- Prehypertension, defined as systolic blood pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, affects approximately 80 million Americans and is responsible for half of all deaths from heart disease and stroke worldwide. - A recent study found that prehypertensive men have significantly lower acute release of tissue-type plasminogen activator (t-PA) from the endothelium in response to clot formation compared to normotensive men, indicating impaired endogenous fibrinolytic capacity. - This impaired fibrinolytic capacity may be a primary mechanism contributing to the increased risk of cardiovascular disease in prehypertensive individuals by reducing the ability to eliminate microvascular clots and propagating thrombosis and

1. COMMENTARY
It is time to contend with the endothelial consequences of
prehypertension
GP Van Guilder
Journal of Human Hypertension advance online publication,
8 January 2015; doi:10.1038/jhh.2014.122
Worldwide, 41 billion people over the age of 25 years suffer
from high blood pressure, defined as systolic pressure
⩾ 140 mm Hg and/or diastolic ⩾ 90 mm Hg, making hypertension
the single most important cause of early mortality.1
Hypertension
claims more lives annually than obesity, prediabetes and high
cholesterol combined and was responsible for ~ 9.4 million deaths
(13% of total global mortality) in 2010.2
Although trends in
awareness, treatment and control of hypertension have signifi-
cantly improved, particularly in the United States and Western
Europe, reducing its population prevalence continues to be a
major global health crisis. From 2001 to 2009, the number of
Americans with hypertension actually increased, with current
estimates indicating ~ 78 million people are affected,3
accounting
for 1000 deaths each day.4
Yet, in low- and middle-income
countries, hypertension has emerged as an even more serious
public health problem. Indeed, although the number of people
with hypertension is highest in these regions compared with high-
income countries,1
many more people are undiagnosed and
poorly treated, accelerating their burden of atherothrombotic
disease.5
Future projections are discouraging. Analysis from the
World Economic Forum and the Harvard School of Public Health in
collaboration with the World Health Organization indicates that
low- and middle-income countries will suffer an economic loss of
nearly $4 trillion in the next decade solely attributed to
cardiovascular diseases (CVD), most from the widespread clinical
consequences of raised blood pressure.6
In the US alone, the
prevalence of hypertension is expected to increase by 27 million
people in the next 15 years, placing an inconceivable annual
financial toll of $400 billion in hypertension-related medical costs.7
What is more concerning is that we have come to realize that
the adverse vascular impacts of elevated blood pressure
commence and progress well before someone becomes hyper-
tensive (o140/90 mm Hg). This notion was first put forth by
Robinson and Brucer in late 1930s following a series of studies
showing a progressive rise of early death from CVD in persons
with blood pressure between 120 and 140 mm Hg.8
As a result of
these important findings, Robinson and Brucer introduced the
term ‘prehypertension’ to indicate an increased mortality risk zone
of raised blood pressure. Seventy-five years later, we have
amassed a large body of impressive data from many epidemio-
logical and prospective cohort studies that clearly show a
considerable vascular risk in the prehypertensive blood pressure
range,9
now defined as untreated systolic pressure 120–139
mm Hg and/or diastolic pressure 80–89 mm Hg.10
Chronic eleva-
tions in blood pressure in the prehypertensive range are
atherogenic, contributing to widespread vascular and structural
damage to all organs and tissues, particularly the heart, brain and
kidneys. Increased carotid intima-media thickness, coronary artery
calcification, abnormal left ventricular morphology and diastolic
dysfunction, reduced large-artery elasticity, aortic stiffening and
vascular endothelial dysfunction are some of the major abnorm-
alities that commence and progress in the prehypertensive state.
The population burden of disease attributable to prehypertension,
which affects ~ 80 million Americans, is responsible for half of all
deaths from ischemic heart disease and stroke worldwide.5
Most
of the mortality risk occurs in those with systolic pressure
o140 mm Hg. Moreover, each 20/10 mm Hg increase in pressure
above 115/75 mm Hg doubles the risk of death from athero-
thrombotic vascular disease, even before the onset of overt
hypertension.11
The cardiovascular health consequences of
prehypertension afflict men, women and children of all ethnicities
who are independent of traditional risk factors, and invariably
affect people across all socioeconomic and education levels.9
Despite this breadth of evidence, the precise mechanisms
underlying the considerable CVD risks associated with prehyper-
tension elude us. Recently, however, new scientific findings
provide important evidence showing that prehypertension
diminishes the inherent properties of the vascular endothelium
to protect against thrombotic clots.
In this issue of the Journal of Human Hypertension, Diehl et al.12
conducted an excellent study to determine the impact of
prehypertension on endothelial fibrinolytic capacity in 42
middle-aged and older men (16 normotensive, 16 prehypertensive
and 10 hypertensive). Fibrinolysis, a critical function of the
endothelium, is an enzyme-regulated process that breaks up
fibrin, the protein network of an intravascular thrombus. Impaired
fibrinolysis is a key event accelerating atherogenesis; indeed, it
leads to uncontrolled fibrin deposition, propagating the progres-
sion to an occlusive thrombus. Fibrinolytic capacity can be
effectively determined by measuring acute endothelial release of
tissue-type plasminogen activator (t-PA), a serine protease
produced in endothelial cells that serves as the primary activator
of the fibrinolytic system. In the presence of an intravascular
thrombus, t-PA converts the proenzyme plasminogen to its active
enzyme plasmin that breaks down fibrin thereby lysing the clot.
Importantly, to initiate spontaneous thrombolysis, acute release of
t-PA is absolutely critical because it rapidly increases its local
concentration promoting faster and more complete resolution of a
clot and preventing it from blocking blood flow. Indeed, the
capacity of the endothelium to release t-PA represents in vivo
fibrinolytic potential and is a well-established independent
predictor of acute thrombotic events.13
Although it is clear from
previous data indicating that prehypertension is characterized by
greater thrombotic tendency (that is, increased plasma levels of
fibrinogen, thrombomodulin and plasminogen activator inhibitor-
1 antigen),14
until now no study investigated its effects on
endothelial fibrinolytic capacity. Using a cross-sectional approach,
Department of Health and Nutritional Sciences, South Dakota State University, Brookings, SD, USA. Correspondence: Assistant Professor Dr GP Van Guilder, Department of Health
and Nutritional Sciences, South Dakota State University, Box 2203, Intramural 116, Brookings, SD 57007, USA.
E-mail: gary.vanguilder@sdstate.edu
Journal of Human Hypertension (2015), 1–2
© 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15
www.nature.com/jhh

2. Diehl et al. employed a well-established intra-arterial fibrinolytic
protocol coupled with forearm venous occlusion plethysmogra-
phy to assess acute endothelial release of t-PA in response to
bradykinin. One main finding of the study was a considerably
lower (~35%) release of t-PA in prehypertensive men (220 ± 24 ng
per 100 ml tissue) compared with normotensive men (341 ± 34 ng
per 100 ml tissue). This degree of impairment with prehyperten-
sion is consistent with other major CVD risk factors including
aging, obesity, metabolic syndrome and even clinical hyperten-
sion. These novel data provide experimental support, suggesting
that a primary mechanism contributing to the increased risk of
CVD with prehypertension is of poor capacity to eliminate
microvascular fibrin clots, which may propagate the progression
to thrombosis and ischemic events. Their findings confirm and
extend work done by Hrafnkelsdottir et al.15
who initially
demonstrated impaired t-PA release with hypertension, by
showing that the onset of endothelial fibrinolytic dysfunction
with elevated blood pressure manifests in the prehypertensive
state. Certainly, Diehl et al. showed that the level of impairment in
t-PA release with prehypertension was similar in severity to
hypertensive subjects (213 ± 47 ng per 100 ml tissue). This is an
important clinical finding as it reinforces the fact that endothelium
is particularly sensitive to the deleterious effects of mild increases
in blood pressure well before hypertension. Furthermore, as
mentioned by the authors, it emphasizes the critical need to
intervene early in prehypertension by encouraging lifestyle
choices to lower blood pressure to optimal levels (that is, below
120/80 mm Hg) and thwart further endothelial dysfunction and
vascular disease.
An interesting aspect of the study conducted by Diehl et al. was
that all subjects, particular the normotensive and prehypertensive
men, were well matched for age, body composition, fitness, and
plasma lipids, lipoproteins and glucose. In addition, and perhaps
even more important, all subjects were non-medicated, free of
traditional risk factors (other than elevated blood pressure), and
did not have CVD and metabolic disease. Although it could be
argued that the study sample does not represent the typical
clinical characteristics of the general population (most people with
prehypertension also have additional CVD risk factors), this
experimental approach was necessary to isolate the independent
effects of prehypertension on t-PA release. As pointed out by the
authors, it is not possible to eliminate all variables that might
influence outcomes in cross-sectional studies. Nevertheless, given
the careful subject screening and experimental expertise of the
investigative team, it is likely that the observed impairment in
endothelial t-PA release with prehypertension was a primary effect
of elevated blood pressure and not owing to other factors,
particularly the presence of additional risk factors that have been
shown to reduce t-PA release.
The important work by Diehl et al. has brought to the forefront
many pressing unanswered questions regarding the adverse
endothelial fibrinolytic impacts of prehypertension. What is the
underlying endothelial pathology contributing to impaired release
of t-PA in the prehypertensive blood pressure range? Do
differences in sex, age or ethnicity impair fibrinolytic capacity to
a similar degree in prehypertensive individuals or is it worse in
different groups of people? Do recommended lifestyle strategies
to lower blood pressure (that is, DASH diet, weight loss and
regular exercise training) restore endothelial health in prehyper-
tensive persons?
The endothelial consequences of prehypertension are consider-
able and cannot be overlooked. Along with the present findings of
poor endothelial fibrinolytic capacity, prehypertension is also
characterized by reduced nitric oxide-mediated endothelium-
dependent vasodilation, increased endothelin-1 vasoconstriction,
increased arterial stiffness and reduced endothelial repair. The
array of vascular abnormalities occurs at blood pressure levels that
were once considered healthy. Indeed, they are central to the
accelerated risk of CVD in prehypertensive persons. Now is the
time to move towards a more comprehensive approach to
prevent and treat this growing global health concern.
CONFLICT OF INTEREST
The author declares no conflict of interest.
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Commentary
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