Metabolic Syndrome and Cardiovascular Disease: A Health Challenge in Mexico

Abstract

Metabolic Syndrome (MetS) is a cluster of risk factors that, taken alone or synergically, are independent predictors of type 2 diabetes and cardiovascular disease (CVD), which are both major public health problems that requires urgent containment actions. Current controversies regarding MetS are focused on ascertain the unifying explanation of molecular and pathophysiological mechanisms originating the syndrome, involving insulin resistance and low-grade chronic inflammation. This review aims to present the clinical relevance of MetS and its complications, as well as the hypotheses addressing its etiopathogenic relation with CVD. We conclude that health policies should emphasize basic research promotion, timely detection and early treatment of MetS, which will help to reduce the risk of CVD and their impact on public health and health-care related costs.

Full text

REVIEW ARTICLE
Metabolic Syndrome and Cardiovascular Disease: A Health Challenge
Antonio Gonzalez-Ch
avez,
a
Jos
e Alejandro Ch
avez-Fern
andez,
b
Sandra Elizondo-Argueta,
c
Alonso Gonz
alez-Tapia,
d
Jos
e Israel Le
on-Pedroza,
a,e
and Cesar Ochoa
f
a
Servicio de Medicina Interna, Hospital General de M
exico, Dr. Eduardo Liceaga, Ciudad de M
exico, M
exico
b
Servicio de Cardiolog
ıa, Hospital General de M
exico, Dr. Eduardo Liceaga, Ciudad de M
exico, M
exico
c
Division de Proyectos Especiales en Salud, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
d
Instituto Nacional de Cardiolog
ıa, Ciudad de M
exico, M
exico
e
Divisi
on de Estudios de Posgrado, Programa de Maestr
ıa en Administraci
on de Sistemas de Salud, Facultad de Contadur
ıa y Administraci
on, Universidad
Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
f
Western Diabetes Institute, Western University of Health Sciences, Pomona, California, USA
Received for publication July 1, 2018; accepted October 12, 2018 (ARCMED_2018_187).
Metabolic Syndrome (MetS) is a cluster of risk factors that, taken alone or synergically,
are independent predictors of type 2 diabetes and cardiovascular disease (CVD), which
are both major public health problems that requires urgent containment actions. Current
controversies regarding MetS are focused on ascertain the unifying explanation of molec-
ular and pathophysiological mechanisms originating the syndrome, involving insulin
resistance and low-grade chronic inflammation. This review aims to present the clinical
relevance of MetS and its complications, as well as the hypotheses addressing its etiopa-
thogenic relation with CVD. We conclude that health policies should emphasize basic
research promotion, timely detection and early treatment of MetS, which will help to
reduce the risk of CVD and their impact on public health and health-care related
costs. Ó2018 IMSS. Published by Elsevier Inc. All rights reserved.
Key Words: Inflammation, Insulin resistance, Atherosclerosis, Metabolic syndrome, Cardiovascular
disease.
Introduction
Metabolic Syndrome (MetS) is a multifactorial disorder
defined by a combination of altered metabolism of glucose,
lipids, obesity and/or arterial pressure elevation (1). Addi-
tion of several factors is strongly related to atherosclerotic
cardiovascular disease (CVD) and type 2 diabetes (DT2)
development (2). This constellation of biochemical and
clinical abnormalities are related to insulin resistance
(3,4), low grade inflammation (5), oxidative stress (6) and
adiposity dysfunction, and it is associated, in the long term,
with cardiovascular events and death.
Even though concept development and globalization are
recent, association of its components and consequences is
historical. For example, Joannes Baptista Morgagni
(1682e1771) in his IV Anatomo-clinical epistle liber pri-
mus described an obese, sedentary, with migraine man that
developed cardiac insufficiency and died from a cerebro-
vascular event (arterial hypertension) and pulmonary
edema. Necropsy findings suggested advanced atheroscle-
rotic disease (probably dyslipidemia) together with vesical
lithiasis (hyperuricemia) (7). On the other hand, archaeolo-
gist Joyce Tyldesley described in Hatshepsut mummy
(Egyptian queen-pharaoh 1490e1468 BC) the coexistence
of obesity, T2D and cancer (8), showing the natural history
of the MetS and its complications.
MetS can be used as risk marker for CVD and death. A
meta-analysis published by Ford E. reviewed prospective
studies from 1998e2004; it concluded that MetS increases
risk for CVD (Relative Risk (RR): 1.65; CI 95%:
1.38e1.99; p50.009) and T2D (RR: 3.08, CI 95%:
Address reprint requests to: Antonio Gonzalez-Ch
avez, Dr., Servicio
de Medicina Interna, Hospital General de M
exico, Dr Eduardo Liceaga,
Dr Balmis 148, Col. Doctores, 06720, Ciudad de M
exico, M
exico; Phone:
(þ52) (55) 2789-2000 ext 1051; E-mail: antoniogonzalezchavez51@
gmail.com
0188-4409/$ - see front matter. Copyright Ó2018 IMSS. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.arcmed.2018.10.003
Archives of Medical Research 49 (2018) 516e521

2.16e4.40; p50.001). On the other hand, mortality by any
cause had no significative increase (9). Moreover, ARIC
study (1987e1989) reported similar results in a cohort of
14,502 subjects under ATP III diagnostic criteria; those
meeting MetS criteria doubled their risk of myocardial
infarction (MI) or coronary revascularization requirement
and RR for stroke was 1.42 (CI 95%:0.96e2.11) in men
and 1.96 (CI 95%: 1.28e3.00) in women (10).
It is clear that MetS is an entity that includes risk factors
that, either individually or in group, have predictive ability.
Current controversies are mainly focused on ascertain its
cause and explaining the pathophysiological and immuno-
logical process leading to adverse events. Therefore, it is
of crucial importance to describe existing hypothesis about
MetS origin and its interrelation with CVD.
Hypothetical origin of MetS and cardiovascular disease:
interrelation of multiple mechanisms
Combination of sedentarism, physical inactivity, genetical
factors and overnutrition predispose to metabolic dysregu-
lation leading into insulin resistance, ectopic fat depots,
low-grade inflammation and endoplasmic reticulum stress.
The time elapsed from cellular dysfunction to clinical overt
disease is several years and can be modified with dietary
style changes, exercise and/or specific pharmacotherapy.
Insulin Resistance
Insulin resistance (IR) (11) is a general term that describes
that circulating insulin subsides its physiological effects in
sensitive tissues, as skeletal muscle, adipose tissue, liver
and pancreas (target tissues for glucose metabolism) (12).
Insulin resistance is associated with asymptomatic athero-
sclerosis and coronary artery disease. Fasting insulin level
(IR marker) is an independent predictor of cardiovascular
events even in non-diabetic subjects. A meta-analysis of
65 studies revealed that IR (evaluated by HOMA) was a
stronger predictor of cardiovascular events compared to
fasting insulin or glucose levels alone. IR could cause
atherogenesis and plaque progression by multiple mecha-
nisms. Several studies, even in patients without stablished
CVD, have reported altered lipid metabolism and low-
grade inflammation as key biochemical processes involved
in pathogenesis of the atherosclerotic coronaropathy.
Insulin resistance, lipids and atherogenesis: a maladaptive
answer. Visceral fat accumulation increases morbidity and
mortality, and it ends in CVD (13e15).Hypertrophyof
visceral adipose cells promote macrophage infiltration react-
ing to inflammatory mediators, such as TNF-like weak
inducer of apoptosis (TWEAK) (16). These adipocytes have
a lower insulin sensitivity to its antilipolytic effects, and they
generate a proinflammatory microenvironment (17).This
produces a charge of free fatty acids (FFA) in portal circula-
tion delivered to the liver and other organs, promoting IR
and ectopic storage of fat. Portal flux of FFA stimulates liver
production of very low-density cholesterol (VLDL), result-
ing in hypertriglyceridemia (18). This triglycerides (TGD)
overflow is transferred to particles of low-density cholesterol
(LDL); hepatic lipase-mediated hydrolysis produces dense
low-density cholesterol particles (dLDL), more oxidizable
than LDL, with a higher ability to get in arterial walls and
thus, more atherogenic. Therefore, IR favors atherogenic
dyslipidemia with an increase in LDL/dLDL ratio (14,19).
Nevertheless, it is not fully understood how plasma FFA
are linked with MetS early pathogenic process and what
are their role in adults with normal weight and IR.
IR with high levels of FFA in portal blood flow along with
peripheral decrease of insulin sensitivity promote gluconeo-
genesis that contributes to hyperglycemia. Pancreatic beta
cells respond increasing insulin secretion (hyperinsuline-
mia). Eventually, this continued stimulation causes hypertro-
phy, endoplasmic reticulum stress, pyroptosis and death by
autophagia of these cells, leading to T2D. As a matter of
fact, hyperglycemia has a correlation with CVD even in
non-diabetic ranges, beginning from 86e110 mg/dL and
glycated hemoglobin of 5e6.9% (20,21).
Insulin Resistance, Immune and Inflammatory Response
The unbalance in caloric consumption/energetic expense
leads to adipocyte hypertrophy that makes blood supply
to this tissue insufficient. The resulting hypoxia triggers
oxidative stress associated with increasing levels of tumor
necrosis factor (TNF) and leptin, and lowers levels of
anti-inflammatory factors, like IL-10 and adiponectin. The
apoptosis of adipocytes induces infiltration of macrophages
and T lymphocytes (mainly Th1 and CD8þ), systemic in-
crease in macrophage chemoattractant protein-1 (MCP-1),
macrophage migration inhibitory factor (MIF-1) and che-
mokine CCL5. These proinflammatory cytokines have au-
tocrine or paracrine effects inducing IR in peripheral
tissues as well as in macrophages; probably by AMPK
decrease, ending up with mitochondrial dysfunction and in-
crease in oxygen reactive species, inflammasome NLRP3
and finally IL-1b(22).
Macrophages contribute to atherosclerosis development.
Hyperglycemia enhances monocyte adhesion and migration
to the intima and induces hyperplasia of smooth muscle
cells. The insulin-resistant macrophages are more suscepti-
ble to apoptosis in atherosclerotic plaques, which might
promote plaque necrosis and rupture (inflammation,
decreased collagen production and deterioration by prote-
ases) and thrombosis, yielding higher risk for CVD (for
instance; MI or stroke) (11).
Insulin Resistance, Endothelium, Thrombosis and Arterial
Hypertension
Endothelial dysfunction is strongly related to IR. Hypergly-
cemia and IR cause leukocyte adherence, superoxide
517Metabolic Syndrome and Cardiovascular Disease: A Health Challenge

production and alter endothelial function through inhibition
of nitric oxide production, increase of adhesion molecule
type 1 (ICAM-1), vascular cell adhesion molecule
(VCAM-1), endothelin and E-selectin expression, and
angiotensin II and plasminogen activator inhibition in an
Akt-dependent manner (5,6). Noteworthy, IR and hypergly-
cemia increase thrombus formation and platelet aggregation
and are associated to impaired fibrinolysis by an increase of
plasminogen activator inhibitor type 1 (up to 2.5 times
more). Therefore, MetS patients tend to thrombus forma-
tion and fibrinolysis resistance (23).
Arterial hypertension is widely related to MetS (24). Hy-
perinsulinemia diminishes sodium excretion, resulting in a
positive sodium balance that increases intravascular volume,
damaging vascular and cardiac relaxation (25). Inflamed ad-
ipose tissue (responsible for up to 30% of extra-adrenal aldo-
sterone production) causes angiotensin-aldosterone system
activation (RAS) (26). Sympathetic nervous system (SNS)
is activated by leptin increase (27), which chronically re-
duces natriuresis and availability of nitric oxide. Therefore,
sodium positive balance, RAS, SNS alterations, hyperlepti-
nemia and IR induce plasmatic volume expansion and in-
crease peripheral vascular resistance, which in a long term
might develop left ventricular concentric hypertrophy, dia-
stolic dysfunction (24) or CVD.
Metabolic Syndrome: Prevalence and Diagnosis
According to National Health and Nutrition Examination
Survey (NHANES) current prevalence of MetS in the
United States of America is about 34% in young adults un-
der 60 years or age and 54% for older ones. In other coun-
tries prevalence is less, but also significant: in China, 24%
and India, 33.5% (24).
A review by O’Neill et al. (2) reported MetS prevalence
in several countries according to NCEP-ATPIII classifica-
tion: 24.4% for Australian men and 19.9% for women;
9.8% for Chinese men and 17.8% for women; 18.6% in
Danish men and 14.3% for women, and 17.1% for Indian
men and 19.4% for women. However, these data could be
different if different criteria are applied, such those from In-
ternational Diabetes Federation (IDF).
In Mexico, according to the National Survey ENSANUT
2006 (28) (Encuesta Nacional de Salud y Nutrici
on 2006)
prevalence of MetS is between 36.8 and 49.8%, depending
on the criteria used. In the more recent ENSANUT Medio Ca-
mino 2016 (29) prevalence of MetS is still not determined, but
behavior of associated factors might point out to its increase
with a prevalence of up to 50% in older than 18 years (one
out of two Mexicans would have MetS) mostly associated to
overweight and obesity. In Tab l e 1 , comparative data of
different surveys related to chronic diseases, are presented.
Since 1988, when Reaven described this syndrome,
different diagnostic criteria have been proposed (Table 2)
where one of the main differences is the measurement of
central obesity. One of the more accepted definitions comes
from a working team that in 2009 defined MetS as risk fac-
tors for CVD and T2D, associated more frequently than ex-
pected only by chance, including glucose alterations,
increase in arterial pressure and TGD, low levels of high-
density lipoproteins and central obesity (30).
Table 1. Comparison of prevalence of self-reported chronic diseases in
National Health and Nutrition Surveys (ENSANUT) 2012 and 2016
Disease ENSANUT 2012 ENSANUT MC 2016
Diabetes 9.2% 9.4%
Hypertension 27.2% 25.5%
Obesity 71.3% 72.5%
Abdominal obesity 74% 76.6%
Table 2. Diagnostic criteria for metabolic syndrome
Diagnostic criteria Obesity (abdominal) Triglycerides, mg/dL HDL-C, mg/dL
Blood pressure,
mmHg Glucose level, mg/dL
IDF, 2005
Central
obesity þ$2
components
Waist according to cut
point by ethnical
group (W)
$150 or !40 (M) $130/85 or $100 or
!50 (W) or
Hypolipemiant
treatment
Hypolipemiant
treatment
Antihypertensive
treatment
DM2 diagnosis
Update ATP III, 2005
$3 components
Waist $150 or !40 (M) $130/85 or Fasting glucose $110
or
!50 (W)or
O102 (men) Hypolipemiant
treatment
Hypolipemiant
treatment
Antihypertensive
treatment
DM2 diagnosis
O88 (women)
Harmonized Criteria,
2009
$3 components
Waist according to cut
point by ethnical
group (W)
$150 !40 M $130/85 $100
!50 W
M, Men; W, Women; DM2, Diabetes mellitus type 2; IDF, International Diabetes Federation; ATP III, Adult Treatment Panel III.
518 Gonzalez-Ch
avez et al./ Archives of Medical Research 49 (2018) 516e521

Clinical presentation of MetS has wide phenotypic
variations, making difficult to have a specific definition.
Thus, it becomes necessary to improve our understanding
of MetS as a heterogenic entity, that worsens with time.
Recently, four stages of MetS have been described: at
first, risk factors are present, such as overweight, seden-
tarism, familial history of T2D, hypertension or prema-
ture death due to MI (stage A). Without proper
interventions modifying life style, one or two compo-
nents of MetS can appear (stage B of MetS). When three
components are present, this fulfill classic criteria (stage
CofMetS).Finally,targetorgandamage(T2D,morbid
obesity, non-alcoholic hepatic steatosis, obstructive sleep
apnea, chronic renal disease or CVD) occurs (stage D of
MetS) (31).
Ischemic Heart Disease and Metabolic Syndrome
A cohort of 622 patients (377 men and 245 women) with
mean age 64.4 12.76 years, diagnosed with ischemic heart
disease according to ACCF/AHA/ACP (32) from the Coro-
nary Artery Disease Clinic at the Hospital General de
M
exico, was followed for 18 months. The prevalence of
MetS components in these patients with stablished CVD
was high: 70% (CI 95% 66.4, 73.6) had arterial hyperten-
sion, 80% (CI 95% 76.9, 83.1) had hypertriglyceridemia,
65% (CI 95% 75.8, 82.2) had T2D, 79% (CI 95%
75.8,82.2) had abdominal obesity and 70% (CI 95% 66.4,
73.6) with low HDL-C. When MetS diagnosis was assessed
in agreement to harmonized criteria (31); 88% (CI 95% 85.4,
90.6) prevalence was observed. Cardiovascular risk stratifi-
cation score by Framingham was 26.44 and by ASCVD
(Atherosclerotic cardiovascular disease) was 26.3 with a
mean vascular age of 78 years. Other values of clinical
and biochemical variables are shown in Tab l e 3 and Figure 1.
In this Mexican cohort of patients with stablished CVD, it
can be observed that MetS is strongly related to CVD, given
the fact that prevalence of MetS is far higher than in general
population. Previous studies (33e35) have demonstrated a
low-grade chronic inflammation in obese Mexican subjects
which, along with IR, correlates with the presence of meta-
bolic dysfunction leading progressively to dyslipidemia,
abnormal tolerance to glucose and visceral fat deposition.
The ulterior immunological response triggered by these
changes produces tissular, cellular and molecular alterations
that are the etiopathogenic substrate of complications of
MetS (36). Among patients with diagnosed atherosclerotic
coronaropathy, almost 9 out of 10 had MetS. Taking into
Table 3. Mean of evaluated variables
Variable Mean
Body Mass Index 29.82
Waist perimeter 96.49 cm
Systolic arterial pressure 134 mmHg
Diastolic arterial pressure 76.83 mmHg
Glucose 122.7 mg/dL
Hb A1c 7.36%
Total cholesterol 227 mg/dL
HDL Cholesterol 39 mg/dL
LDL Cholesterol 131 mg/dL
Triglycerides 246 mg/dL
TC/HDL Ratio 6.15
LDL/HDL Ratio 3.63
TGL/HDL Ratio 6.3
3
9
26
35
27
0
5
10
15
20
25
30
35
40
1 component 2 components 3 components 4 components 5 components
FREQUENCY
NUMBER OF COMPONENTS OF METABOLIC SYNDROME
Figure 1. Prevalence of number of components of Metabolic Syndrome (MetS) in a cohort with ischemic heart disease.
519Metabolic Syndrome and Cardiovascular Disease: A Health Challenge

consideration that ENSANUT shows that almost one out of
two Mexicans have MetS, it is not surprising that CVD
represent the first cause of mortality in Mexico.
The ATTICA study (37) followed up for 10 years a cohort
of patients with a prevalence of MetS of 20%. At the end,
MetS prevalence had increased up to 50% using harmonized
criteria, and almost in the same percentage when using IDF
and ATP III criteria. The presence of MetS according with
ATP III criteria increased the risk for CVD (OR: 1.83,
95% CI: 1.24e2.72). Moreover, Chen Q, et al. (38) in a
4.9 years follow-up cohort showed that MetS, according to
harmonized criteria, had an increase of 1.26 times the risk
of death from any cause (95% CI, 1.01e1.59) and 1.41 times
the risk of death from CVD (1.06e1.87). The number of
MetS components was related to a gradual increase in mor-
tality from any cause or CVD ( p!0.05).
Conclusions
Several actions are required to achieve an epidemiological
impact on CVD and MetS in Mexican population. To
mention some of them, we suggest basic research invest-
ment, general population screening, and more aggressive
follow-up of cases detected. Basic and molecular research
will open the way towards precision medicine, and a deeper
understanding of the mechanisms involved in these chronic
non-transmissible diseases will be the key driver for inno-
vative biomarkers and treatments. Wider screening for
MetS will permit detect and provide appropriate clinical
management. Detected cases shall be carefully followed
in order to reduce their risk of atherosclerotic coronary dis-
ease, sleep apnea and non-alcoholic hepatic steatosis; emer-
gent clinical expressions of MetS.
It is worth noting that these actions represent a challenge
for Mexican health-care system: they require higher invest-
ment, complete re-organization of the primary care system
and specific development of a program that consider actual so-
ciocultural and educative level. If we are capable to do this, we
will achieve a sustainable development of well-being with a
suitable life quality, in agreement with national and interna-
tional commitments, as such as 2030 Agenda for Sustainable
Development (39) which stablishes that, by 2030, premature
mortality, including from CVD, shall be reduced by one-
third, and recognizes chronic non-transmissible diseases as
one of the biggest challenges to sustainable development.
Conflict of Interest
Authors have no conflicts of interest to declare.
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521Metabolic Syndrome and Cardiovascular Disease: A Health Challenge