Review

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Personalized hypertension management in

practice

The revolution occurring in genomic and personalized medicine is likely to have a

significant impact on the management of hypertension. However, from the perspective
of translating new knowledge into clinical practice, progress has been slow. This
review article summarizes recent advances in hypertension-related diagnostics while
also offering new perspective on hypertension management for the future. Such new
perspectives will likely require a paradigm shift toward more integrated and holistic
approaches for better prevention and treatment of hypertension in both individuals
and the population as a whole.
Keywords: feedback genomics hypertension lifestyle personalized

The first recording of blood pressure was

made in 1733, in a horse, but was not
described as a disease in humans until 1808.
The invention of cuff-based sphygmomanometry, later in 1881, provided the means to
measure blood pressure in the clinic[1] . Over
the early part of the 20th Century some of
the causes of hypertension were discovered
and the term essential hypertension began
to be used to specify that no cause could be
found. The consequences of chronic severe
hypertension such as stroke, retinopathy,
cardiac and renal failure soon became apparent to clinicians and was deemed malignant
hypertension. This often occurred in an
accelerated fashion, which without treatment often led to an early demise. However,
at that time the long-term consequences of
mild forms of hypertension were unknown
and mild hypertension was generally considered benign. The continuous relationship of
these end organ diseases with milder forms
of hypertension did not become known until
longitudinal studies, such as the Framingham study, were performed[2] . Despite its
importance mild hypertension has continued
to be under-recognized, in part due to difficulties with definition of the condition but
also with its measurement.

10.2217/PME.14.83 2015 Future Medicine Ltd

Moving forward to the 21st Century

automated and miniaturized sphygmomanometry has democratized the measurement
of blood pressure, allowing home-based
monitoring. Home-based devices and ambulatory monitoring are able to demonstrate
diurnal blood pressure variation and average blood pressure load, which can identify
mild hypertension, and those with white
coat and masked hypertension with greater
accuracy [3] . However, office-based blood
pressure measurements and centralized management is still considered the standard of
care. Although the widespread use of sphygmomanometry has aided in the recognition
of hypertension, in its present form the measurement and treatment of peripheral blood
pressure may not be addressing the root cause
of the condition.
Increasing peripheral vascular resistance
and, in part, arterial stiffness have been
established as underlying causes for elevated
blood pressure[4] . Pulse wave reflections,
summated in large arterial vessels, are the
reason for the blood pressure waveform and
its amplitude. Arterial pulse wave velocity and an augmentation index can now be
measured using equipment once only available within a research laboratory. However,

Per. Med. (2015) 12(3), 297311

Patrick A Gladding*,1, Alasdair

Patrick2, Paul Manley2, Laura
Mash2, Phillip Shepherd3,
Rinki Murphy4, Silas
Vilas-Boas5 & Todd
TSchlegel6
1
Theranostics Laboratory, North Shore
Hospital, Shakespeare Rd, Auckland,
New Zealand
2
MacMurray Hypertension Clinic Ltd,
Auckland, New Zealand
3
Sequenom Facility, University of
Auckland, New Zealand
4
Department of Medicine, University of
Auckland, New Zealand
5
Centre for Microbial Innovation,
University of Auckland, New Zealand
6
Nicollier-Schlegel Srl, Trlex,
Switzerland
*Author for correspondence:
Tel.: +6494861491
patrickg@theranosticslab.com

part of

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Review Gladding, Patrick, Manley et al.

complexity and an absence of therapies targeting arterial stiffness, has limited its clinical utility. However
the information that arterial stiffness provides may be
enhanced by combining its measurement with whole
genome sequencing providing a more holistic view of
cardiovascular health[5] .
Addressing the underlying cause of hypertension in
each individual patient using such a holistic approach,
is expected to usher in a era of early detection, prevention and targeted treatments. Tailored management for
nonessential causes of hypertension such as Conns syndrome, glucocorticoid remediable hyperaldosteronism,
Cushings syndrome and renal artery stenosis has been
the driver to elucidating the cause of secondary forms
of hypertension, leaving the bulk of essential hypertension (95% of all cases) still without an underlying
cause. Glucocorticoid remediable hyperaldosteronism,
although rare, provides a prototype for personalized
medicine, where a chimeric CYP11B1/CYP11B2 genes
function can be in part rectified with administration of
physiological glucocorticoid treatment[6] .
The rapid advances in genomic technologies are
beginning to deliver on some of these hopes for essential
hypertension. Although further research is required for
many discoveries to become part of daily routine, there
is emerging evidence which can be applied in contemporary practice. As this evidence often falls short of a
randomized controlled megatrial the barrier to widespread adoption remains high. With the rapid pace of
change, emergence of big data science and an inability to test all potential hypotheses it is arguable that
the randomized megatrial, as we know it, has passed
its use by date. Tradition needs to be supplanted by a
new model of care. This review article hopes to address
these issues from a new perspective.
Genomics of hypertension
The heritability of essential hypertension is estimated
to be between 63 and 68%, indicating a significant
genetic component[7] . Despite this, the underlying
molecular mechanisms have not been readily apparent. The era of nonhypothesis driven genome wide
association studies (GWAS) has identified a number
of genes and single nucleotide polymorphisms (SNPs)
associated with essential hypertension[79] . However,
the contribution of these individual gene variants to
blood pressure is small, accounting for differences
of only approximately 1 mmHg. Such findings have
been common to all GWAS studies of chronic disease, in part due to the nature of the variants tested.
These SNP variants, by definition, are common in
the population and in isolation account for only small
effects as they act in a complex interactive fashion with
other genes. This complexity is compounded by the

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hypertensive phenotype being difficult to define, influenced strongly by environmental factors and being
highly dynamic[10] . To reduce bias and noise, GWAS
studies often include large numbers of patients and
results are not always reproducible in other cohorts.
For these reasons SNP variants, identified by GWAS,
and their representative genes provide only a starting point and often carry no clinical utility when
actionable interventions and evidence-based (EBM)
outcomes are unavailable. GWAS has however been
highly successful in the identification of novel biology
in the pathogenesis of a condition, as is the case with
hypertension. In addition, GWAS may identify genes
related to behavioral attributes indirectly relevant to
an asymptomatic disease, such as hypertension. For
example nonadherence to drug therapy[11] .
Next-generation genome sequencing, on the other
hand, holds the promise of identifying causal rare variants, which are more likely to contribute to the presence of disease[12,13] . These rare variants, however,
are often highly personal to an individual or a family,
and without previous description, their functional relevance may be uncertain. Hence, the pressure to apply
next generation sequencing to ever increasing, broadly
phenotyped, populations to link causal effect, with
these variants of uncertain significance (VUS). As the
cost of next generation sequencing plummets the number of sequenced genomes is increasing rapidly and
the richness of this information is being dramatically
realized.
Despite all of these issues, early genomic studies have identified a number of genes that may have
clinical relevance in the management of hypertension
(Examples in Table 1) . Thirty nine SNPs have been
identified in genes such as ATP2B1 (encoding ATPase,
Ca++ transporting plasma membrane 1)[14] , CYP17A1
(cytochrome P450, family 17, subfamily A, polypeptide1) [14] and 5,10-methylenetetrahydrofolate reductase (MTHFR) [15] . Many of the genes identified by
these analyses were not previously linked to hypertension, revealing novel pathways and druggable targets
for future study. Some genes identified by GWAS had
already been associated with hypertension in the preGWAS era, thereby validating their significance and
highlighting the power of GWAS methodology.
Two genes of interest include CYP17A1, which
encodes a key enzyme in a steroidogenic pathway[3] . Loss
of function of CYP17A1 can lead to an uncommon form
of congenital adrenal hyperplasia, with hypertension.
The protein encoded by MTHFR catalyzes the conversion of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate in the metabolism of methionine. The loss
of function gene variant C677T (rs1801133), within the
MTHFR gene, has been associated with elevated homo-

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Personalized hypertension management in practice

cysteine, coronary artery disease, cancer and hypertension in population studies. However ethnicity and diet
appear to be strong confounders and these results have
not been consistently reproduced[1619] .
Unravelling the relevant SNPs associated with
hypertension will require further observational longi-

Review

tudinal studies. Ideally, randomized crossover studies

would be performed however, with the numerous permutations of genetic variants and the power required
to conduct such studies, testing treatment strategies
based upon these variants may not always be feasible[20] . Biobanks, self-tracking and observational stud-

Table 1. Emerging biomarkers in hypertension, obesity and exercise physiology.

Gene

Biomarker/dbSNP
position

Response

Ref.

PRKCA

rs16960228

Hypertension and response to

hydrochlorothiazide

[12,78]

GNAS-EDN3

rs2273359

EBF1

rs4551053

Hypertension and, in aggregate,

response to hydrochlorothiazide

SH2B3

rs3184504

FGF5

rs1458038

FGF5

rs1458038

Hypertension and, in aggregate,

response to atenolol

CHIC2

rs871606

MOV10

rs2932538

HFE

rs1799945

CAMK1D

rs10752271

Response to Losartan

[95]

TCF7L2

rs7917983

Risk of developing diabetes with

hydrochlorothiazide

[79]

SLC22A11 SLC2A9

rs2078267
rs13129697

Risk of developing thiazide-associated

gout

[80]

TAS2R38

rs1726866, rs713598,
rs10246939

Bitter taste receptor, control of eating

[96]

CYP1A2

rs762551

Caffeine metabolism and association

with hypertension

[52,53]

MTHFR

rs1801133

Hypertension and response to

riboflavin

[44,45]

IsoP

F2-isoprostanes

Risk of renal failure in hypertensives

and cardiovascular risk

[55,56]

MPO

Myeloperoxidase,
rs2333227

Hypertension and cardiovascular risk

[57,60]

SLC4A5

rs7571842, rs10177833

Salt sensitivity on blood pressure

[47]

4-hydroxyhippurate

Hypertension, diet and gut

microbiome

[40]

Pharmacogenetics

[8]

[8]

Nutrigenetics

Obesity and exercise physiology

PPARG

rs1801282

Improved glucose homeostasis in

response to exercise

[97]

FTO

rs9930506

Obesity and response to exercise

[98]

Non-SNP biomarker, in other words, metabolite or plasma protein. Please see[100] under projects for an up-to-date list of hypertension
related SNP/genes as well as open-source Sequenom iPLEX primers (Supplementary Data).
dbSNP:Database of short genetic variation.

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Review Gladding, Patrick, Manley et al.

ies embedded in electronic medical records (EMRs),
may provide the most rational solution to this problem[9,21] . Citizen science that assesses dietary as well as
pharmacological interventions and integrates genomics
and social networks is an untapped route to progress in
the field of hypertension management[22,23] .
Treatment strategies
The first option for the management of essential hypertension remains lifestyle intervention where possible.
Public health policy over recent years has been important in identifying and educating the public on healthy
foods (including salt restriction) and lifestyle behaviors
(increased physical activity). Government legislature
worldwide of food labeling and regulating food constituents has made significant achievements in improving access to healthy foods and environmental planning. However market forces and individual choice are
two impediments to achieving universal adoption of
healthy lifestyle options and adherence to those treatment plans. It is important therefore to realize that
personalized medicine includes not only genomics, but
also delivering personalized care plans, relating to diet
and lifestyle. It is worth noting that industries outside
of medicine have utilized personalization for years to
influence behavior, increase efficiency and lower cost
in the delivery of services.
Personalized medicine also means
personalized care

The concept of personalization is not limited to the

field of genomics and is in wide use in industries other
than medicine. There are a number of underlying
principles to personalization, though one of the most
important is the focus on patient-centered principles.
Using personalization in clinical care can be simple and
inexpensive to administer, such as targeting a screening
program based on a family history. A study performed
by Hovell et al. in the 1980s demonstrated the value of
such simple interventions in the management of hypertension, and emphasized the importance of personalized care, which is not to be confused with its subset of
personalized (genomic) medicine[24,25] . In the quasi
experimental design in this study, patients were managed either with specialized, individualized attention,
which included courteous service and appointments,
made at the patients convenience. This included feedback on blood pressure values, progress and attainment
of goals. Patients in the control arm were treated with
a more business-like approach, wherein patients did
not receive any feedback on their own measurements,
progress or achievements. Interestingly in those receiving personalized care blood pressure values reduced by
8 mmHg systolic and 5 mmHg diastolic, equivalent to

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the effect of a single antihypertensive drug, compared

with those who received a business-like approach[24] .
An important aspect to personalized care includes
the respect of a patients autonomy, including not
only the delivery of care appropriate to the individual
patient, which may differ based on age, religion and
other preferences but also their willingness to receive
it [26,27] . The desire to opt for nonpharmacological
treatment options for mild hypertension needs to be
respected, particularly in an era where alternative and
complementary health options are beginning to challenge traditional dogma[28,29] . Transcendental meditation, for instance, has been shown to reduce both
blood pressure and cardiovascular outcomes in African
Americans. Although time consumptive this approach
should not be underestimated, particularly given its
wide range of psychosocial benefits, which contemporary treatment cannot provide[30] . Counter to this
however is the need for contemporary input in cases
of hypertension where end-organ damage has occurred
or in cases of life-threatening accelerated hypertension.
Renal denervation (RDN) has become an emerging option for patients with refractory hypertension,
though is now complicated by the result of an apparently negative randomized trial. The SIMPLICITY-3
trial, compared RDN with a sham procedure, and
showed no difference in blood pressure, when results
were averaged across each treatment group[31] . From
a one-size-fits-all perspective this appears to be a failed
treatment; though it would seem probable that RDN
may be effective when reserved for selected patients,
such as those with neurally mediated renovascular
hypertension [32,33] . Similarly manipulation of the
autonomic nervous system, through baropacing of
the carotid sinus, may also be appropriate in some
individuals [34] . Sophisticated computational modeling has already demonstrated some of the underlying
mechanisms behind the hypertension, for instance
the importance of baroreceptor and autonomic dysfunction in the long-term regulation of arterial pressure [35] Supporting that view is the observation that
heart rate variability, a measure of autonomic function,
becomes abnormal prior to the development of hypertension [36,37] . In the future randomized clinical trials
may be supplanted by simulations and the use of computational modeling of physiology, to select the best
treatment strategy for an individual.
Rather than SIMPLICITY-3 denoting failure this
result should be a reminder that reductionistic practices
and uniform population-based approaches to problems often seem to fail. This particularly appears the
case where a single intervention is undertaken which
ignores the wide variability in human response and
adaptive nature of biological systems. Individualized,

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Personalized hypertension management in practice

multidisciplinary care, by contrast, has been shown

repeatedly to be far more effective at both an individual and population level[38] . As it is too complex to
test multiple management strategies in a single clinical
trial, randomized registries and biobanks, will be the
best method to demonstrate that this methodology is
efficacious and cost effective[39] .
This patient-centered approach to care respects
autonomy and understands that in a world of finite
resources and limited access to healthcare professionals, patients must be engaged in monitoring and managing their own health. With the advent of pervasive
wireless connectivity, ubiquitous health monitoring
and cloud computing, it will be possible for patients to
experience greater independence, feedback and sense
of attainment from managing their own health, with
the options they choose (Figure 1) .
Nonpharmacological management
Metabolomics, the gut microbiome
&nutrigenetics

Although the pharmacological options for hypertension appear to be limited, lifestyle options that
involve nutrition are likely to become more sophisticated and effectivein the future. There is a growing
appreciation that the microbiome (gut flora) has profound clinical significance, as it is integrally involved
in absorption and metabolism of drugs, nutrition and
the health of an individual. In the context of hypertension, this has been demonstrated through the study
of metabolomics. This technology uses NMR or mass
spectroscopy to profile small molecules, produced by
host metabolism and microorganisms. Although this
method has not been applied to many hypertensive
populations, an association has been made between
blood pressure and varying metabolites such as sex steroid metabolites, 4-hydroxyhippurate and alanine[40] .
Interestingly 4-Hydroxyhippurate is produced by gut
flora, the metabotype of which differs between individuals and is modifiable by dietary intake of fish and
other nutrients[41,42] . This raises the distinct possibility of using this or similar biomarkers, in personalized
dietary programs and as a monitoring tool for dietary
intake, including the use of functional foods, listed in
Table 2 [43] . The MTHFR 677TT (rs1801133) variant
is of particular interest in nutrigenomics as the folate
pathway is modified with the administration vitamin B2 (riboflavin)[44,45] . A randomized trial, using
genomic enrichment for hypertensive patients with
the TT genotype, has shown that blood pressure can
be reduced by approximately 6 mmHg systolic with
administration of riboflavin[45] .
Salt intake has been linked in epidemiological studies to blood pressure, and populations with a low intake

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Action

Choices

Review

Personalized data

Relevance

Personally relevant actionable information is delivered to

patients to support behavioral change
Figure 1. Feedback loops, motivation and behavior
change. Personally relevant actionable information is
delivered to patients to support behavioral change.

are relatively free of hypertensive disease. However, the

reduction of dietary salt at a population level has met
with mixed success[46] . This in part may be due to
genetic variants influencing the variable response to
salt loading and restriction not only throughout life,
but also in utero [47,48] . Recent reports have indicated
that the salt intake, targets recommended by guidelines, are too low for some patients, and may in fact
increase cardiovascular risk[49] . A J-shaped effect is
also evident with blood pressure, indicating that strict
population targets cannot be applied to the individual patient, and hence the Joint National Committee
(JNC8) guidelines have relaxed blood pressure targets
in some patient groups, particularly the elderly[50] . In
this regard biological age, rather than chronological
age should be factored into treatment decisions, when
managing the hypertensive patient[51] .
The association between hypertension, caffeine
intake and cardiovascular events in epidemiological
studies has also been shown to be equivocal. However, when a genotype related to caffeine metabolism
is considered, a clear dose responsive association of coffee consumption, hypertension and clinical outcomes
is demonstrated[52,53] . In addition GWAS studies of
high-caffeine consumers have identified genes related
to smoking initiation, higher adiposity and fasting
insulin and glucose levels[54] .
Biomarkers of oxidative stress and inflammation
complete the axis linking nutrition, obesity, hypertension and cardiovascular risk. F2 isoprostane and myeloperoxidase exemplify such biomarkers. F2 isoprostane
has been shown to predict the development of renal
failure in patients with hypertension and is a prognostic marker of cardiovascular risk[55,56] . The inflammatory biomarker plasma myeloperoxidase (MPO)
is also deeply involved the cardiovascular system and
hypertension. Myeloperoxidase is a strong independent

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Table 2. Functional foods and nutriceuticals with antihypertensive properties, categorized by antihypertensive class.
Antihypertensive
therapeutic class

Foods and ingredients listed by therapeutic class

Nutrients and supplements listed by

therapeutic class

Angiotensin converting Egg yolk, Fish (specific): bonito, dried salted fish, fish
enzyme inhibitors
sauce, sardine muscle/protein, tuna, garlic, gelatin,
hawthorne berry, Milk products (specific): casein sour
milk, whey (hydrolyzed) sake, sea vegetables (kelp),
sea weed (wakame), wheat germ (hydrolyzed), zein
(corn protein)

Melatonin, omega-3 fatty acids,

pomegranate, pycnogenol, zinc

Angiotensin receptor
blockers

Celery, fiber, garlic, MUFA

Coenzyme Q10, gamma linolenic acid,

N-acetyl cysteine, oleic acid, resveratrol,
potassium, taurine, vitamin C, vitamin B6,
(pyridoxine)

Beta blockers

Hawthorne berry, Celery, garlic, MUFA

Alpha lipoic acid, calcium, magnesium,

N-acetyl cysteine, oleic acid, omega-3
fatty acids:, eicosapentaenoic acid,
docosahexaenoic acid taurine, vitamin B6,
vitamin C, vitamin E

Central alpha agonists

(reduce SNS activity)

Celery, fiber, garlic, protein

Coenzyme Q 10, gamma linolenic acid,

potassium, restriction of sodium, taurine,
vitamin C, vitamin B6, zinc

Direct renin inhibitors

Vitamin D

Direct vasodilators

Celery, cooking oils with monounsaturated fats, fiber, Alpha linolenic acid, Arginine, calcium,
garlic, MUFA soy
flavonoids, magnesium Omega-3 fatty
acids, Potassium, taurine, vitamin C,
vitamin E

Diuretics

Celery, hawthorn, berry, protein

Calcium, coenzyme Q 10, fiber gamma

linolenic acid, l-carnitine, magnesium,
potassium, taurine, vitamin B6, vitamin C,
Vitamin E, high gamma/delta tocopherols
and tocotrienols

MUFA:Monounsaturated fatty acid; SNS:Sympathetic nervous system.

Reproduced with permission from [101] (Table also presented in [43]).

predictor of cardiovascular risk[57] and identifies the

presence of endothelial dysfunction[58] , which may be
the cause or consequence of chronic hypertension[59] .
Furthermore, a polymorphism within the MPO gene
(rs2333227) is associated with hypertension[60] and
cancer risk, with the latter genetic relationship being
mitigated through diet[61] . Conversely the association between plasma levels of MPO and hypertension
is strengthened in the presence of hyperglycemiainduced oxidative stress, which could be targeted in a
personalized nutritional program[62,63] .

some patients. This highlights the need for personalized management planning, addressing the underlying
cause with problem-focused interventions. This may
include tailored diet and exercise advice. For example,
in diabetes and the metabolic syndrome, genetic variants have been identified which influence the response
to exercise, risk of obesity and weight gain associated
with certain foods[66] . Given the widespread deliverability of genomics, metabolomics and other personalized measures, including personalized nutrition, these
sciences have a greater chance of turning the tide on the
obesity epidemic than do surgical interventions[67,68] .

Obesity, sleep & lifestyle diseases

Disordered sleep is an underappreciated cause for

hypertension. Not only have abnormal breathing patterns been associated with hypertension, for example,
due to obstructive sleep apnea, but also abnormal slow
wave sleep and sleep architecture[64,65] . Obesity itself is
also associated with hypertension, and abnormal sleep
may be a potential root cause for both conditions in

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Pharmacological management
Since the introduction of hydralazine in the 1950s
there has been a steady addition of other antihypertensive agents to the clinicians armamentarium[69] .
These pharmaceuticals historically emerged in the
order of diuretics, -blockers, calcium channel blockers (CCHB), -1 blockers, angiotensin converting

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Personalized hypertension management in practice

enzyme inhibitors (ACE-I) and angiotensin-1 receptor blockers (ARB). Centrally acting agents such as
clonidine and methyldopa are also included in this
list, but often considered last line. Of historic interest
is the fact that clonidine was originally developed as a
nasal decongestant but drug repurposing found its use
in hypertensive management[70] . The pace of discovery has slowed with the most recent addition of direct
renin inhibitors to this list. Existing within each class
are a number of agents and for the individual patient
the options are multiplied further by the permutations
of preferred drug combinations. Although numerous,
randomized clinical trials have tested the efficacy of
monotherapy and combination therapy, they have
been unable to test all possible therapeutic iterations.
Despite this, important conclusions can be extrapolated from trials such as ACCOMPLISH, ASCOT and
its substudy the CAF trial, which have cumulatively
shown that combination therapy with a CCHB/ACE-I
is preferable to a drug combination which includes a
diuretic, and that -blockers have less efficacy than
other agents[69,71] .
Due to the inaccurate nature of office based blood
pressure assessment and the long-term relationship
with adverse events, clinical trials have required large
numbers of patients and have been difficult to perform.
Despite the impediments, a number of lessons have
been learned from large trials. First, the response to any
single agent is on average 9.1 mmHg systolic and 5.5
mmHg diastolic; however, the variability in response
to a single agent in the population varies widely across
a range of 2030 mmHg, with some experiencing no
benefit at all or even a rise in blood pressure[69] . The
heritability and consistency of response of an individual to a single agent would suggest that it should be
possible to predict who is likely to benefit most from a
particular agent[72] . However, in the absence of such
a predictive test the question then arises whether one
should trial cycling monotherapy testing numerous
agents, sequentially in a single patient; or stepped care
where single agents are titrated to effect before the
additional agents are included or to give low-dose combination therapy. With the knowledge that blood pressure targets are rarely met in those who present with
moderate to high blood pressure and that drug side
effects become more apparent with increasing dose of
single agents, the most logical and practical approach
would be low dose combination therapy. This approach
has been tested in the STRATHE trial, where introducing low-dose combination therapy, as a first line,
appeared superior to sequential monotherapy and
stepped care[73] . The STRATHE trial enrolled only
patients with mean blood pressures of 160 mmHg
systolic and 95 mmHg diastolic. As it was only a

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small exploratory trial its results do not preclude the

possibility of personalizing monotherapy for individual patients with mild hypertension[74] . Furthermore,
the permutations of combination therapy expand the
universe of options to the individual patient. It remains
likely that combination therapy will also lend itself to
personalization.
This then leads to the concept of the polypill, which
in itself has been proven effective and might be particularly beneficial where access to primary and secondary care is limited[75] . The polypill, which currently addresses a number of cardiovascular risk factors
including hypertension, is however reductionistic, as
are public health concepts of universal dietary supplementation or restrictions[76,77] . Although effective
to a degree, these measures cannot address the wide
population variability in response to diet, exercise and
medication [46] . To the individual, the idea of taking
a treatment with components that may not work or
could possibly cause harm will be unpalatable, especially if low cost options for predicting response are
available. With the advent of mass customization and
as pharmaceutical patents expire, it is highly probable that personalized combination polytherapy, possibly delivered in a single pill, could be tailored to an
individuals needs.
Pharmacogenomics & chronotherapy

GWAS-identified and other SNPs have been associated

with response to antihypertensive drug therapy[12,78] .
However the effect size for each individual SNP is small
and insufficient to recommend use with high-cost genotyping. As the cost of genotyping is reducing exponentially, the costeffectiveness of using this information is
improving. More promising are the evolution of SNP
panels, which use cumulative scores based on a number
of SNPs. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study has evaluated the
response of various antihypertensives, including hydrochlorothiazide, -blockers and others, and shown that
an additive SNP panel may have clinical value in choosing optimal monotherapy for a patient[8] . Conversely a
gene variant associated with diabetes, in other words,
a TCF7L2 SNP (rs7917983), is significantly associated with diabetes associated with thiazide use[79] .
Thiazide-induced gout is also influenced by genedrug
interactions (rs2078267 in SLC22A11, rs13129697 in
SLC2A9) [80] . Biomarkers to guide antihypertensive
therapy need not always be genetic and plasma renin
itself has been shown to predict blood pressure response
to -blockers and hydrochlorothiazide[81] .
Genomics may also allow clinical trials of antihypertensive patients to be made smaller, by prescreening
patients for particular gene variants (genomic enrich-

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ment). Conversely the number of patients required to
show a pharmacogenomic effect can be reduced by
using multiple methods of monitoring blood pressure,
particularly at-home, which reduces the signal-to-noise
ratio (S/N) and provides greater precision[82] . Studies
of self-measured home blood pressure monitoring have
shown a graded cardiovascular risk, even among those
with normal blood pressure recordings[83] . This is in
part due to circadian patterns of blood pressure variability, which has been strongly associated with early

atherosclerosis [84] . An absence of a nocturnal dip in

blood pressure is associated with an increased risk of a
cardiovascular event, equivalent to most traditional risk
factors [85,86] . Furthermore, blood pressure variation,
over many years, is predictive of cardiovascular events,
which argues for lifelong blood pressure trajectories to
be plotted against a personal baseline[87] .
Self-monitoring and self-directed treatment of hypertension at home, using an algorithm, has been shown
to be more effective than traditional office-based prac-

Figure 2. Diagnostic patterns obtained from standard clinical data. (A) A 43-year-old male who presented
with accelerated hypertension and a nonspecifically abnormal conventional ECG showing sinus tachycardia
and ventricular ectopy. Biomarker testing suggested possible heart failure (NT-BNP = 333 pmol/l [reference
<35pmol/l]). (B) Echocardiography showed left ventricular hypertrophy (LVH), a severely dilated left ventricle
(LV) with systolic dysfunction. (C) A cardiac MRI confirmed NICM. A coronary angiogram (not shown) showed mild
coronary artery disease. The presumed diagnosis was severe hypertensive cardiomyopathy.
CAD:Coronary artery disease; EDV:End diastolic volume; EF:Ejection fraction; ESV:End systolic volume;
FS:Fractional shortening; HOCM: Hypertrophic cardiomyopathy; ICM:Ischemic cardiomyopathy; LVIDd:Left
ventricular internal diastolic dimension; LVIDs:Left ventricular internal systolic dimension; LVPWd:Left ventricular
posterior wall dimension; NICM:Non-ischemic cardiomyopathy; SV:Stroke volume.

304

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Personalized hypertension management in practice

Review

Canonical Plot 3D

Healthy

HOCM

Canonical Plot

NICM

CAD

Canonical 2

+ 2

Canonical 2

LVH

40

1
ICM

+
+

35
-14

-12

-10

-8

Canonical 1

-6
Canonical 1

Figure 2. Diagnostic patterns obtained from standard clinical data (cont.). (D & E)Shows advanced ECG (A-ECG)
results at presentation (marker 1) using linear discriminant analysis against a large, pre-existing clinical ECG
database[92,99] . Thus, A-ECG correctly diagnosed the nonischemic cardiomyopathy (i.e., marker 1 was nearest
the purple NICM population centroid at presentation), as well as the subsequent trajectory, with treatment
(sequential markers 2 and 3), through basal left ventricular hypertrophy (LVH, aqua centroid) toward a healthier
state (small green centroid). Red, orange and blue centroids:other centroids of advanced ECG results in patients
with CAD, ICM and HOCM, respectively.
CAD:Coronary artery disease; EDV:End diastolic volume; EF:Ejection fraction; ESV:End systolic volume;
FS:Fractional shortening; HOCM: Hypertrophic cardiomyopathy; ICM:Ischemic cardiomyopathy; LVIDd:Left
ventricular internal diastolic dimension; LVIDs:Left ventricular internal systolic dimension; LVPWd:Left ventricular
posterior wall dimension; NICM:Non-ischemic cardiomyopathy; SV:Stroke volume.

tice [88] . Altering the timing of medication administration, or chronotherapy, is also showing promise in
improving the response to medication, for example, dosing with an ARB at night time[89] , though these findings need further validation. As diurnal variation is itself
genetic, with variable individual metabolic variation, it
is not surprising that the timing of antihypertensive
medication can itself be personalized[90] .
Integrating clinical biobanks, EMRs and telemonitoring is already reducing the cost and complexities
of running pharmacogenetic clinical trials[91] . In the
future this is likely to demonstrate further links with
the autonomic nervous system, the importance of diurnal variation, environmental and stressful stimuli and
should reveal otherwise imperceptible patterns in clinical data (Figure 2) [92] . These integrated biobank initiatives need to be collaborative, locally supported and
viewed as part of clinical care rather than research[21] .
Conclusion & the future of hypertension
management
The management of hypertension has changed significantly over the last century. It is worth noting that

future science group

Figure 3. 20th century. Organ-focused and

reductionistic.

www.futuremedicine.com

305

Review Gladding, Patrick, Manley et al.

Liddle syndrome

ECE1

SCNN1B
SCNN1G
WNK1
SCNN1A
WNK4

Apparent mineralocorticoid excess, hypertension due to

Pseudohypoaldosteronism
HSBD

PTGIS

NR3C2
GNB3

TJP2
BAAT

Hypercholanemia
EPHX1

CYP3A5
Hypertension

STOX1 Preeclampsia
AGT
Placental abruption
Nos3

AGTR1 KCNMB1
RETN

Coronary spas

Alzheimer disease
MH
PAXIP1
histiocyte disease
MPO

Renal tubular dysgenesis

Hyperproreninemia
Angiotensin I-coverting enzyme
ACE
PSEN1
SARS, progression of
Pick disease

Supranuclear palsy

Dementia
ITM2B
MAPT
SNCB
Pallidopontonigral degeneration

Figure 4. 21st century.Molecular and network-based.

definitions surrounding the condition have been dictated by methods of measurement and the emergence
of new pharmaceutical agents. As these methods and
treatment strategies change, so too will the perception of the condition. Compared with other traditional risk factors hypertension contributes the most
to the burden of cardiovascular disease in the population. However, despite evidence-based approaches to
care, hypertension continues to be under-recognized
and under-treated. This is compounded by the fact
that the disease is silent and treatment does not alter
symptoms.

These issues highlight a significant failure of the

technologies of the 20th Century to provide feedback to patients, an essential component to behavioral change programs. A convergence of genomics,
biosensors, ubiquitous computing and home-based
monitoring are beginning to provide a wealth of
patient-specific data, never before attainable. This
information will hopefully be able to identify patterns of behavior and better target of interventions
(Figure 3, Figure 4 & Table 3) . Although seemingly the
antithesis of population-based approaches to healthcare, personalization has shown extraordinary effi-

Table 3. Future perspective of hypertension management.

20th century

21st century

Organ based and reductionistic

Molecular and network based

Defined by the methods of measurement

Defined by identifying patterns in multiple heterogenous
and treatment class options. Evidence-base diagnostic inputs and managed by addressing the underlying
provided by averaging patient data
cause. Evidence provided by response in the individual
patient
Clinician centric. Pharmacologically driven
model of care and delivered in the office

306

Per. Med. (2015) 12(3)

Patient-centric, with clinician guidance. Systems-based driven

model of care, delivered in the office and by telemedicine

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Personalized hypertension management in practice

ciency, in the delivery of services in nonhealthcare

related sectors.
As discussed in this review article, there are a number
of practical approaches that can be used to personalize
the management of hypertension to the individual
patient. The plethora of options and dearth of randomized evidence begs the question whether the current
model of evidence-based medicine and burden of proof
required before implementation, is outdated. With
the volume of data now at hand it is more a matter of
implementing, monitoring, learning and adapting[93] .
This should particularly be the case with information
that is already collected as current standard of care
but also with genomic information which has become
increasingly cheaper to obtain. Emerging genetic and
metabolite biomarkers are showing promise in the ability
to personalize both dietary and pharmacological interventions. Some of these should now be put into practice (Supplementary Data ; see online at: www.futuremedicine.com/doi/full/10.2217/PME.14.83) [94] . In

Review

addition new procedural technologies need to be incorporated into clinical decision trees and monitored as
they are implemented, targeting treatment to the right
patients. Given the complexity and rapid emergence
of new information in this field, an interdisciplinary
expert team is required to provide the best integrated,
holistic care for the individual patient.
Financial & competing interests disclosure
PA Gladding holds an issued patent on the use of pharmacogenetic technology and is the founder of Theranostics Laboratory, which receives licensing fees from Cleveland HeartLab.
TT Schlegel is principal inventor on several NASA patents related to advanced electrocardiography. The authors have no
other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.

Executive summary
Background
Current definitions of hypertension are dictated by methods of measurement, rather than identification of
the underlying cause.
Contemporary management of hypertension is based on reductionist pharmacology.

Genomics of hypertension
Genomics is providing insights into the underlying mechanisms of essential hypertension and can be used to
predict treatment efficacy and adverse reactions.

Treatment strategies: nonpharmacological

Personalized medicine also means personalized care
Personalized care can be used to motivate patients using individualized feedback and treatment
strategies.

Metabolomics, the gut microbiome & nutrigenetics

Obesity, sleep & lifestyle diseases
A number of emerging genetic, metabolite and cytokine biomarkers can be used to risk stratify patients
with hypertension.

Treatment strategies: pharmacological

Pharmacogenomics & chronotherapy
Sleep architecture, chronobiology, diet and lifestyle are important considerations in a holistic personalized
approach to hypertension management.

Conclusion
The best method to generate the evidence base to support individualized care will be to implement the
technology, monitor its use, learn from the outcomes and if proven cost-effective, adapt to the new model
ofcare.

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