of claim 1, wherein the biological sample comprises
blood, serum, or plasma.
4. The method of claim 1, further comprising: determining the level
of one of more additional biomarkers selected from the group
consisting of: atrial natriuretic peptide (ANP), proANP, N-terminal
(NT)-proANP, brain natriuretic peptide (BNP), proBNP, NT-proBNP,
cardiac troponin I, C-reactive protein, creatinine, and Blood Urea
Nitrogen (BUN) in the biological sample; comparing the level of the
one or more additional biomarkers in the biological sample to a
reference level of the one of more additional biomarkers; and
selecting an anti-hypertensive therapy for a subject having an
elevated level of the one or more additional biomarkers in the
biological sample compared to the reference level of the one or
more additional biomarkers.
5. The method of claim 4, wherein the one or more additional
biomarkers are selected from the group consisting of BNP, proBNP,
and NT-proBNP.
6. A method of treating a subject, the method comprising:
determining a level of soluble ST2 in a biological sample from a
subject; comparing the level of soluble ST2 in the biological
sample to a reference level of soluble ST2; and administering to a
subject having an elevated level of soluble ST2 in the biological
sample compared to the reference level of soluble ST2 an
anti-hypertensive therapy, or monitoring a subject decreased low
level of soluble ST2 in the biological sample compared to the
reference level of soluble ST2.
7. The method of claim 6, wherein the reference level of soluble
ST2 is a level of soluble ST2 in a healthy subject.
8. The method of claim 6, wherein the biological sample comprises
blood, serum, or plasma.
9. The method of claim 6, further comprising: determining the level
of one of more additional biomarkers selected from the group
consisting of: atrial natriuretic peptide (ANP), proANP, N-terminal
(NT)-proANP, brain natriuretic peptide (BNP), proBNP, NT-proBNP,
cardiac troponin I, C-reactive protein, creatinine, and Blood Urea
Nitrogen (BUN) in the biological sample; comparing the level of the
one or more additional biomarkers in the biological sample to a
reference level of the one of more additional biomarkers; and
administering to a subject having an elevated level of the one or
more additional biomarkers in the biological sample compared to the
reference level of the one or more additional biomarkers an
anti-hypertensive therapy, or monitoring a subject having decreased
low level of the one or more additional biomarkers in the
biological sample compared to the reference level of the one or
more additional biomarkers.
10. The method of claim 6, wherein the one or more additional
biomarkers are selected from the group consisting of BNP, proBNP,
and NT-proBNP.
11. A method for selecting a subject for participation in a
clinical study of a treatment for reducing the risk of developing
hypertension, the method comprising: determining a level of soluble
ST2 in a biological sample from a subject; comparing the level of
soluble ST2 in the biological sample to a reference level of
soluble ST2; and selecting a subject having an elevated level of
soluble ST2 in the biological sample compared to the reference
level of soluble ST2 for participation in a clinical trial of a
treatment for reducing the risk of developing hypertension.
12. The method of claim 11, wherein the reference level of soluble
ST2 is a level of soluble ST2 in a healthy subject.
13. The method of claim 11, wherein the biological sample comprises
blood, serum, or plasma.
14. The method of claim 11, further comprising: determining the
level of one of more additional biomarkers selected from the group
consisting of: atrial natriuretic peptide (ANP), proANP, N-terminal
(NT)-proANP, brain natriuretic peptide (BNP), proBNP, NT-proBNP,
cardiac troponin I, C-reactive protein, creatinine, and Blood Urea
Nitrogen (BUN) in the biological sample; comparing the level of the
one or more additional biomarkers in the biological sample to a
reference level of the one of more additional biomarkers; and
selecting a subject having an elevated level of the one or more
additional biomarkers in the biological sample compared to the
reference level of the one or more additional biomarkers for
participation in a clinical trial of a treatment for reducing the
risk of a developing hypertension.
15. The method of claim 11, wherein the one or more additional
biomarkers are selected from the group consisting of BNP, proBNP,
and NT-proBNP.
16. A method for evaluating the risk of developing hypertension in
a subject, the method comprising: determining a level of soluble
ST2 in a biological sample from a subject; comparing the level of
soluble ST2 in the biological sample to a reference level of
soluble ST2; and identifying a subject having an elevated level of
soluble ST2 in the biological sample compared to the reference
level of soluble ST2 as having an increased risk of developing
hypertension, or identifying a subject having decreased low level
of soluble ST2 in the biological sample compared to the reference
level of soluble ST2 as having a decreased risk of developing
hypertension.
17. The method of claim 16, wherein the reference level of soluble
ST2 is a level of soluble ST2 in a healthy subject.
18. The method of claim 16, wherein the risk of developing
hypertension is the risk of developing hypertension within three
years.
19. The method of claim 16, wherein the biological sample comprises
blood, serum, or plasma.
20. The method of claim 16, further comprising: determining the
level of one of more additional biomarkers selected from the group
consisting of: atrial natriuretic peptide (ANP), proANP, N-terminal
(NT)-proANP, brain natriuretic peptide (BNP), proBNP, NT-proBNP,
cardiac troponin I, C-reactive protein, creatinine, and Blood Urea
Nitrogen (BUN) in the biological sample; comparing the level of the
one or more additional biomarkers in the biological sample to a
reference level of the one of more additional biomarkers; and
identifying a subject having an elevated level of the one or more
additional biomarkers in the biological sample compared to the
reference level of the one or more additional biomarkers as having
an increased risk of developing hypertension.
21. The method of claim 20, wherein the one or more additional
biomarkers are selected from the group consisting of BNP, proBNP,
and NT-proBNP.
22. The method of any one of claims 1-21, wherein the subject is
human.
23. A kit for use in a method described herein, the kit comprising
an antibody that specifically binds to soluble ST2; and optionally
instructions for performing any of the methods of claims 1-22.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/382,810, filed on Dec. 19, 2016, which is a
continuation of U.S. patent application Ser. No. 13/969,116, filed
Aug. 16, 2013, issued as U.S. Pat. No. 9,523,696, which claims
priority to U.S. Patent Application Ser. No. 61/683,956, filed Aug.
16, 2012, the contents of which are incorporated herein by
reference in their entirety.
TECHNICAL FIELD
[0002] This invention relates to the field of molecular biology and
cardiovascular medicine, including methods using biomarkers, e.g.,
serum levels of ST2, to predict risk of developing hypertension, as
well as methods for treating subjects to reduce the risk of
developing hypertension and methods for selecting and/or
stratifying subjects for clinical trials of treatments to reduce
the risk of hypertension.
BACKGROUND OF THE INVENTION
[0003] Hypertension, often referred to colloquially as "high blood
pressure" is a condition characterized by the presence of a
systolic blood pressure .gtoreq.140 mmHg and a diastolic blood
pressure .gtoreq.90 mmHg (referred to as 140/90). Blood pressures
between 120/80 and 140/90 are typically considered prehypertension,
while pressure below 120/80 is normal. Other than pregnancy, the
treatment of hypertension is the most common reason for physician
office visits and use of prescription drugs among US adults (Egan
et al., JAMA 303(20):2043, 2010). Hypertension is a major risk
factor for cardiovascular disease: an estimated 69% of patients
with incident myocardial infarction, and 74% with incident heart
failure have preceding hypertension (Roger et al., Circulation
125:e2-e220, 2012). Treatment and control of hypertension reduces
the risk of these cardiovascular diseases (Meredith, Journal of
Renin-Angiotensin-Aldosterone System, 7(2):64-73, 2006). Therefore,
identifying subjects who are at risk of developing hypertension,
and treating them to reduce that risk, would reduce their risk of
cardiovascular disease.
SUMMARY
[0004] The invention is based, at least in part, on the discovery
that subjects having an elevated level of soluble ST2 have an
increased risk of developing hypertension. Thus, provided herein
are methods for selecting a treatment for a subject that include
determining a level of soluble ST2 in a biological sample from a
subject, comparing the level of soluble ST2 in the biological
sample to a reference level of soluble ST2, and selecting an
anti-hypertensive treatment (anti-hypertensive therapy) for a
subject having an elevated level of soluble ST2 in the biological
sample compared to the reference level of soluble ST2. Also
provided are methods of treating a subject that include determining
a level of soluble ST2 in a biological sample from a subject,
comparing the level of soluble ST2 in the biological sample to a
reference level of soluble ST2, and administering to a subject
having an elevated level of soluble ST2 in the biological sample
compared to the reference level of soluble ST2 an anti-hypertensive
agent. Also provided are methods for selecting a subject for
participation in a clinical study of a treatment for reducing the
risk of developing hypertension, and methods of evaluating the risk
of developing hypertension in a subject that include determining a
level of soluble ST2 in a biological sample from a subject. Also
provided are kits that contain an antibody that specifically binds
to soluble ST2 and instructions for performing any of the methods
described herein.
[0005] Also provided is the use of a pharmaceutical agent for
reducing hypertension (e.g., any of exemplary pharmaceutical agents
for reducing hypertension described herein) for treating a subject
identified as having an increased risk of developing hypertension
(using any of the methods described herein).
[0006] By the term hypertension is meant a medical condition that
is characterized by an abnormal, elevated blood pressure (i.e., a
systolic blood pressure .gtoreq.140 mmHg, a diastolic blood
pressure .gtoreq.90 mmHg).
[0007] By the term "soluble ST2" is meant a soluble protein
containing a sequence at least 90% identical (e.g., at least 95%,
96%, 97%, 98%, 99%, or 100% identical) to NCBI Accession No. NP
003847.2 (SEQ ID NO: 1) or containing a sequence at least 90%
identical (e.g., at least 95%, 96%, 97%, 98%, 99%, or 100%
identical) to amino acids 19-328 of SEQ ID NO: 1, or a nucleic acid
containing a sequence at least 90% identical (e.g., at least 95%,
96%, 97%, 98%, 99%, or 100% identical) to NCBI Accession No.
NM_003856.2 or containing a sequence at least 90% identical (e.g.,
at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to nucleotides
285 to 1214 of NCBI Accession No. NM_003856.2.
[0008] By the term "elevated" or "elevation" is meant a difference,
e.g., a statistically significant or detectable increase in a
determined or measured level (e.g., a human soluble ST2 protein
level) compared to a reference level (e.g., a level of human
soluble ST2 in a subject (or population of subjects) not having an
increased risk of developing hypertension, or a threshold level of
human soluble ST2). In some embodiments, the reference is a
threshold level, and any level above that is considered "elevated."
Additional reference levels of human soluble ST2 are described
herein and are known in the art.
[0009] As used herein, a "biological sample" includes one or more
of blood, serum, plasma, urine, and body tissue. Generally, a
biological sample is a sample containing serum, blood, or
plasma.
[0010] By the term "health care facility" is meant a location where
a subject may receive medical care or treatment from a health care
professional (e.g., a nurse, a physician, or a physician's
assistant). Non-limiting examples of health care facilities include
hospitals, clinics, surgical centers, and assisted care facilities
(e.g., a nursing home).
[0011] By the term "reference level" is meant a threshold level or
a level in a control subject or control patient population. A
reference level will depend on the assay performed and can be
determined by one of ordinary skill in the art. A reference level
may be a baseline level or a level in the same patient measured at
an earlier point in time. In some embodiments, a reference level is
a level of soluble ST2 in a control subject or population of
control subjects that does not have an increased risk of developing
hypertension. In some embodiments, a reference level is a level of
soluble ST2 in a healthy subject. Additional examples of reference
levels of soluble ST2 and methods of determining the same are known
in the art and are described herein.
[0012] In some embodiments, the ratio of two soluble ST2 levels in
a subject is compared to a reference ratio (e.g., a ratio of
soluble ST2 levels measured in a control subject, e.g., any of the
control subjects described herein or the same subject at earlier
time points). Additional examples of reference ratios of soluble
ST2 are known in the art and are described herein.
[0013] As used herein, a "subject" is a mammal, e.g., a human. In
all embodiments, human nucleic acids, human polypeptides, and human
subjects can be used.
[0014] By the term "healthy subject" is meant a subject that does
not have a disease (e.g., a cardiac disease). For example, a
healthy subject has not been diagnosed as having a disease and is
not presenting with two or more (e.g., two, three, four, or five)
symptoms of a disease state.
[0015] By the term "disease state" is meant the manifestation of
one or more (e.g., at least two, three, four, or five) symptoms in
a subject that indicate either an abnormal decrease in the
viability and/or an abnormal decrease/malfunction of a biological
activity of one or more (e.g., at least two, three, four, or five)
tissues in the body of the subject. Non-limiting examples of
disease states in a subject include a cardiac disease (e.g.,
arrhythmia, heart failure, heart attack, coronary artery disease,
cardiovascular disease, acute coronary syndrome, and angina),
inflammation, stroke, renal failure, obesity, high cholesterol, and
dyslipidemia.
[0016] By the phrase "physical symptoms associated with a disease
state" is meant the one or more (e.g., at least two, three, or
four) symptoms that are manifested by a subject having a particular
disease state. Physical symptoms associated with several disease
states are known in the art by medical health professionals (e.g.,
physicians). Non-limiting examples of physical symptoms associated
with a cardiac disease (e.g., arrhythmia, heart failure, coronary
artery disease, cardiovascular disease, acute coronary syndrome,
and angina) include shortness of breath, heart palpitations,
increased heart rate, weakness, dizziness, nausea, sweating, chest
discomfort or pressure, chest pain, arm pain, fullness,
indigestion, sweating, wheezing, sleep apnea, and anxiety.
[0017] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Methods
and materials are described herein for use in the present
invention; other, suitable methods and materials known in the art
can also be used. The materials, methods, and examples are
illustrative only and not intended to be limiting. All
publications, patent applications, patents, sequences, database
entries, and other references mentioned herein are incorporated by
reference in their entirety. In case of conflict, the present
specification, including definitions, will control.
[0018] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
DETAILED DESCRIPTION
[0019] The invention is based, in part, on the discovery that
subjects having an elevated level of soluble ST2 or an increase in
soluble ST2 over time have an increased risk of developing
hypertension. Thus, provided herein are methods for identifying
subjects who are at increased risk of developing hypertension. Also
described herein are methods for selecting a treatment for a
subject that include determining a level of soluble ST2 in a
biological sample from a subject, comparing the level of soluble
ST2 in the biological sample to a reference level of soluble ST2,
and selecting an anti-hypertensive therapy (anti-hypertensive
treatment) for a subject having an elevated level of soluble ST2 in
the biological sample compared to the reference level of soluble
ST2. Also provided are methods of treating a subject that include
determining a level of soluble ST2 in a biological sample from a
subject, comparing the level of soluble ST2 in the biological
sample to a reference level of soluble ST2, and administering to a
subject having an elevated level of soluble ST2 in the biological
sample compared to the reference level of soluble ST2 an
anti-hypertensive therapy (anti-hypertensive treatment). Also
provided are methods for selecting a subject for participation in a
clinical study of a treatment for reducing the risk developing
hypertension, and methods of evaluating the risk of developing
hypertension in a subject that include determining a level of
soluble ST2 in a biological sample from a subject. Also provided
are kits that contain an antibody that specifically binds to
soluble ST2 and instructions for performing any of the methods
described herein.
ST2
[0020] The ST2 gene is a member of the interleukin-1 receptor
family, whose protein product exists both as a trans-membrane form,
as well as a soluble receptor that is detectable in serum (Kieser
et al., FEBS Lett. 372(2-3):189-93 (1995); Kumar et al., J. Biol.
Chem. 270(46):27905-13 (1995); Yanagisawa et al., FEBS Lett.
302(1):51-3 (1992); Kuroiwa et al., Hybridoma 19(2):151-9 (2000)).
ST2 was recently described to be markedly up-regulated in an
experimental model of heart failure (Weinberg et al., Circulation
106(23):2961-6 (2002)), and preliminary results suggest that ST2
concentrations may be elevated in those with chronic severe heart
failure (Weinberg et al., Circulation 107(5):721-6 (2003)), as well
in subjects with acute myocardial infarction (MI) (Shimpo et al.,
Circulation 109(18):2186-90 (2004)).
[0021] The transmembrane form of ST2 is thought to play a role in
modulating responses of T-helper type 2 cells (Lohning et al.,
Proc. Natl. Acad. Sci. U.S.A. 95(12):6930-6935 (1998); Schmitz et
al., Immunity 23(5):479-90 (2005)), and may play a role in
development of tolerance in states of severe or chronic
inflammation (Brint et al., Nat. Immunol. 5(4):373-9 (2004)), while
the soluble form of ST2 is up-regulated in growth stimulated
fibroblasts (Yanagisawa et al., 1992, supra). Experimental data
suggest that the ST2 gene is markedly up-regulated in states of
myocyte stretch (Weinberg et al., 2002, supra) in a manner
analogous to the induction of the BNP gene (Bruneau et al.,
Cardiovasc. Res. 28(10):1519-25 (1994)).
[0022] Tominaga, FEBS Lett. 258:301-304 (1989), isolated murine
genes that were specifically expressed by growth stimulation in
BALB/c-3T3 cells; they termed one of these genes St2. The St2 gene
encodes two protein products: ST2 (IL1RL1), which is a soluble
secreted form; and ST2L, a transmembrane receptor form that is very
similar to the interleukin-1 receptors. The HUGO Nomenclature
Committee designated the human homolog of ST2, the cloning of which
was described in Tominaga et al., Biochim. Biophys. Acta.
1171:215-218 (1992), as Interleukin 1 Receptor-Like 1 (IL1RL1). The
two terms are used interchangeably herein.
[0023] The cDNA sequence of the shorter, soluble isoform of human
ST2 can be found at GenBank Acc. No. NM_003856.2 (SEQ ID NO: 2),
and the polypeptide sequence is at GenBank Acc. No. NP_003847.2
(SEQ ID NO: 1; shown below). The mRNA sequence for the longer form
of human ST2 is at GenBank Acc. No. NM_016232.4; and the
polypeptide sequence is at GenBank Acc. No. NP_057316.3. Additional
information is available in the public databases at GeneID: 9173,
MIM ID # 601203, and UniGene No. Hs.66. In general, in the methods
described herein, the soluble form of ST2 polypeptide is measured.
Non-limiting examples of soluble ST2 protein include proteins
containing a sequence at least 90% identical (e.g., at least 95%,
96%, 97%, 98%, 99%, or 100% identical) to the sequence of SEQ ID
NO: 1. Non-limiting examples of soluble ST2 nucleic acids include
nucleic acids containing a sequence at least 90% identical (e.g.,
at least 95%, 96%, 97%, 98%, 99%, or 100% identical) to the
sequence of NCBI Accession No. NM_003856.2 (SEQ ID NO: 2).
TABLE-US-00001 Human Soluble ST2 Protein (SEQ ID NO: 1) 1
mgfwilailt ilmystaakf skqswglene alivrcprqg kpsytvdwyy sqtnksipt 61
ernrvfasgq llkflpaava dsgiytcivr sptfnrtgya nvtiykkqsd cnvpdylmys
121 tvsgseknsk iycptidlyn wtaplewfkn cqalqgsryr ahksflvidn
vmtedagdyt 181 ckfihnenga nysvtatrsf tvkdeqgfsl fpvigapaqn
eikeveigkn anltcsacfg 241 kgtqflaavl wqlngtkitd fgepriqqee
gqnqsfsngl acldmvlria dvkeedlllq 301 ydclalnlhg lrrhtvrlsr
knpskecf
[0024] Methods for detecting and measuring soluble ST2 are known in
the art, e.g., as described in U.S. Patent Application Publication
Nos. 2003/0124624, 2004/0048286, and 2005/0130136, the entire
contents of each of which are incorporated herein by reference. In
some embodiments, the methods include determining the identity of
the nucleotide sequence at RefSNP ID: rs1041973.
[0025] Kits for measuring soluble ST2 polypeptide are also
commercially available, e.g., the ST2 ELISA Kit manufactured by
Medical & Biological Laboratories Co., Ltd. (MBL International
Corp., Woburn, Mass.), No. 7638, and the Presage.RTM. ST2 Assay,
Critical Care Diagnostics, San Diego, Calif. In addition, devices
for measuring soluble ST2 and other biomarkers are described in
U.S. Patent Publication No. 2005/0250156. Levels of soluble ST2
protein can also be measured using the antibodies produced from the
hybridoma deposited at American Type Culture Collection and
designated by Patent Deposit Designation PTA-10432, and those
antibodies described in U.S. Patent Application Publication No.
2011/0256635 and WO 2011/127412 (each of which is herein
incorporated by reference).
ST2 Reference Levels
[0026] Once a level of soluble ST2 has been determined in a
biological sample from a subject, the level may be compared to a
reference level (e.g., any of the reference levels described herein
or known in the art). In some embodiments, e.g., where the level of
soluble ST2 is determined using an ELISA, the reference level may
represent a threshold level, above which the subject is identified
as having an increased risk of developing hypertension or selected
for participation in a clinical study of a treatment for preventing
or reducing the risk of developing hypertension. The reference
level chosen may depend on the methodology (e.g., the particular
antibody or ELISA kit) used to measure the levels of soluble ST2.
Reference levels of soluble ST2 are known in the art and may
readily be determined by one skilled in the art. In some
embodiments, the threshold or reference level is the median level
of ST2 in a population of subjects, wherein those above the median
level have an increased risk of developing hypertension. In some
embodiments, the threshold or reference level is a level that
represents a cut-off when the population is divided, e.g., divided
by risk or by ST2 levels, e.g., the cut-off level for the top
quartile or the top tertile.
[0027] Non-limiting threshold levels of soluble ST2 may represent
the median level of soluble
[0028] ST2 in particular patient populations, e.g., subjects with
an increased risk of developing hypertension; in some embodiments,
the subjects are stratified by various characteristics, e.g.,
having a BMI of less than 25, 25-29, or over 30; subjects with
normal or impaired renal function; subjects without a cardiac
disease (e.g., without a diagnosis of any of the cardiac diseases
described herein); or healthy (e.g., undiagnosed with disease,
having a low risk of developing disease, and not presenting with
two or more symptoms of a disease) men, women, or children. For
example, a threshold value for soluble ST2 may fall within the
range of about 1.0 to 10 ng/mL, 5.0 ng/mL to 10 ng/mL, about 10.0
ng/mL to 20.0 ng/mL, about 10.0 ng/mL to 15.0 ng/mL, about 15.0
ng/mL to 20.0 ng/mL, about 20.0 ng/ml to 40 ng/mL, about 20 ng/mL
to 30 ng/mL, about 20 ng/mL to 25 ng/mL, about 25 ng/mL to 30
ng/mL, about 30 ng/mL to about 40 ng/mL, about 30 ng/mL to 35
ng/mL, about 35 ng/mL to 40 ng/mL, about 40 ng/mL to about 60
ng/mL, about 40 ng/mL to about 50 ng/mL, and about 50 ng/mL to
about 60 ng/mL. In some embodiments, the threshold value is about
25 ng/ml, e.g., about 24.8 ng/ml.
[0029] In some embodiments, the threshold value for soluble ST2 in
men and women may be any value listed in the Table 1. For example,
the threshold value of soluble ST2 in men may be between 17.0 ng/mL
to 19.0 ng/mL, 19.0 ng/mL to 21.0 ng/mL, 21.0 ng/mL to 23.0 ng/mL,
23.0 ng/mL to 25.0 ng/mL, 25.0 ng/mL to 27.0 ng/mL, 27.0 ng/mL to
29.0 ng/mL, 29.0 ng/mL to 31.0 ng/mL, 31.0 ng/mL to 33.0 ng/mL,
33.0 ng/mL to 35.0 ng/mL, 35.0 ng/mL to 37.0 ng/mL, 37.0 ng/mL to
39.0 ng/mL, 39.0 ng/mL to 41.0 ng/mL, 41.0 ng/mL to 43.0 ng/mL,
43.0 ng/mL to 45.0 ng/mL, 45.0 ng/mL to 47.0 ng/mL, 47.0 ng/mL to
49.0 ng/mL, and 49.0 ng/mL to 51.0 ng/mL. Exemplary threshold
values of soluble ST2 in women may be 12.0 ng/mL to 14.0 ng/mL,
14.0 ng/mL to 16.0 ng/mL, 16.0 ng/mL to 18.0 ng/mL, 18.0 ng/mL to
20.0 ng/mL, 20.0 ng/mL to 22.0 ng/mL, 22.0 ng/mL to 24.0 ng/mL,
24.0 ng/mL to 26.0 ng/mL, 26.0 ng/mL to 28.0 ng/mL, 28.0 ng/mL to
30.0 ng/mL, 30.0 ng/mL to 32.0 ng/mL, 32.0 ng/mL to 34.0 ng/mL,
34.0 ng/mL to 36.0 ng/mL, 36.0 ng/mL to 38.0 ng/mL, and 38.0 ng/mL
to 40.0 ng/mL.
[0030] As noted above, a threshold level of soluble ST2 may vary
depending on the methodology used to measure the levels of soluble
ST2. For example, if an antibody produced from the hybridoma
deposited at American Type Culture Collection, designated with
Patent Deposit Deposition PTA-10432, is used to determine a soluble
ST2 level, non-limiting threshold values of soluble ST2 may
include: below 20 ng/mL, 5 ng/mL to 15 ng/mL, 5.0 ng/mL to 10
ng/mL, 10 ng/mL to 20 ng/mL, 10 ng/mL to 15 ng/mL, 14.5 ng/mL to
25.3 ng/mL, 15 ng/mL to 25 ng/mL, 15 ng/mL to 20 ng/mL, 18.0 ng/mL
to 20.0 ng/mL, 18.1 ng/mL to 19.9 ng/mL, 20 ng/mL to 30 ng/mL, 20
ng/mL to 25 ng/mL, 25 ng/mL to 35 ng/mL, 25 ng/mL to 30 ng/mL, 30
ng/mL to 40 ng/mL, 30 ng/mL to 35 ng/mL, 35 ng/mL to 45 ng/mL, 35
ng/mL to 40 ng/ml, and 40 ng/mL to 45 ng/mL. Additional soluble ST2
reference values that may be used, when the antibody produced from
the hybridoma designated PTA-10432 is used to determine a soluble
ST2 level, include: for women, 12.4 ng/mL to 19.9 ng/mL, 12.0 ng/mL
to 20 ng/mL, 15.3 ng/mL to 17.4 ng/mL, 15.0 to 17.0 ng/mL, below 20
ng/mL, and below 18 ng/mL; and for men, less than 31.0 ng/mL, less
than 26.0 ng/mL, 17.6 ng/mL to 30.6 ng/mL, 17.0 ng/mL to 30.0
ng/mL, 21.3 ng/mL to 25.1 ng/mL, and 21.0 ng/mL to 25.0 ng/mL.
Additional non-limiting threshold values that may be used, when a
soluble ST2 level is measured using the antibody produced from the
hybridoma designated PTA-10432, include: 10 ng/mL, 11 ng/mL, 12
ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL,
19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, 25
ng/mL, 26 ng/mL, 27 ng/mL, 28 ng/mL, 29 ng/mL, 30 ng/mL, or 31
ng/mL.
TABLE-US-00002 TABLE 1 Serum ST2 Concentrations in Healthy Males
and Females ST2 (ng/mL) Percentiles Combined Male Female 2.5 8.0
8.6 7.3 25 14.5 17.6 12.4 50 18.8 23.6 16.2 75 25.3 30.6 19.9 90
34.3 37.2 23.7 95 37.9 45.4 29.0 97.5 45.6 48.5 33.1 99 50.2 52.7
39.9
[0031] In additional non-limiting examples, when a soluble ST2
level is measured using the ST2 ELISA Kit (MBL International Corp.,
Woburn, MA), the threshold levels of soluble ST2 include: 0.1 ng/mL
to 0.6 ng/mL, 0.2 ng/mL to 0.6 ng/mL, 0.2 ng/mL to 0.5 ng/mL, 0.3
ng/mL to 0.5 ng/mL, 0.2 ng/mL to 0.3 ng/mL, 0.3 ng/mL to 0.4 ng/mL,
and 0.4 ng/mL to 0.5 ng/mL. Additional non-limiting threshold
values that may be used, when the ST2 ELISA Kit (MBL International
Corp.) is used to measure a soluble ST2 level, include: 0.17 ng/mL,
0.18 ng/mL, 0.19 ng/mL, 0.20 ng/mL, 0.21 ng/mL, 0.22 ng/mL, 0.23
ng/mL, 0.24 ng/mL, 0.25 ng/mL, 0.26 ng/mL, 0.27 ng/mL, 0.28 ng/mL,
or 0.29 ng/mL of blood, serum, or plasma.
[0032] In some embodiments, the reference level of soluble ST2 is a
level of soluble ST2 present in a control subject who does not have
and is not at risk of developing hypertension, as determined by
standard empirical methods. In some embodiments, the control
subject has not been diagnosed as having hypertension, is not at
risk of developing hypertension, has a body mass index of less than
25, and has a cholesterol (total cholesterol, high density
lipoprotein, and/or low density lipoprotein), and triglyceride
profile within a normal range.
Additional Markers
[0033] Some embodiments of all of the methods described herein may
further include determining the level of one or more (e.g., at
least two, three, four, or four) additional markers in a biological
sample from the subject. The additional markers may be selected
from the group of: proANP, NT-proANP, ANP, proBNP, NT-proBNP, BNP,
troponin, CRP, creatinine, Blood Urea Nitrogen (BUN), galectin,
liver function enzymes, albumin, and bacterial endotoxin. The one
or more additional markers can be measured in any of the biological
samples herein. The presence of an elevated level (e.g., at least
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%,
170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%,
280%, 290%, or 300%) of one or more (e.g., at least two, three, or
four) of proANP, NT-proANP, ANP, proBNP, NT-proBNP, BNP, troponin,
CRP, creatinine, Blood Urea Nitrogen (BUN), galectin, liver
function enzymes, albumin, and bacterial endotoxin in a subject
compared to a reference level for each of these additional
biomarkers may further indicate that the subject has an increased
risk developing hypertension, the subject should receive treatment
(e.g., treatment on an inpatient basis), or the subject should be
selected for participation in a clinical study of a treatment to
decrease the risk of developing hypertension.
[0034] Once a level of an additional biomarker has been determined
in a biological sample from a subject, the level may be compared to
a reference level of the additional biomarker (e.g., any of the
reference levels described herein or known in the art). In some
embodiments, e.g., where the level of an additional biomarker is
determined using an ELISA, the reference level may represent a
threshold level, above which the subject is identified as having an
increased risk of developing hypertension, selected for
anti-hypertensive treatment (anti-hypertensive therapy), or
selected for participation in a clinical study of a treatment for
preventing development of hypertension. The reference level of the
additional biomarker chosen may depend on the methodology (e.g.,
the particular antibody or ELISA kit) used to measure the levels of
the additional biomarker. Reference levels of additional biomarkers
are known in the art and may readily be determined by one skilled
in the art.
[0035] Non-limiting threshold levels of additional biomarkers may
represent the median level of an additional biomarker in particular
patient populations, e.g., subjects with a BMI of less than 25,
subjects with normal renal function, subjects without cardiac
disease (e.g., any of the cardiac diseases described herein),
healthy (e.g., undiagnosed with disease, having a low risk of
developing disease, and not presenting with two or more symptoms of
a disease) men, healthy (e.g., undiagnosed with disease, having a
low risk of developing disease, and not presenting with two or more
symptoms of a disease) women, and healthy (e.g., undiagnosed with
disease, having a low risk of developing disease, and not
presenting with two or more symptoms of disease) children.
[0036] In some embodiments, the reference level of an additional
biomarker is a level of an additional biomarker present in a
healthy subject (e.g., a subject that does not have a disease
(e.g., any of the cardiac diseases described herein), has not been
diagnosed as having a disease, and/or is not presenting with two or
more (e.g., two, three, four, or five) symptoms of a disease
state). In some embodiments, a reference level of an additional
biomarker is a level of the additional biomarker from the same
subject at an earlier point in time. In some embodiments, the
reference level of an additional biomarker is a level of the
additional biomarker from a subject that does not have a cardiac
disease, has not been diagnosed as having a cardiac disease, and/or
does not have two or more symptoms associated with a cardiac
disease (e.g., arrhythmia, heart failure, heart attack, coronary
artery disease, cardiovascular disease, acute coronary syndrome,
and angina), inflammation, stroke, renal failure, obesity, high
cholesterol, or dyslipidemia. In some embodiments, the reference
level of an additional biomarker is a level of the additional
biomarker from a subject that has not been diagnosed as having a
cardiac disease and is not at risk for developing a cardiac disease
(e.g., arrhythmia, heart failure, heart attack, coronary artery
disease, cardiovascular disease, acute coronary syndrome, and
angina).
[0037] In some embodiments, the ratio of two different levels of an
additional biomarker in a subject is compared to a reference ratio
of the additional biomarker. In some embodiments, the reference
ratio of an additional biomarker can be a threshold ratio (e.g., a
reference ratio of 1.00, 1.00, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,
1.8, or 2.0). In some embodiments, the reference ratio of an
additional biomarker is a ratio of two levels of the additional
biomarker measured in a control subject (e.g., any of the control
subjects described herein or the same subject). For example, a
reference ratio of an additional biomarker can be a ratio of the
levels of an additional biomarker collected at two different time
points in a healthy subject (e.g., a subject that does not have a
disease (e.g., any of the cardiac diseases described herein), has
not been diagnosed as having a disease, and/or is not presenting
with two or more (e.g., two, three, four, or five) symptoms of a
disease state). In some embodiments, a reference ratio is a ratio
of levels of an additional biomarker from the same subject at an
earlier point in time. In some embodiments, the reference ratio of
an additional biomarker is a ratio of the levels of an additional
biomarker from a subject that does not have a cardiac disease, has
not been diagnosed as having a cardiac disease, and/or does not
have two or more symptoms associated with a cardiac disease (e.g.,
arrhythmia, heart failure, heart attack, coronary artery disease,
cardiovascular disease, acute coronary syndrome, and angina). In
some embodiments, the reference ratio is a ratio of levels of an
additional biomarker from a subject that has not been diagnosed as
having a cardiac disease and is not at risk for developing a
cardiac disease (e.g., arrhythmia, heart failure, heart attack,
coronary artery disease, cardiovascular disease, acute coronary
syndrome, and angina).
[0038] Methods for determining the levels of these additional
markers are known in the art. Kits for determining these additional
markers are commercially available.
Methods for Selecting a Treatment for a Subject
[0039] Provided herein are methods of selecting a treatment for a
subject that include determining a level of soluble ST2 in a
biological sample from a subject, comparing the level of soluble
ST2 in the biological sample to a reference level of soluble ST2
(e.g., any of the reference levels of soluble ST2 described
herein), and selecting an anti-hypertensive treatment
(anti-hypertensive therapy) (e.g., with an anti-hypertensive agent,
e.g., one or more of Diuretics, Beta-blockers,
Angiotensin-converting enzyme inhibitors (ACE inhibitors),
Angiotensin II receptor blockers (ARBs), Calcium channel blockers,
Alpha-blockers, Centrally acting drugs, Vasodilators, and/or Renin
inhibitors; see, e.g., Kaplan, "Systemic hypertension: Treatment."
In: Bonow et al., eds. Braunwald's Heart Disease: A Textbook of
Cardiovascular Medicine. 9th ed. Philadelphia, Pa: Saunders
Elsevier; 2011:chap 46, which is incorporated herein by reference
in its entirety), or increased monitoring (e.g., increased
frequency of cardiac function tests) for a subject having an
elevated level of soluble ST2 in the biological sample compared to
the reference level of soluble ST2, or selecting low frequency
outpatient monitoring for a subject having a decreased or no
significant change in the level of soluble ST2 as compared to the
reference level of soluble ST2.
[0040] Also provided are methods of selecting a treatment for a
subject that include determining a first level of soluble ST2 in a
biological sample from a subject at a first time point, determining
a second level of soluble ST2 in a biological sample from the
subject at a second time point, comparing the second level of
soluble ST2 to the first level of soluble ST2, and selecting an
anti-hypertensive treatment (e.g., with an anti-hypertensive
agent), e.g., one or more of Diuretics, Beta-blockers,
Angiotensin-converting enzyme inhibitors (ACE inhibitors),
Angiotensin II receptor blockers (ARBs), Calcium channel blockers,
Alpha-blockers, Centrally acting drugs, Vasodilators, and/or Renin
inhibitors; see, e.g., Kaplan, "Systemic hypertension: Treatment."
In: Bonow et al., eds. Braunwald's Heart Disease: A Textbook of
Cardiovascular Medicine. 9th ed. Philadelphia, Pa: Saunders
Elsevier; 2011:chap 46, which is incorporated herein by reference
in its entirety) or increased monitoring (e.g., increased frequency
of cardiac function tests) for a subject having an elevated second
level of soluble ST2 compared to the first level of soluble ST2, or
selecting low frequency outpatient monitoring for a subject having
a decreased or no significant change in second level of soluble ST2
as compared to the first level of soluble ST2.
[0041] The methods described herein can be performed by a medical
professional (e.g., a physician, a physician's assistant, a nurse,
a nurse's assistant, or a laboratory technician) or veterinary
professional. These methods can be performed in a hospital, a
clinic, a primary care facility (e.g., a nursing home), or a
clinical laboratory, or any combination thereof.
[0042] In some embodiments, the biological sample, the first
biological sample, and/or the second biological sample contain
blood, serum, or plasma. In some embodiments, the biological
sample, the first biological sample, and/or the second biological
sample are stored (e.g., at a temperature below 25.degree. C.,
e.g., at a temperature below 15.degree. C. or 0.degree. C.) for a
period of time (e.g., at least 2, 4, 6, 8, 10, 12, 24, 36, or 48
hours) prior to determining the level of soluble ST2 and/or
determining the level of one or more additional biomarkers (e.g.,
BNP, proBNP, or NT-proBNP).
[0043] In some embodiments, the level of soluble ST2 is determined
using an enzyme-linked immunosorbent assay (ELISA) (e.g., using any
of the soluble ST2 ELISA kits described herein or known in the
art.
[0044] Some embodiments further include detecting a level of one or
more additional biomarkers (e.g., any of the additional biomarkers
described herein, e.g., BNP, proBNP, and NT-proBNP) in the
biological sample from the subject. In these embodiments, an
anti-hypertensive treatment (anti-hypertensive therapy) or
increased cardiac monitoring is selected for a subject having an
elevation in the level of the one or more additional biomarkers in
the biological sample compared to a reference level of the one or
more additional biomarkers, or low frequency outpatient monitoring
is selected for a subject having a decreased or no significant
change in the level of the one or more additional markers as
compared to the reference level of the one or more additional
biomarkers. Some embodiments further include determining a first
level of one or more additional biomarkers (e.g., any of the
additional biomarkers described herein, e.g., BNP, proBNP, and
NT-proBNP) in a biological sample from the subject at a first time
point, determining a second level of the one or more additional
biomarkers in a biological sample at a second time point, comparing
the first level and the second level of the one or more additional
biomarkers, and selecting an anti-hypertensive treatment
(anti-hypertensive therapy) or increased cardiac monitoring for a
subject having an elevated second level of the one or more
additional biomarkers compared to the first level of the one or
more additional biomarkers, or selecting low frequency outpatient
monitoring for a subject having a decreased or no significant
change in the second level of the one or more additional markers
compared to the first level of the one or more additional
markers.
Methods of Treating a Subject
[0045] Also provided are methods of treating a subject that include
determining a level of soluble ST2 in a biological sample from a
subject, comparing the level of soluble ST2 in the biological
sample to a reference level of soluble ST2, identifying the subject
as having an increased risk of developing hypertension (based on an
elevated level of soluble ST2 compared to the reference level of
soluble ST2), and administering to the subject having an elevated
level of soluble ST2 an anti-hypertensive agent or performing
increased cardiac monitoring of the subject, or monitoring (e.g.,
monitoring with a low frequency on an outpatient basis) a subject
having a low level of soluble ST2 in the biological sample compared
to the reference level of soluble ST2.
[0046] Also provided are methods of treating a subject that include
determining a first level of soluble ST2 in a biological sample
from a subject at a first time point, determining a second level of
soluble ST2 in a biological sample from the subject at a second
time point, comparing the second level to the first level of
soluble ST2, and (1) identifying a subject having an elevated
second level of soluble ST2 as compared to the first level of
soluble ST2 as having an increased risk of developing hypertension
and administering to the subject identified as having an increased
risk of hypertension (based on the comparison of the second and
first soluble ST2 levels) an anti-hypertensive agent or performing
increased cardiac monitoring on the subject, or (2) identifying a
subject having a reduced or no significant change in the second
level of soluble ST2 compared to the first level of soluble ST2 as
having a reduced risk of developing hypertension and monitoring
(e.g., monitoring with low frequency on an outpatient basis) the
subject identified as having a reduced risk of developing
hypertension (based on the comparison of the second and first
soluble ST2 levels).
[0047] Some embodiments further include detecting a level of one or
more additional biomarkers (e.g., any of the additional biomarkers
described herein, e.g., BNP, proBNP, and NT-proBNP) in a biological
sample from the subject (e.g., the biological sample, the first
biological sample, and/or the second biological sample). In these
embodiments, a subject having an elevation in the level of the one
or more additional biomarkers in the biological sample compared to
a reference level of the one or more additional biomarkers (e.g.,
any of the reference levels of the one or more additional
biomarkers described herein) is administered an anti-hypertensive
agent or increased cardiac monitoring, or a subject having decrease
or no significant change in the level of the one or more additional
biomarkers compared to a reference level of the one or more
additional biomarkers is monitored with low frequency on an
outpatient basis. Some embodiments further include determining a
first level of one or more additional biomarkers (e.g., any of the
additional biomarkers described herein, e.g., BNP, proBNP, and
NT-proBNP) in a biological sample from the subject at the first
time point, determining a second level of the one or more
additional biomarkers in a biological sample at the second time
point, comparing the first level and the second level of the one or
more additional biomarkers, and administering an anti-hypertensive
agent or performing increased cardiac monitoring on a subject
having an elevation in the second level of the one or more
additional biomarkers compared to the first level of the one or
more additional biomarkers, or monitoring (e.g., monitoring with
low frequency on an outpatient basis) a subject having a decreased
or no significant change in the second level of the one or more
additional biomarkers as compared to the first level of the one or
more additional biomarkers.
[0048] Some embodiments further include administering to the
subject one or more (e.g., two, three, or four) pharmaceutical
agents selected from the group of: Diuretics, Beta-blockers,
Angiotensin-converting enzyme inhibitors (ACE inhibitors),
Angiotensin II receptor blockers (ARBs), Calcium channel blockers,
Alpha-blockers, Centrally acting drugs, Vasodilators, and/or Renin
inhibitors; see, e.g., Kaplan, "Systemic hypertension: Treatment."
In: Bonow et al., eds. Braunwald's Heart Disease: A Textbook of
Cardiovascular Medicine. 9th ed. Philadelphia, Pa: Saunders
Elsevier; 2011:chap 46, which is incorporated herein by reference
in its entirety.
Methods for Determining the Risk of Developing Hypertension
[0049] Also provided are methods of evaluating the risk of
developing hypertension in a subject that include determining a
level of soluble ST2 in a biological sample from a subject,
comparing the level of soluble ST2 in the biological sample to a
reference level of soluble ST2, and identifying a subject having an
elevated level of soluble ST2 in the biological sample compared to
the reference level of soluble ST2 as having an increased risk of
developing hypertension, or identifying a subject having no
significant change or a decreased level of soluble ST2 in the
biological sample compared to the reference level of soluble ST2 as
having a decreased risk of developing hypertension. In some
embodiments, a subject having an elevated level of soluble ST2
(relative to a reference level of soluble ST2) has an increased
risk (e.g., an increased risk of at least 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%
higher than a reference subject, e.g., a control subject as
described herein) of developing hypertension. In some embodiments,
a subject having a low level of soluble ST2 compared to the
reference level of soluble ST2 indicates has a decreased risk
(e.g., a risk decreased by at least 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) of developing
hypertension.
[0050] Also provided are methods of evaluating the risk of
developing hypertension in a subject that include determining a
first level of soluble ST2 in a biological sample from a subject at
a first time point, determining a second level of soluble ST2 in a
biological sample from a subject at a second time point, comparing
the second and first levels of soluble ST2, and identifying a
subject having an elevated second level of soluble ST2 compared to
the first level of soluble ST2 as having an increased risk of
developing hypertension, or identifying a subject having no
significant change or a decreased second level of soluble ST2
compared to the first level of soluble ST2 as having a decreased
risk of developing hypertension. In some embodiments, a subject
having an elevated second level of soluble ST2 (relative to the
first level of soluble ST2) has an increased risk (e.g., an
increased risk of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%,
130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% higher than a
reference subject, e.g., a control subject as described herein) of
developing hypertension. In some embodiments, a subject having a
low second level of soluble ST2 compared to the first level of
soluble ST2 indicates that the subject has a decreased risk (e.g.,
a risk decreased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%) of developing
hypertension.
[0051] The above methods may be used to determine the risk of
developing hypertension within 3 years (e.g., risk of developing
hypertension within 3 years, within 1 year, within 9 months, within
6 months, or within 30 days of the time at which the biological
sample was obtained from the subject).
[0052] Some embodiments further include detecting a level of one or
more additional biomarkers (e.g., any of the additional biomarkers
described herein, e.g., BNP, proBNP, and NT-proBNP) in a biological
sample from the subject (e.g., the biological sample, the first
biological sample, and/or the second biological sample). In these
embodiments, a subject having an elevation in the level of the one
or more additional biomarkers in the biological sample as compared
to a reference level of the one or more additional biomarkers is
identified as having an elevated risk of developing hypertension,
or a subject having no significant change or a decrease in the
level of the one or more additional biomarkers as compared to the
reference level of the one or more additional biomarkers is
identified as having a decreased risk of developing
hypertension.
[0053] Some embodiments further include administering at least one
anti-hypertensive agent or performing increased cardiac monitoring
on a subject identified as having an increased risk of developing
hypertension (using any of the methods described herein), or
performing low frequency outpatient monitoring on a subject
identified as having a decreased risk of developing hypertension
(using any of the methods described herein).
[0054] Some embodiments include one or more of: updating a
subject's clinical file (e.g., a computer readable medium) to
indicate the subject's determined risk of developing hypertension
and suggested treatment based on the subject's determined risk of
developing hypertension, informing a subject identified as being at
increased risk of developing hypertension of symptoms of
hypertension, instructing a subject identified as being at
increased risk of developing hypertension to self-monitor him or
herself for symptoms of hypertension, instructing subject to
implement changes in lifestyle (e.g., perform or increase exercise
therapy, change diet, reduce salt intake, and cease or decrease
smoking), testing or determining the risk of hypertension in a
lineal family member of a subject determined to have an increased
risk of developing hypertension, performing one or more
confirmatory diagnostic tests on a subject identified as having an
increased risk of developing hypertension, and informing a lineal
family member about a subject's determined increased risk of
developing hypertension.
Methods for Selecting a Subject for Participation in a Clinical
Study
[0055] Also provided are methods of selecting a subject for
participation in a clinical study of a treatment for reducing the
risk of developing hypertension that include determining a level of
soluble ST2 in a biological sample from a subject, comparing the
level of soluble ST2 in the biological sample to a reference level
of soluble ST2, and selecting a subject having an elevated level of
soluble ST2 in the biological sample compared to the reference
level of soluble ST2 for participation in the clinical trial, or
stratifying patients based on levels of soluble ST2. In some
embodiments, a subject can be excluded from participation in a
clinical study of a treatment for reducing the risk of developing
hypertension if the subject has a low level of soluble ST2 in the
biological sample compared to the reference level of soluble ST2
(e.g., any of the reference levels of soluble ST2 described
herein).
[0056] The clinical studies may be performed by a health care
professional (e.g., a physician, a physician's assistant, a nurse,
a phlebotomist, or a laboratory technician) in a health care
facility (e.g., a hospital, a clinic, or a research center). The
biological samples may be obtained from subjects that present with
one or more (e.g., at least two, three, four, or five) symptoms of
a disease state (e.g., arrhythmia, cardiovascular disease, angina,
or heart failure), subjects that are admitted in a hospital, or
subjects who are asymptomatic.
[0057] Some embodiments further include detecting a level of one or
more additional biomarkers (e.g., any of the additional biomarkers
described herein, e.g., BNP, proBNP, and NT-proBNP) in a biological
sample from the subject (e.g., the biological sample, the first
biological sample, and/or the second biological sample). In these
embodiments, a subject having an elevation in the level of the one
or more additional biomarkers in the biological sample as compared
to a reference level of the one or more additional biomarkers is
selected for participation in a clinical study of a treatment for
reducing the risk of developing hypertension.
[0058] Additional factors may further indicate that the subject
should be included in a clinical study of a treatment for reducing
the risk of developing hypertension. Non-limiting examples of these
additional factors include: prior diagnosis with cardiovascular
disease, angina, heart attack, heart failure, renal failure,
inflammation, or stroke; or presentation of one or more (e.g., two,
three, or four) of the following symptoms: shortness of breath,
heart palpitations, increased heart rate, weakness, dizziness,
nausea, sweating, chest discomfort or pressure, chest pain, arm
pain, fullness, indigestion, sweating, wheezing, sleep apnea, and
anxiety. Additional exemplary factors that indicate that a subject
should be included in a clinical study of a treatment for reducing
the risk of developing hypertension include a BMI of 25-30, a BMI
of greater than 30, or continued therapy with one or more (e.g., at
least two, three, four, or five) pharmaceutical agents selected
from the group of nitrates, calcium channel blockers, diuretics,
thrombolytic agents, digitalis, renin-angiotensin-aldosterone
system (RAAS) modulating agents (e.g., beta-adrenergic blocking
agents, angiotensin-converting enzyme inhibitors, aldosterone
antagonists, renin inhibitors, and angiotensin II receptor
blockers), and cholesterol-lowering agents (e.g., a statin).
Kits
[0059] Also provided are kits for use in a method described herein,
containing an antibody that specifically binds to soluble ST2 and
optionally instructions for using the kit (e.g., the antibodies in
the kit) to perform any of the methods described herein. The
antibody that specifically binds ST2 may be polyclonal, monoclonal,
recombinant, e.g., a chimeric or humanized, fully human, non-human,
e.g., murine, mono-specific, or a single-chain antibody. Any of the
kits described herein may also be provided as an ELISA assay (e.g.,
may further include one or more secondary antibodies and/or a
substrate for detection). For example, any of the kits described
herein may include an antibody produced from the hybridoma
deposited at American Type Culture Collection and designated by
Patent Deposit Designation PTA-10432, or any of the exemplary
anti-ST2 antibodies described in WO 2011/127412 or U.S. Patent
Application Publication No. 2011/0256635.
[0060] Any of the kits described herein may also include one or
more (e.g., two, three, four, or five) additional antibodies for
one or more (e.g., two, three, four, or five) additional markers
selected from the group of: proANP, NT-proANP, ANP, proBNP,
NT-proBNP, BNP, troponin, CRP, galectin, creatinine, liver function
enzymes, albumin, and bacterial endotoxin. Antibodies for ST2,
galectin, proANP, NT-proANP, ANP, proBNP, NT-proBNP, BNP, troponin,
CRP, creatinine, liver function enzymes, albumin, and bacterial
endotoxin are commercially available.
[0061] The invention is further described in the following example,
which does not limit the scope of the invention described in the
claims.
EXAMPLE
Example 1
Soluble ST2 can be Used to Assess the Risk of Developing
Hypertension in Apparently Healthy Subjects
[0062] A set of experiments was performed to determine if soluble
ST2 (sST2) is useful for predicting the occurrence of hypertension
in apparently healthy individuals. The FHS Offspring study is a
prospective, observational, community-based study. Children (and
spouses of the children) of FHS original-cohort participants were
enrolled in 1971 and have since been followed with serial
examinations. Of 3,532 participants attending the sixth examination
(baseline, 1995-1998), 3,273 participants returned for follow-up at
the seventh examination (1998-2001). Of these, 52 were excluded due
to missing BP data, 1,305 were excluded due to prevalent
hypertension at the baseline examination, 34 due to missing sST2
measurement, 8 due to heart failure, 33 due to coronary heart
disease, 1 due to stage IV chronic kidney disease (defined as
estimated glomerular filtration rate <30 ml/min/1.73 m.sup.2),
and 6 due to missing covariates, leaving 1,834 for inclusion in
this study. All participants provided informed consent and the
study was approved by the appropriate Institutional Review
Board.
[0063] In these experiments soluble ST2 was measured in stored
samples from the sixth examination visit. The levels of soluble ST2
were determined using a commercially available ELISA (Presage.RTM.
ST2 Assay, Critical Care Diagnostics, San Diego, Calif.)
(Dieplinger et a.1., Clin Chim Acta. 2009;409:33-40; Lu et al, Clin
Chim Acta 2010;411:1825-1826) according to the manufacturer's
instructions.
[0064] The primary outcome to be assessed in this study was the
time to the first occurrence of hypertension. Hypertension was
defined as a systolic blood pressure .gtoreq.140 mmHg, a diastolic
blood pressure .gtoreq.90 mmHg, or current use of antihypertensive
medication. Change in systolic BP, diastolic BP, and pulse pressure
was defined as the continuous change between the baseline and
follow-up examinations. Blood pressure was measured in the left arm
using a mercury sphygmomanometer, with the subject in a seated
position after at least five minutes of rest. The examination BP
was the average of two physician-obtained measurements.
[0065] Trends for increased risk of hypertension were found with
log-transformed (1n) sST2 (HR 1.21 [95% CI 1.06-1.39] in an age and
gender adjusted model, P=0.006 and HR 1.22 [95% CI 1.05-1.42], in a
fully adjusted model, P=0.051 respectively). The full model
includes age, gender, systolic and diastolic BP at baseline,
diabetes mellitus, body-mass index, and smoking. The following
Table 2 also shows that the highest concentrations of sST2, as
defined by the 4.sup.th quartile, 24.8-98.8 ng/ml, are also
prognostic for hypertension in both the minimal and fully adjusted
models.
TABLE-US-00003 TABLE 2 Age- and Multivariable-adjusted sex-adjusted
model model* OR (95% CI) P OR (95% CI) P Log-sST2.dagger. 1.21
(1.06-1.39) 0.006 1.22 (1.05-1.42) 0.01 Quartile 1 referent
Referent Quartile 2 1.28 (0.87-1.90) 1.34 (0.88-2.04) Quartile 3
1.52 (1.03-2.23) 1.43 (0.94-2.18) Quartile 4 1.77 (1.20-2.62) 1.79
(1.17-2.73) P for trend 0.003 0.008
[0066] In sum, the data show that measurement of sST2 can be used
to assess the risk of developing hypertension in individuals who
are otherwise apparently healthy.
Sequence CWU 1
1
21327PRTHomo sapiens 1Met Gly Phe Trp Ile Leu Ala Ile Leu Thr Ile
Leu Met Tyr Ser Thr 1 5 10 15 Ala Ala Lys Phe Ser Lys Gln Ser Trp
Gly Leu Glu Asn Glu Ala Leu 20 25 30 Ile Val Arg Cys Pro Arg Gln
Gly Lys Pro Ser Tyr Thr Val Asp Trp 35 40 45 Tyr Tyr Ser Gln Thr
Asn Lys Ser Ile Pro Thr Glu Arg Asn Arg Val 50 55 60 Phe Ala Ser
Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp65 70 75 80 Ser
Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr 85 90
95 Gly Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val
100 105 110 Pro Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys
Asn Ser 115 120 125 Lys Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp
Thr Ala Pro Leu 130 135 140 Glu Trp Phe Lys Asn Cys Gln Ala Leu Gln
Gly Ser Arg Tyr Arg Ala145 150 155 160 His Lys Ser Phe Leu Val Ile
Asp Asn Val Met Thr Glu Asp Ala Gly 165 170 175 Asp Tyr Thr Cys Lys
Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser 180 185 190 Val Thr Ala
Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser 195 200 205 Leu
Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val 210 215
220 Glu Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly
Lys225 230 235 240 Gly Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu
Asn Gly Thr Lys 245 250 255 Ile Thr Asp Phe Gly Glu Pro Arg Ile Gln
Gln Glu Glu Gly Gln Asn 260 265 270 Gln Ser Phe Ser Asn Gly Leu Ala
Cys Leu Asp Met Val Leu Arg Ile 275 280 285 Ala Asp Val Lys Glu Glu
Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala 290 295 300 Leu Asn Leu His
Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys305 310 315 320 Asn
Pro Ser Lys Glu Cys Phe 325 22542DNAHomo sapiens 2gaggagggac
ctacaaagac tggaaactat tcttagctcc gtcactgact ccaagttcat 60cccctctgtc
tttcagtttg gttgagatat aggctactct tcccaactca gtcttgaaga
120gtatcaccaa ctgcctcatg tgtggtgacc ttcactgtcg tatgccagtg
actcatctgg 180agtaatctca acaacgagtt accaatactt gctcttgatt
gataaacaga atggggtttt 240ggatcttagc aattctcaca attctcatgt
attccacagc agcaaagttt agtaaacaat 300catggggcct ggaaaatgag
gctttaattg taagatgtcc tagacaagga aaacctagtt 360acaccgtgga
ttggtattac tcacaaacaa acaaaagtat tcccactcag gaaagaaatc
420gtgtgtttgc ctcaggccaa cttctgaagt ttctaccagc tgcagttgct
gattctggta 480tttatacctg tattgtcaga agtcccacat tcaataggac
tggatatgcg aatgtcacca 540tatataaaaa acaatcagat tgcaatgttc
cagattattt gatgtattca acagtatctg 600gatcagaaaa aaattccaaa
atttattgtc ctaccattga cctctacaac tggacagcac 660ctcttgagtg
gtttaagaat tgtcaggctc ttcaaggatc aaggtacagg gcgcacaagt
720catttttggt cattgataat gtgatgactg aggacgcagg tgattacacc
tgtaaattta 780tacacaatga aaatggagcc aattatagtg tgacggcgac
caggtccttc acggtcaagg 840atgagcaagg cttttctctg tttccagtaa
tcggagcccc tgcacaaaat gaaataaagg 900aagtggaaat tggaaaaaac
gcaaacctaa cttgctctgc ttgttttgga aaaggcactc 960agttcttggc
tgccgtcctg tggcagctta atggaacaaa aattacagac tttggtgaac
1020caagaattca acaagaggaa gggcaaaatc aaagtttcag caatgggctg
gcttgtctag 1080acatggtttt aagaatagct gacgtgaagg aagaggattt
attgctgcag tacgactgtc 1140tggccctgaa tttgcatggc ttgagaaggc
acaccgtaag actaagtagg aaaaatccaa 1200gtaaggagtg tttctgagac
tttgatcacc tgaactttct ctagcaagtg taagcagaat 1260ggagtgtggt
tccaagagat ccatcaagac aatgggaatg gcctgtgcca taaaatgtgc
1320ttctcttctt cgggatgttg tttgctgtct gatctttgta gactgttcct
gtttgctggg 1380agcttctctg ctgcttaaat tgttcgtcct cccccactcc
ctcctatcgt tggtttgtct 1440agaacactca gctgcttctt tggtcatcct
tgttttctaa ctttatgaac tccctctgtg 1500tcactgtatg tgaaaggaaa
tgcaccaaca accgtaaact gaacgtgttc ttttgtgctc 1560ttttataact
tgcattacat gttgtaagca tggtccgttc tatacctttt tctggtcata
1620atgaacactc attttgttag cgagggtggt aaagtgaaca aaaaggggaa
gtatcaaact 1680actgccattt cagtgagaaa atcctaggtg ctactttata
ataagacatt tgttaggcca 1740ttcttgcatt gatataaaga aatacctgag
actgggtgat ttatatgaaa agaggtttaa 1800ttggctcaca gttctgcagg
ctgtatggga agcatggcgg catctgcttc tggggacacc 1860tcaggagctt
tactcatggc agaaggcaaa gcaaaggcag gcacttcaca cagtaaaagc
1920aggagcgaga gagaggtgcc acactgaaac agccagatct catgagaagt
cactcactat 1980tgcaaggaca gcatcaaaga gatggtgcta aaccattcat
gatgaactca cccccatgat 2040ccaatcacct cccaccaggc tccacctcga
atactgggga ttaccattca gcatgagatt 2100tgggcaggaa cacagaccca
aaccatacca cacacattat cattgttaaa ctttgtaaag 2160tatttaaggt
acatggaaca cacgggaagt ctggtagctc agcccatttc tttattgcat
2220ctgttattca ccatgtaatt caggtaccac gtattccagg gagcctttct
tggccctcag 2280tttgcagtat acacactttc caagtactct tgtagcatcc
tgtttgtatc atagcactgg 2340tcacattgcc ttacctaaat ctgtttgaca
gtctgctcaa cacgactgca agctccatga 2400gggcagggac atcatctctt
ccatctttgg gtccttagtg caatacctgg cagctagcca 2460gtgctcagct
aaatatttgt tgactgaata aatgaatgca caaccaaaaa aaaaaaaaaa
2520aaaaaaaaaa aaaaaaaaaa aa 2542
* * * * *