Current Hypertension Reports (2018) 20:15

https://doi.org/10.1007/s11906-018-0801-2

HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)

Cardiovascular Risk in Patients with Prehypertension

and the Metabolic Syndrome
Sergey Kachur 1 & Rebecca Morera 1 & Alban De Schutter 2 & Carl J. Lavie 3

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Prehypertension (pHTN) and metabolic syndrome (MetS) are both lifestyle diseases that are potentiated by increased adiposity, as both
disease processes are closely related to weight. In the case of pHTN, increased adiposity causes dysregulation of the renin-angiotensin-
aldosterone-system (RAAS) as well as adipokine- and leptin-associated increases in adrenergic tone. In MetS, excess weight potentiates
hyperglycemia and insulin resistance which causes positive feedback into the RAAS system, activates an inflammatory cascade that
potentiates atherosclerosis, and causes lipid dysregulation which together contribute to cardiovascular disease, especially coronary heart
disease (CHD) and heart failure (HF). The relationship with all-cause mortality is not as clear-cut in part because of some protective
effects associated with the obesity paradox in chronic diseases such as CHD and HF. However, in healthy populations, the absence of
excess weight and its associated effects on prehypertension and MetS are associated with a longer absolute and disease-free lifespan.

Keywords Metabolic syndrome . Obesity . Prehypertension . Heart failure . Insulin resistance

Abbreviations IR Insulin resistance

BMI Body mass index JNC Joint National Committee
BP Blood pressure LV Left ventricle/ventricular
CHD Coronary heart disease MetS The metabolic syndrome
CVD Cardiovascular disease NCEP National Cholesterol Education Program
DBP Diastolic blood pressure NHANES National Health and Nutrition Examination
ESH European Society of Hypertension Survey
ESC European Society of Cardiology NO Nitric oxide
FFA Free fatty acid RAAS Renin-angiotensin-aldosterone system
HF Heart failure ROS Reactive oxygen species
HTN Hypertension REGARDS The Reasons for Geographic and Racial
pHTN Prehypertension Differences in Stroke Study
SBP Systolic blood pressure
WC Waist circumference

This article is part of the Topical Collection on Hypertension and the

Kidney
Introduction
* Sergey Kachur
Sergey.kachur@gmail.com Prehypertension (pHTN) is defined by JNC 7 guidelines as a
systolic blood pressure (SBP) of 120–139 mmHg and diastol-
1
Department of Graduate Medical Education, Ocala Regional Medical ic blood pressure (DBP) of 85–89 mmHg [1•]. This definition
Center, 1431 SW 1st Ave., Ocala, FL 34471, USA is contested, with recent European Society for Hypertension
2
New York University School of Medicine, New York, NY, USA (ESH) and European Society of Cardiology (ESC) guidelines
3
Department of Cardiovascular Diseases, John Ochsner Heart and
classifying SBP of 130–139 mmHg and DBP of 85–
Vascular Institute, Ochsner Clinic School-the University of 89 mmHg as a “high normal” BP range [2]. Interestingly
Queensland School of Medicine, New Orleans, LA, USA enough, the Eighth Joint National Committee guidelines do
15 Page 2 of 9
not address pHTN at all. The purpose behind this definition,
regardless of the criteria, is to help identify patients who
would benefit from early intervention to prevent the develop-
ment of HTN and additional cardiovascular disease (CVD).
This concept came about after a meta-analysis published by
Lewington et al., which revealed that BPs above 115/
75 mmHg substantially increased the risk of coronary heart
disease (CHD) and stroke with each rise in 20 mmHg for SBP
and 10 mmHg in DBP [3••]. pHTN does not appear to dis-
criminate: subgroup analysis of the REGARDS study re-
vealed that pHTN was found equally among men and women
and no significant difference was noted between blacks and
whites. What was notable was the difference in age, as the
pHTN patients were on average 3 years younger than HTN
patients (62.9 vs. 65.2–65.9, respectively) [4].
The metabolic syndrome (MetS) is a cluster of interrelated
conditions that, when present within the same individual, offer
a substantially increased risk of morbidity and mortality. The
definition of MetS has undergone various changes throughout
the years, with diagnostic criteria shifting depending on the
latest guidelines and recommendations. The most recent and
widely used definition comes from the National Cholesterol
Education Program (NCEP) Adult Treatment Panel III, which
lists the diagnostic criteria as having three or more of the
following abnormalities: fasting blood glucose > 100 mg/dL
(or undergoing pharmacotherapy for elevated blood glucose);
HDL cholesterol < 40 mg/dL (men) or < 50 mg/dL (women)
or undergoing pharmacotherapy for low HDL; triglycerides
(TGs) > 150 mg/dL or undergoing pharmacotherapy for ele-
vated TGs; waist circumference (WC) > 102 cm (men) or >
88 cm (women) for Caucasian and African American popula-
tion, although lower cut points are used in Asians and
Mediterranean population; or HTN defined as > 130/
88 mmHg or undergoing pharmacotherapy for HTN [5•].
The most recent estimate of the prevalence of MetS be-
tween the years 2003 and 2012 is about 33% with a signifi-
cantly higher prevalence in women than in men, and the
highest prevalence by race was found in Hispanics, followed
by non-Hispanic whites, and then blacks. Per their analysis of
recent data from National Health and Nutrition Survey
(NHANES), it appears that the prevalence of MetS is increas-
ing [6]. This falls in line with prior data from NHANES,
which reported the prevalence of MetS between the years
1999 and 2006 at 34% [7].
Obesity is perhaps the predominant risk factor for devel-
oping MetS, as every single definition of the disease has had
either body mass index (BMI) or WC as a defining trait [5•,
8–11]. Some versions, such as those from the International
Diabetes Federation and the American Association of
Clinical Endocrinologists, list WC or BMI as mandatory pa-
rameters for the diagnosis of MetS [10, 11]. However, since
it is possible to have MetS without the presence of obesity or
an increased WC, the NCEP criteria and several other
Curr Hypertens Rep (2018) 20:15
definitions have moved obesity to the list of optional criteria
to meet [5•, 8–11].
The link between MetS and pHTN is significant as the
“hypertensive” criteria for MetS by the NCEP (SBP >
130 mmHg, DBP > 88 mmHg) sit firmly within the
pHTN/“high normal” criteria as defined by both the JNC 7
and ESH-ESC [1•, 2, 5•]. In this paper, we will review the
mechanisms of disease related to BP and the components of
MetS, as well as their effects on CVD outcomes and health.
Weight and Its Link to BP
Risk factors for pHTN include age, childhood obesity, in-
creases in adiposity and BMI, smoking, sedentary habits,
and pre-diabetes/diabetes [12•, 13]. The effects extend into
multiple organ systems, increasing the risks of renal disease,
stroke, CHD, and mortality [14–17].
Reversible mechanisms for increases in BP revolve around
endothelial dysfunction that is mediated by a combination of
the renin-angiotensin-aldosterone-system (RAAS), adrenergic
tone, and interactions of these systems with the immune re-
sponse which are closely tied to weight and levels of adiposity
(Fig. 1) [18•]. The Framingham cohort demonstrated that 34%
of HTN in men and 62% of HTN in women age 35–75 years
were attributable to excess weight (defined as a BMI of 25 kg/
m2 or more) [19•]. The Physician’s Health Study described an
8% increase in risk of incident HTN with each 1-unit increase
in BMI during a median follow-up of 14.5 years [20]. In a
longitudinal study of 6863 children, HTN was related directly
to BMI regardless of body composition [21]. Another analysis
of the Framingham cohort indicated that the effect is revers-
ible by demonstrating that sustained weight loss of 1.8 kg or
more was associated with a long-term HTN risk reduction of
22% in middle-age patients and a 26% reduction in older
patients [22]. This has very important prognostic implications
given the association of tight BP control and improved CVD
outcomes by the SPRINT research group [23••].
One of the mechanisms of BP increases is weight-
associated elevations in circulating blood volume; there is a
disproportionate increase in cardiac output that is related to an
increase in free fatty acids (FFA) and leptin-mediated sympa-
thetic activity [24•, 25]. Weight increases in those with MetS
are also associated with disproportional increases in adipose
tissue-derived angiotensinogen—the major precursor for
components of the RAAS. Angiotensinogen production in
adipose tissue is volume insensitive and serves as a cause
and effect of adipocyte hypertrophy and leads to elevation
of BP through the action of angiotensin II, which induces
systemic vasoconstriction, direct sodium and water retention,
and increased aldosterone production. These signaling mole-
cules also cause a presynaptic potentiating effect, impairing
baroreceptor sensitivity [26].
Curr Hypertens Rep (2018) 20:15
Fig. 1 Mechanisms of
vasoconstriction
Additionally, excess circulating FFA appear to contribute
to increased sympathetic tone in obese patients with HTN who
demonstrate excess vascular α-adrenergic sensitivity and an
increase in α-adrenergic tone [27, 28]. Increased FFA associ-
ated with obesity also inhibits sodium/potassium exchange
pumps as well as sodium ATP pumps, which contribute to
increased smooth muscle tone, peripheral resistance, and as-
sociated BP [29•]. Adipocytes also secrete leptin, which in-
creases sympathetic tone in the renal vasculature through ac-
tivity in the arcuate nucleus of the hypothalamus [30]. This
adds to a positive feedback loop, as chronic increased sympa-
thetic tone triggers excessive RAAS activation which leads to
renal vasoconstriction and renin-dependent chronic HTN.
These effects are likely the causes of a direct relationship
between increases in insulin levels, BMI and BP, and plasma
norepinephrine levels [31, 32].
Page 3 of 9 15
Together, dysregulation of these mechanisms raises BP and
increases sodium and water excretion through initial pressure
diuresis [33•]. However, over time, the higher BP resets the
kidney fluid apparatus to tolerate a HTN level, causing extra-
cellular fluid volume expansion without reflexive diuresis,
consistent with a pressure-independent mechanism of volume
overload [34].
Obesity, MetS, and the Inflammatory Cascade
The concept of insulin resistance (IR) was thought to be a
defining feature of MetS, and was included in various iterations
of the definition, such as Group for the Study of Insulin
Resistance, the World Health Organization, and American
Association of Clinical Endocrinologists, which all list it as
15 Page 4 of 9
the required trait for the diagnosis of MetS [9–11]. It is notably
absent from the commonly accepted NCEP definition, but its
absence from the definition does not mean it is absent from the
condition itself. Many of the existing criteria, such as hypertri-
glyceridemia, hyperlipidemia, and hyperglycemia, can all be
attributed to increased IR. The pathway is believed to start with
adipocyte hypertrophy and associated hypoxia which leads to
impaired insulin signaling and poor glucose uptake and results
in secretion of FFA and adipokines [35]. Increased FFA triggers
hepatic IR and a rise in de novo lipogenesis and TG synthesis as
well as macrophage infiltration into adipose and hepatic tissue
that potentiates dysfunction, causing increased FFA, further
adipokine secretion, and worsening hyperglycemia [35]. Pro-
inflammatory effects of FFA and their deposition in the vascular
intima cause a positive feedback loop via a cascade of cytokines
such as tumor necrosis factor-alpha (TNF-α) and interleukin-6
(IL-6) that attract macrophages and exacerbate endothelial dys-
function and atherosclerosis (Fig. 2) [36••, 37]. The inflamma-
tion caused by the macrophage infiltration limits adipose re-
sponse to insulin, which would normally limit the glycerol con-
version discussed earlier [38]. Increased hyperglycemia is also
self-potentiating as it triggers hepatic acetyl-CoA, which in turn
activates pyruvate carboxylase leading to increased glycerol
conversion to glucose.
In both human and animal subjects with type II diabetes,
endothelial-dependent vasodilation is markedly reduced [39,
40•]. Given the role of endothelial vasoconstricting and
vasodilating mechanisms in regulating blood flow, it is not
surprising that there is increasing evidence of endothelial dys-
function as a culprit in the oxygen imbalance of myocardial
circulation that may lead to cardiac ischemia and infarction
[41, 42•, 43]. As a result, endothelial dysfunction is consid-
ered to be an early predictor of various CVDs such as athero-
sclerosis and heart attack and has been implicated in the path-
ogenesis of diabetes-induced angiopathy [44].
Oxidative stress is tightly regulated by mechanisms that
balance reactive oxygen species (ROS) production with
Fig. 2 Effects of metabolic
syndrome
Curr Hypertens Rep (2018) 20:15
ROS removal by antioxidant enzymes such as superoxide dis-
mutase [45, 46]. Excessive ROS contributes to damage to
DNA, lipids, and proteins and disrupts cardiovascular reactiv-
ity [47]. Nitric oxide (NO) produced by vascular endothelium
regulates vasodilation, anti-coagulation, leukocyte adhesion,
and smooth muscle proliferation in the vasculature. One meth-
od that hyperglycemia may decrease NO bioavailability is
through increased levels of ROS [48].
Another mechanism of inflammation is FFA independently
mediated inflammation and IR (via C-reactive protein, TNF,
leptin, and adiponectin production) [49]. Van de Voorde et al.
found that cytokine release is also promoted because of cellu-
lar ischemia when adipose tissue accumulation out-strips
available blood supply [50•]. Furthermore, adipokines poten-
tiate macrophage activation and formation of multinucleated
giant cells which also contribute to cytokine secretion in the
forms of IL-1α, TNF-α [51].
The atherosclerotic disease process is characterized by in-
filtration and retention of oxidized lipids in the artery wall,
triggering a disproportionate inflammatory response and mac-
rophage activation [52]. Much of the inflammatory cascade is
attributable to secretion of adipokines from fat cells (cytokines
specific to adipose tissue). Adipokines promote a cascade of
inflammatory activation that includes IL-1β, IL-6, and NO
synthase 2 which also activate macrophages that contribute
to a feedback cycle of endothelial dysfunction and IR [53, 54].
Dyslipidemia is also directly related to adiposity and BMI
through the mechanisms of insulin resistance, FFA release, and
resultant HDL-C inhibition with upregulation of LDL-C—
leading to atherosclerosis [55]. HDL-C protects against athero-
sclerosis by both removing excess cholesterol from macro-
phages and by downregulating adipokine secretion in fat tissue
[56]. On the other hand, excess LDL-C promotes atherosclero-
sis through sub-endothelial deposition of LDL-C-/apolipopro-
tein-B-containing particles that stimulate macrophage activity,
phagocytosis, and foam cell formation that leads to inflamma-
tion (discussed earlier) and results in atherosclerotic plaques
Curr Hypertens Rep (2018) 20:15
[57]. Both oxidized and dense LDL-C are associated with a
higher level of oxidative stress, MetS, smooth muscle induc-
tion, and higher risks for CHD [58, 59•, 60•].
Leptin likewise is a hormone related to adiposity and has
been associated with many of the changes in lipid metabolism
and CVD. Du et al. found that when treated with leptin, cells
activated the p38 mitogen-activated protein kinase signaling
pathway, enhanced the expression of proprotein convertase
subtilisin/kexin type 9 (PCSK9) and hepatocyte nuclear factor
1α in HepG2 cells, causing decreased LDL-R expression and
promoting free LDL-C circulation. When this effect was mea-
sured in an environment of atorvastatin exposure (which
causes upregulation of LDL-C receptors) in this cell line, lep-
tin was found to inhibit the action of atorvastatin [61•].
Additionally, leptin causes pro-coagulant and antifibrinolytic
effects that promote atheroma formation; this is thought to be
by the action of leptin receptors on vascular inflammation,
proliferation, and calcification and by increasing oxidative
stress. Thus, the effects of leptin in those with increased adi-
pose mass contribute to a combination of dyslipidemia and
endothelial dysfunction, potentiating the processes of athero-
sclerosis [62].
In summary, MetS promotes an inflammatory cascade
through a combination of insulin resistance and adiposity that
accelerates inflammation and associated atherosclerotic dis-
ease via numerous pathways.
Effects of Combined Illness
Despite our increased understanding of the different aspects
involved in the development of MetS, the intricacies of the
disease process remain poorly understood. What is under-
stood, however, is the end result: The presence of MetS
provides a significant increase in CVD morbidity [63••].
Diabetic patients have a two- to four-fold higher incidence
of CHD and a ~ 10-fold increase in peripheral diseases ow-
ing to accelerated atherogenesis [47, 64]. The mechanisms at
play are actively studied, but the picture so far shows a
multifactorial disease process, much like MetS itself.
RAAS activation, endothelial damage by way of persistent
hyperglycemia and increased FFA synthesis, and sympathet-
ic activation have all been implicated as likely causes of the
increased incidence of CVD events attached to MetS [31, 32,
38, 65]. A meta-analysis of 37 studies across 172,573 indi-
viduals conducted by Gami et al. showed a relative risk of
1.78 (95% CI 1.58–2.00) of CVD events and death in those
patients who had MetS vs. those who did not, and the rela-
tive risk only dropped to 1.53 (95% CI 1.32–1.79) after
adjusting for traditional risk factors for CVD [66••].
Another independent study conducted by Solymoss et al.
indicated a significantly increased risk of CVD morbidity
in patients with MetS, showing a higher incidence of
Page 5 of 9 15
myocardial infarction (16.3 vs. 7.1%) even among patients
who had no significant known CHD [67•].
In addition to the risk of myocardial infarction (MI) and
CHD, MetS carries its own particular risk of developing heart
failure (HF). A recently published scientific statement from
The American Heart Association regarding comorbidities (in-
cluding MetS) in patients with chronic HF also notes an over-
all increased prevalence of HF in MetS patients, particularly
for HF with preserved ejection fraction (HFpEF) [68•].
pHTN is a relatively new concept aimed at identifying
high-risk patients for early intervention, and with good reason.
A meta-analysis performed by Huang et al. showed that pa-
tients with pHTN had a significantly higher risk of developing
CVD (RR of 1.55, 95% CI 1.41–1.71), stroke (RR of 1.71,
95% CI 1.55–1.89), and CHD (RR of 1.50, 95% CI 1.30–
1.74). Subgroup analysis of this same data also revealed a
significantly increased risk for CVD even among patients with
“low-range” pHTN (defined as SBP 120–129 mmHg and
DBP 80–84 mmHg) as compared to those patients with opti-
mal BPs (RR 1.46, 95% CI 1.32–1.62). Increased risk was
also found among patients with “high-range” pHTN (defined
as SBP 130–139 mmHg and DBP 85–89 mmHg) versus those
with “low-range” pHTN (χ2 = 5.69, P = 0.02) [69•].
Obesity is itself an independent risk factor for the develop-
ment of HF even without the presence of MetS. Obesity has
been found to be linked to left ventricular (LV) enlargement,
increased LV mass, wall thickening, and left atrial enlarge-
ment as well as right ventricular enlargement compared to
non-obese people. These findings were found to be indepen-
dent of age or BP and are attributed to the increase in work by
the myocardium, promoting cardiac remodeling, including
atrial and ventricular enlargement and increase in wall tension
[70, 71•]. As opposed to HF caused by CHD, which is more
likely to be systolic in nature, HF caused by obesity is more
likely to be diastolic in nature (HFpEF) [68•]. One study by
Fuentes et al. performed among 607 patients cited a signifi-
cantly higher prevalence of diastolic dysfunction in those with
pre-MetS (17–18%; defined as meeting 1–2 criteria of MetS)
and MetS (29–35%) versus those with neither (7–9%)
(p < 0.001) [72•].
Morbidity and Mortality
Data regarding CVD in patients with pHTN is fairly clear. A
recent meta-analysis performed by Guo et al. demonstrated
that patients who fell within the range of SBP 130–139 and
DBP 85–89 (or the “high normal” BP criteria established by
ESH-ESC as earlier) showed an increased risk in CVD mor-
tality [73]. An analysis conducted by Vasan et al. evaluated
patients with high normal BP who were enrolled in the
Framingham Heart Study, and assessed their risk of CVD.
They found that high normal BP was associated with a hazard
15 Page 6 of 9
ratio for CVD (adjusted for risk factor) of 1.6 (95% CI 1.1–
2.2) for men and 2.5 (95% CI 1.6–4.1) for women, as com-
pared to participants with optimal BP [74].
Increased CVD morbidity in the presence of MetS has been
well documented, but some data concerning the cardiac-
related mortality in MetS is conflicting. As discussed before,
Gami et al. noted a significant increase in CVD mortality in
patients with MetS [66••]. A study conducted by Isomaa et al.
followed 4483 subjects who had type 2 diabetes to assess for
the presence of MetS based on the WHO criteria, and assessed
CVD mortality in 3606 of those subjects. Along with a three-
fold risk of CHD in the subjects with MetS, they also reported
a significant increase in CVD mortality versus those without
the MetS (12.0 vs. 2.2%, p < 0.001) [75].
One source of conflict regarding the data comes from stud-
ies involving patients with both MetS and HF. The AHA sci-
entific statement notes that studies have had conflicting results
regarding mortality. They report that some studies have shown
increased mortality in patients who have HF and MetS, and
other studies that show a decrease in mortality with patients
with an increasing number of MetS criteria, citing a potential
“paradoxical effect.” They do report that MetS is associated
with higher all-cause and CVD mortality overall, but that
more studies are needed to understand the paradox surround-
ing the improved survival noted in some HF patients [68•].
The obesity paradox is a phenomenon that is under increas-
ing scrutiny as there is a large body of evidence that obesity
confers survival benefits in patients with chronic diseases,
particularly those with CVD, as compared to normal weight
patients with the same conditions [71•, 76, 77]. One proposed
mechanism for this effect involves the interactions between
lean muscle mass and overall body fat, which reaches a bal-
ance in the overweight and obese such that the improvement
in metabolic reserve contributed by lean muscle mass over-
comes the harms associated with excess body fat, thus reduc-
ing mortality. Once BMI shifts (either lower or higher), the
balance is disrupted and mortality rises accordingly [78•].
This subset of overweight and obese people without MetS is
termed “metabolically healthy obese” [71•]. Despite this ap-
parent paradox, a large trial by Ahmad et al. demonstrated that
overall survival in healthy obese individuals is shorter than in
those with normal BMI. In this study, the authors found that
those with increased BMI succumbed to chronic illness (such
as HF) earlier in life and lived with chronic illness significant-
ly longer than those with normal BMI, who would on average
become chronically ill at a more advanced age but have a
shorter lifespan once illness had developed [79•].
Summary
pHTN and MetS are both lifestyle diseases that are potentiated
by increased weight and increased adiposity. In both cases,
Curr Hypertens Rep (2018) 20:15
dysregulation of normal homeostasis causes vascular remod-
eling and dysfunction that potentiates inflammatory responses
leading to more rapid atherosclerosis and symptomatic
CVD—including stroke, CHD, and HF.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant
to this manuscript.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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