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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3701_Библиотеки_им_академика_М_И_Перельмана
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Novel Pathogenesis and Treatments for Cardiovascular Disease
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the Hispanic, black, and white is higher than in Asians, respectively. In women, the
prevalence is almost the same as the men. The black women have the most prevalence
following the Hispanic, white, and Asian showing there is a socioeconomic inequality
structure as well. In addition, children and adolescents are also affected; between
and -year-olds are obese and the males and females are equally [].
In general terms, the trends in obesity prevalence around the world are getting
up constantly, which means it highlights the significant impact that the obesity will
continue to have on CVD the incidence, prevalence, and deaths globally.
At this time, obesity is linked to numerous diseases of the cardiovascular system:
stroke, venous thromboembolic disease and pulmonary hypertension, cardiovascular
disease, heart failure, arrhythmias such as atrial fibrillation, and sudden cardiac
death [].
. Visceral adiposity, liver fat, and cardiovascular risk
There is a strongly correlation between overall obesity and abdominal obesity;
although, there are two kinds of patients: either the ones with overall obesity but not
abdominal obesity.
Abdominal obesity is linked to increased cardiovascular diseases. Along these
lines, there still exists underdiagnosis to classify the CVD risk among obese patients.
Trying to unmask and making a good clinical patient evaluation, organizations,
expert panels, and a lot of evidence support have shown and recommended the waist
circumference (WC) measurements with body mass index (BMI) applied in the clinical practice may add critical information and successful prediction of cardiovascular
risk and mortality focusing on visceral adiposity.
Fortunately imaging techniques can be used to quantify adipose tissue and ectopic
fat depots volumes. The National Library of Medicine described the adipose tissue as a
storage of energy in the form of triacylglycerols and ectopic fat depots and is defined
by excess adipose tissue in locations not classically associated with adipose tissue storage, some fat depots are more linked to risk factors for disease than others. Techniques
such as computed tomography (CT) and magnetic resonance imaging (MRI) are
extraordinary and the most advanced in the study of human body composition and
of its relationship with CVD risk. However, other techniques such as bio-impedance
body composition are more available in the practice [].
The abdominal adiposity can be divided into: obesity, subcutaneous, and visceral
obesity. Overweight or obese patients with low levels of visceral adipose tissue (VAT)
have been identified as having a more favorable cardiovascular risk profile, commonly known as metabolically healthy obese patients. Some recent data suggest that
metabolically healthy obesity may be a transitory phenotype, the time of which may
be variable by race, ethnicity, and gender. The relationship between visceral adipose
tissue and cardiovascular risk is known, the first one being a clear accelerator for the
development of cardiovascular diseases.
The concept called adipose tissue expandability refers to the ability of the
adipocyte to be contained in the places where it normally lives. When this expansion
capacity of adipose tissue is exceeded, it begins to be located in organs abnormally,
developing diseases such as hepatic steatosis, which is directly related to a higher
risk of developing cardiovascular events. Thus, it is important to identify that
patients with increased visceral adiposity are the ones with the highest risk independent of weight.
Obesity and Cardiovascular Risk
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. Ectopic fat depots and CVD risk
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. Ectopic fat depots
Although the major known ectopic fat depot is the hepatic depot, there are other
abnormal fat depots that contribute to the development of cardiovascular diseases.
Some of these are: pericardial and epicardial depots despite being used many times in
an undifferentiated way, they have a different anatomical locations and their relationship with cardiovascular diseases is different. The pericardial depot is located at the
level of the pericardial sac and has been related to a high BMI, traditional cardiovascular risk (CVR) risk factors, and elevated atherogenic cholesterol. Additionally, the
amount of pericardial fat has been associated with an increased risk of coronary heart
disease, atherosclerosis, and heart failure adjusting for age, sex, BMI, and abdominal
circumference; but not adjusting for traditional CVR factor and either when adjusting
for levels of more atherogenic cholesterol particles [].
VAT on the other hand represents the visceral fat contained between the
external myocardium wall and the visceral lamina of the pericardium. It has been
associated with a general CVR score and arterial stiffness in patients with CVD
and DM [].
Reports from multiple studies presented a high association between the pericardial
depots and CVD. For example, a study of atherosclerosis showed the pericardial fat
and a higher risk of all CVD causes, hard atherosclerotic CVD, and HF but not intrathoracic fat []. Another study that analyzed all-cause mortality risk after adjustment
for age, sex, lifestyle variables, lipids, glucose, and adipocytokines was higher by
increment in pericardial fat, but it did not proof enough information to predict the
events of CVD beyond traditional risk factors [].
Epicardial adipose tissue (EAT) is the visceral fat layer located around the heart
and is believed to be important for the buffering of the coronary arteries and in
providing fatty acids as a source of energy for the cardiac muscle. Reviews have
shown that this deposit may be considered highly insulin resistant and also indicator of cardiovascular risk because of the secretion of pro-inflammatory cytokines
and carotid artery stiffness. In addition, this can produce sleep apnea severity in
woman independently of BMI, and this last one is associated with higher CVD
risk[, ].
Currently, the way to reduce the announced ectopic fat (adipose tissue depots)
has been investigated. There are a lot of nonpharmacological strategies to be applied
based on lifestyle interventions, some authors dare to say could be more effective than
pharmacological therapies. One of those strategies are exercises such as aerobic in
nature, which may reduce VAT unchanged on weight loss; and reports of losing VAT
by only resistance and high-intensity raining are equivocal [, ]. Thus, exercise
interventions not just can decrease the VAT, apparently have impact in reducing
hepatic, epicardial, and pericardial fat. However, there is not enough information to
support a significant reduction in epicardial fat with exercise as the caloric restriction
strategy to reduce it [].
The recommendation for physical activity of min per week may be sufficient to
reduce VAT with no further reduction with additional activity. It is very important to
highlight that exercise can reduce VAT even in the absence of weight loss [].
According to data from the National Health and Nutrition Examination Survey,
central obesity has higher risk of cardiovascular mortality compared with patients
with the same BMI but without central adiposity. This has been called normal weight
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central obesity and expected survival estimates were consistently lower for those with
central obesity when controlled for age and BMI [, ].
. Endotelial disfunction
. Atherosclerosis in obesity
The process to atherosclerosis begins with fatty streaks resulting in thickening
ofthe intima arterial layer. Obesity is considered a storm, which accelerates this process by several mechanisms such as insulin resistance through adipocytokines, endothelial dysfunction, hypercoagulability, and inflammation. The VAT makes systemic
and vascular inflammation that promotes atherogenesis. Further, insulin resistance has
been associated to metabolic syndrome, proinflammatory, and prothrombotic states.
Endothelial dysfunction in obesity has two principal causes: diminished bioavailability of nitric oxide and increased oxidative stress. A good marker of early atherosclerosis is carotid intima media thickness [].
Several prospective epidemiological studies demonstrate that obesity and higher
risk of incident coronary artery disease (CAD) are strongly linked. Excess visceral
fat rather than body weight has been linked to increased risk of cardiovascular
events. BMI, higher measures of central adiposity, including WC and waist-to-hip
ratio (WHR), were aligned with a higher risk of CAD and cardiovascular mortality
independently of BMI [, ].
Another important concept is the duration of obesity and abdominal adiposity,
expressed as excess BMI-years and WC-years, which are stronger predictors of CAD,
highlighting these measurements must be evaluated together [].
. Microvascular disease and obesity
The chronic inflammatory conditions developed from the obesity are linked to
abnormalities in the coronary microvasculature. Coronary microvascular disease is
pathophysiologically associated with endothelial dysfunction and possibly to small
vessel remodeling and also disturbing coronary blood flow; this microvascular disease
is independently associated with higher BMI [].
Obesity has implications in macrophages and adipocytes that generate a proinflammatory state that increases the cytokines and reduces the nitric oxide. All this
cascade promotes endothelial dysfunction (Figure ).
Proinflamatory state:
Endothelial Dysfunction: ROS, angiotensinogen, calprotectin NO, Ghrelin.
Metabolic disorders: Changes in glucose and lipid metabolism, insulin resistance,
hypertension, atherosclerosis.
IL1 β: Interleukin 1 β, IL6: Interleukin 6, TNF Tumor Necrosis Factor, Nitric Oxide,
ROS: Reactive Oxygen Species.
Normally the endothelium regulates vascular homeostasis; it is the natural inner
lining of the vessels. Its layers are: tunica intima, tunica media, and the vascular
smooth muscle cell (VSMC). But there is a combination-coordination of multiple
factors such as blood flow, distribution of nutrients, hormones, and other macronutrients, and migration and proliferation of VSMC. The VSMC is an important
ILβ, IL , Leptin, TNFα, PCR, NO.
Obesity and Cardiovascular Risk
DOI: http://dx.doi.org/10.5772/.106877
Figure 1.
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OBESTITY and PROINFLAMATORY STATE.
component of vessel wall remodeling in response to injury, which controls coagulation and fibrinolysis activities, reduces vascular tone and regulates cellular and vascular adhesions, inhibits leukocyte adhesions, and modulates inflammatory activities
and angiogenesis (Figure ).
Vasodilators: Apelin, HS, NO, PGI, IgF.
Permeability: NO, VEGF, ROS, PGI, PAI, FGF, Leptin.
Anticoagulant factors: Anti thrombin III, Thrombomodulin.
Angiogenic factors: FGF, TGFβ, VEGF.
Vasoconstrictors: ROS, VCAM, PgH, Ang II, Resistin.
Inflammatory mediators: Leucotriens, integrins Inmunoglobulins.
Procoagulant factors: TF, PAF, vWF, TXA, PAI.
Proliferation: NO, TxA, ROS, PgH.
H2S: Hydrogen Sulfide, NO: Nitric Oxide, PGI: Proctaciclin, IgF1: Insulin Like
growth factor 1, VEGF: vascular endothelial growth factor, PAI1: Plaminogen Activator
Inhibitor, FGF: Fibroblast Growth Factor, TGFβ: Transforming Growth Factor β, ROS:
Reactive Oxygen Species, VCAM: Vascular Cell Adhesion Molecule1, PgH2: Prostaglandin
H2, Ang II: Angiotensin II, TF: Tissue Factor; vWF: Von Willebrand Factor, PAF: Platelet
Activating Factor, TXA2: thromboxane A2, PAI: Plasminogen Activator Inhibitor1.
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Figure 2.
Endothelial dysfunction and obesity.
Nevertheless, the endothelial dysfunction is usually characterized by the disrupt
between secretion and release of vasoconstriction and vasodilation agents, pushing
the vascular endothelial toward prothrombotic and proatherogenic effects [].
Secondly, the distorted provokes that the leukocyte adhesion, activation of
platelets, pro-oxidation of mitogens, impaired PGI, coagulation, and nitric oxide
(NO) productions are the features or ¨faulty physiological properties¨ resulted from a
dysfunction of endothelium, as well decreased synthesis of EDHF, and vasoconstriction factors including Ang II and prostaglandin (PGH), atherosclerosis, and thrombosis (Figure ) [].
The major participating agents of endothelial dysfunction in obesity include:
insulin resistance, oxidized form of low-density lipoprotein (oxLDL), adipose
tissues related inflammation, and decreased NO bioavailability. Others such
as elevated production of ROS and arginase, advanced glycation end products
(RAGE), and phenotypic alterations in perivascular adipose tissue result in mild
inflammation and elevated leptin with subsequent reduction of adiponectin
secretions [].
Further obesity generates a procoagulant state, which is explained by several
mechanisms:
. Adipose tissue in obesity secretes decreased levels of adiponectin, thereby facili-
tating the susceptibility of platelets aggregation with the subsequent increased
PAI-1 production, which further inhibits fibrinolysis.
. Macrophages found in adipose tissue also produce TF, which combines with the
elevated liver secretion of FVII and FVIII to promote the possibility of coagulation abnormalities.
Obesity and Cardiovascular Risk
DOI: http://dx.doi.org/10.5772/.106877
Figure 3.
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Proinflamatory and anti-inflammatory state in obesity.
. Inflammation has been characterized by the imbalance between proinflamma-
tory and procoagulant, and anti-inflammatory and anticoagulant activities of
the endothelium, leading to disturbance of the hemostatic system.
. Endothelial dysfunction, epigenetic modifications, and vascular calcification
Epigenetic modifications such as DNA methylation and histone acetylation are
described. Previous studies have recognized changes in expression of methyltransferase linked with hypomethylation of hypermethylated genomic regions. These findings are linked between epigenetic modifications and atherosclerosis.
Vascular calcification (VC) is one of the mechanisms that influences vascular
remodeling due to the differentiation of vascular smooth muscle cells (VSMCs),
alterations in elastin, collagen, and endothelial dysfunction. VC increases the chances
of cardiovascular mortality and morbidity, especially in individuals with obesity, type
diabetes mellitus (TDM), and chronic kidney disease []. Several studies have
identified the correlation between ROS generation, particularly H O (hydrogen
peroxide), and the progression of vascular calcification. An elevated level of ROS
triggers MMP (matrix metalloproteinase) activity and alteration in collagen and
elastin deposition [].
. How the gut microbiota affects on vascular endothelium
Gut microbiota is the collection of bacteria that inhabitat gastrointestinal tract and
have many repercussions in health. Several studies have indicated that gut microbiota
plays a contributing role in atherosclerosis through modulating inflammation and the
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secretion of microbial metabolites. Recent studies have shown the influence of gut
disbiosis and progression of atherosclerosis and cardiovascular disease. Bacteria such
as Akkermansia muciniphila promote barrier function and have attenuating effect
against atherosclerosis [].
Scientists have found that the relative abundance of Roseburia and Eubacterium
was lower, while Collinsella was higher in atherosclerosis patients compared with
healthy controls [].
Variety of metabolites are derived from the gut microbiota, as well as co-metabolism of gut microbiota such as amines methylamines, polyamines, short-chain fatty
acids (SCFAs), trimethylamine N-oxide (TMAO), and secondary bile acids (BAs).
SCFAs are a group of well-established gut microbial metabolites that are critically
involved in metabolic diseases [].
Diet has an important role in biodiversity of microbiome and hemostasis for
maintaining human health. Disbiosis has been associated with progression of various
diseases including CVD, obesity, diabetes, nonalcoholic fatty liver disease, and some
types of cancer.
. Molecular endothelial dysfunction in obesity
There are many bioquimical makers of endothelial dysfunction: first MCP
(monocyte chemotactic and activating factor). This protein is synthesized by several
types of cells, including inflammatory and inflammation-mediated cells, monocytic
cells, human tubular epithelial cells (TECs), and renal-mediated cells in response
to various stimuli and when joint to chemokine receptor (CCR) initiates various monocyte-mediated proinflammatory signals and monocyte chemoattractant
activities, facilitating monocytes migration to the subendothelium and combines with
ox-LDL to form foam cells, forming a fatty streak and eventual atherosclerotic plaque
(Figure ) [].
. Obesity and atherosclerosis
Obesity increases morbidity and mortality especially when associated to hypertension and CAD [].
Obesity is associated with overt atherosclerotic lesions even after accounting for
the impact of these metabolic cardiovascular risk factors. The association of obesity
with raised atherosclerotic lesions among men in the Pathobiological Determinants
of Atherosclerosis in Youth study was present only for those with a thick abdominal
panniculus, indicating the fundamental role of central adiposity in the development of
atherosclerotic disease []. Chronic inflammation induced by obesity increases the likelihood of low-density lipoprotein oxidation, which promotes atherogenesis []. Other
factors together increase atherosclerosis are insulin resistance and metabolic syndrome.
Endothelial dysfunction in obesity is principally caused by diminished bioavailability of nitric oxide in the setting of inflammation and oxidative stress [].
A prospective study published by Whintlock et al. describes an increase of probability of mortality stroke in a range of –kg/m, each kg/m is associated with
higher stroke mortality. A prospective cohort study with . million person-year
by follow-up from to concluded that overweight and obesity shortened
longevity and increased lifetime risk [].
Obesity and Cardiovascular Risk
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Figure 4.
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Bioquimical markers of endothelial dysfunction.
There are important differences in obesity according to gender that must be taken
into account, such as the impact of hormones in women against the development of
atherosclerosis.
Before menopause, women generally have greater vagal than sympathetic tone,
and lower levels of total cholesterol and LDL-C than men. Additionally, differences
in glucose and lipid metabolism, sex hormones, and cytokine production are thought
to explain why men are at an increased risk of CVD [, ]. This recalls the protective effect of estrogens in maintaining health and distribution of body fat. This is
likely explained by the aforementioned differences in hormone-driven patterns of
fat distribution, with men more likely to deposit visceral fat, compared with subcutaneous fat in women, considering that visceral fat has been associated with greater
cardiometabolic risk [, ].
Obesity is characterized by an increased risk of diabetes, hypertension, and
dyslipidemia, and independently associated with CVD. Several prospective epidemiological studies demonstrate that obesity is associated with higher risk of incident
coronary artery disease []. There are controversies if obesity causes high risk of
CVD or the complications of obesity are the cause of them. Some large prospective
analyses have indicated that the link between obesity and CAD is mediated largely
by hypertension, dyslipidemia, diabetes, and other comorbidities, whereas other
prospective studies suggest a significant residual CAD risk in obesity even after
accounting for these risk factors [].
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A meta-analysis of studies including . million individuals suggested that
approximately half of the associations of overweight and obesity with CAD are
explained by levels of blood pressure, cholesterol, and glucose []. There are three
mechanisms linked to metabolic syndrome, that is, production of adipocytokines,
oxidative stress, and a prothrombotic state [].
Other important causative factor is the ectopic fat deposition, especially pericardial and epicardial spaces, which may further contribute to the burden of coronary
atherosclerosis [].
Some studies of pathobiology have shown that arteries with intramyocardial
course in perfect condition could have atherosclerosis in epicardial segment of
thesame artery. Thus, local production of adipocytokines by epicardial fat may
modulates blood vessel biology through paracrine signaling or through vasa
vasorum [].
. Diagnosis of coronary artery disease (CAD) in obesity
CAD has been associated with higher measures of central adiposity, including
WC and WHR inclusive those with normal weight and BMI. The degree and duration of obesity expressed as excess BMI years and WC years are stronger predictors
of CAD [].
Many changes can occur in the patients with CAD. There are noninvasive and
invasive modalities to assess CAD in patients with obesity. These will be described
below.
. Noninvasive CAD assessment
6.1.1 Electrocadiography
Obesity has the potential to affect the ECG in several ways: displacing the heart by
elevating the diaphragm in the supine position, increasing the cardiac workload, and
increasing the distance between the heart and the recording electrodes.
Several electrocardiographic changes are associated with obesity (Tabl e ).
More frequent ST-segment depression is seen in patients with overweight and
CAD, and insulin concentration may be related to the development of the ST-segment
depression over time [].
Hear rate
QRS interval
QT interval
False-positive criteria for inferior myocardial infraction
PR interval
ST–T abnormalities
Left axis deviation
Table 1 .
Electrocardiographic changes in importance order.
Obesity and Cardiovascular Risk
DOI: http://dx.doi.org/10.5772/.106877
6.1.2 Treadmill stress test
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Many patients with obesity fail to achieve – of the age-predicted heart rate
needed for diagnostically valid results.
Chronotropic competence can be reduced in obesity, with a prior study showing
that peak heart rate, heart rate recovery, and chronotropic index are lower in patients
with obesity, regardless of fitness level [].
6.1.3 Stress ecocardiography
Stress echocardiography is highly feasible in most cases for patients with obesity
through either physiological stress (treadmill exercise) or pharmacological stress
(dobutamine).
However, stress echocardiography is highly operator-dependent and can be
limited in the presence of poor acoustic windows related to pulmonary disease, breast
size, obesity, and respiratory motion. Contrast study in obesity patients is suggested
because the sensitivity is better than without contrast. Contrasted images improved
sensitivity and specificity ( vs and vs. , respectively) [].
6.1.4 PET (positron emission tomography) rubidium
PET rubidium has a sensitivity and specificity and produces less irradia
tion exposure, better quality of images, a greater degree of diagnosis, reduces invasive
examination, and low cardiac death rates in obesity [].
Therefore, PET rubidium is the nuclear imaging technique of choice for patients
with obesity.
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6.1.5 Stress cardiac MRI (magnetic resonance imaging)
Stress cardiac MRI and PET are likely the diagnostic techniques least affected by
obesity.
The presence of ischemia predicted adverse events at years of follow-up, regard
less of whether scar was present. Lack of inducible ischemia is associated with a low
annual major adverse coronary events (MACEs) rate of . at years in patients
with obesity [].
6.1.6 CT calcium score
CAC (coronary artery calcium) is a marker of atherosclerosis that is predictive of
cardiovascular events. This technique offers the possibility of determining the presence and extent of calcified coronary artery plaque. Some studies suggest that waist
circumference (WC) and waist-to-hip ratio (WHR) provide more useful prognostic
information than BMI on the likelihood of elevated CAC. This concept emphasizes
the importance of abdominal obesity and pathophysiology of atherosclerosis [].
6.1.7 Cardiac CT coronary angiography
CT coronary angiography is an alternative for the quantification of calcified or
noncalcified plaque. This approach is useful in specific subset of symptomatic patients
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