Identification of Biomarkers Derived From Adipose Tissue With Potential Utility in the Diagnosis and Prognosis of Cardiovascular Risk of the Obese Patient.
Conditions: Metabolic Syndrome, Diabetes Mellitus, Inflammatory Response
Sponsor: Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado

 
 
 
Medical Unit: Subdirección de Enseñanza e Investigación C.M.N. "November 20” 
 
IDENTIFICATION OF BIOMARKERS DERIVED FROM ADIPOSE TISSUE 
WITH POTENTIAL UTILITY IN THE DIAGNOSIS AND PROGNOSIS OF 
CARDIOVASCULAR RISK OF OBESE PATIENT 
 
DR. JUAN ANTONIO SUAREZ CUENCA, DR. MOISES ORTIZ FERNANDEZ, DRA. JULITA OROZCO 
VÁZQUEZ,  DR. MARIO OSORIO VALERO and DR. ALBERTO MELCHOR LOPEZ.  
 
 
Background 
 
Obesity is a  nutritional disorder that is considered a risk factor for several metabolic 
abnormalities, such as insulin resistance, Diabetes Mellitus type 2 (DM2), NAFLD, 
endothelial dysfunction, cardiovascular risk and is associated with high morbidity and 
mortality. 
According to the panel of experts from the National Heart and Lung Institute of the 
United States, "obesity is a chronic disease that results from the interaction of the 
genotype and the environment." In 1997, the World Health Organization defined obesity 
as "an excess of fat that accumulates in such an amount that health can be adversely 
affected." In Mexico, obesity represents a priority problem for public health, since its 
high frequency places the country in second place of prevalence worldwide. 
A scale to classify obesity is the body mass index (BMI), in which the obese subject is 
one with a BMI ≥ 30kg / m2 and subdivided into 3 classes (Table 1). 
 
Table 1. Body Weight Classification According to the BMI in Adults 
 
BMI 
Normal 
18.5-24.9 kg / m2 
Obese Grade 1 
30-34.9 kg / m2 
Obese Grade 2 
35.0 -39.9 kg / m2 
Obese Grade 3 
≥40 kg / m2  
 
 
 

 
 
Morbid Obesity 
 
Morbid obesity refers to an extreme degree of obesity, which affects basic physiological 
functions and is related to specific risks (Table 2). It has been estimated that a morbid 
obese man reduces his life expectancy by up to 22% compared to an individual of 
normal weight. 
Table 2. Impact on the long-term health of morbid obesity 
Decreased life expectancy  
Dyslipidemia 
Decrease in the quality of life of economic and social opportunities 
Obstructive sleep apnea 
Cardiovascular diseases  
Gastroesophageal reflux disease 
DM2 
Cancer 
Depression 
Osteoarthritis 
Hypertension  
Kidney failure  
 
 
Bariatric Surgery 
Bariatric surgery not only induces weight loss, but also significantly improves the 
covariabilities associated with morbid obesity in those patients accepted. Clinical trials 
and observational studies have shown that bariatric surgery can prolong survival in 
patients with extreme obesity. In fact, the National Institutes of Health of the United 
States recommend bariatric surgery that should be presented with BMI> 40 kg / m2 or> 
35 kg / m2 concomitant related to obesity. 
 
Surgeries to reduce food intake reduce the amount of oral intake through a bag that 
limits the passage of food. It has also been proposed that a) it would induce a sense of 
emergence or suppression of appetite as a mechanism in weight loss; b) compress the 
vagus nerve; c) decreased the secretion of gastrointestinal hormones, such as ghrelin 
or peptide YY. The surgeries that are included in this type are the adjustable gastric 
band and sleeve gastrectomy. 
Hybrid procedures are represented by the gastric Roux-en-Y derivation (DYRG), which 
involves reducing the size of the stomach by 15 ml by resecting the upper stomach 
portion and anastomosing it to the small intestine. The stomach remains viable but the 

 
 
food is derived from the small intestine and the remaining stomach has a lower 
capacity; the duodenum does not absorb the macronutrients responsible for post-
prandial hormonal responses. 
 
Appetite reduction can be partially explained by the YY principle and the glucagon-like 
principle1-3 The duodenum bypass also contributes to decrease the absorption of iron 
and calcium, requiring its supplementation4. The biliopancreatic diversion (BPD) 
involves the resection of the upper 2/3 of the stomach, leaving a stomach capacity of 
250 ml, disconnecting half of the jejunum and ileum from the alimentary tract and 
reconnecting it to the terminal ileum. With the delay in the action of the digestive 
enzymes within the alimentary tract, most of the fat and a significant fraction of the 
proteins is excreted as a result of the decrease in its ingestion. There is a dramatic loss 
in weight, but certain micronutrients are not absorbed, so supplements are required. 
There is a modification of DBP, called "switch" DBP, which consists of a sleeve 
gastrectomy with a less dramatic intestinal derivation. The difference lies in the 
preservation of the pylorus, which leads to fewer complications. 
Postoperative mortality at 30 days ranges from 0.1% to 2% 5-7 and depends on the 
complexity of the operation, the co-morbidities of the patient, the experience of the 
surgeon and the hospital institution. The patient with morbid obesity can be complicated 
early by thromboembolism (1%), respiratory failure (<1%) hemorrhage (1%), peritonitis 
(1%) and / or wound infection (2%). Laparoscopy has been useful in reducing these 
rates. On the other hand, late complications include obstruction, ulcerations, 
hypoglycemia, steatorrhea, and bacterial overgrowth. Dietary modification and 
antibiotics can help control the severity of these side effects. 
 
Bariatric Surgery - Metabolic and Cardiovascular Benefits 
Bariatric surgery offers sustained weight loss. On average, time loses 50% of the weight 
of the 5 years, although this depends on the type, aggressiveness and complexity of the 
surgery. 
Effect on DM2. Up to 50% -60% of patients with DM2 are known as morbidly obese. 
The most relevant clinical impact of surgically induced weight loss is the ability to 
completely reverse DM2 in a large percentage of patients. In a long-term study of 
surgical and conventional therapy, DM2 was reversed in 21% of the control group and 
in 72% of the study group after 2 years of follow-up.55 At 10 years of follow-up, DM2 it 
could be reversed in 13% of the control group and in 36% of the group with surgery. 
The odds ratio on recovery of DM2 with surgery at 2 years was 8.42 (95% confidence 
interval, 5.68 to 12.5) and at 10 years it was 3.45 (95% interval) 
 
 
JUSTIFICATION 
 
Bariatric surgery induces a significant reduction in the co-morbidities associated with 
obesity, such as DM2, dyslipidemia, liver disease, arterial hypertension, obstructive 
sleep apnea and cardiovascular risk. However, this does not happen in all obese 
patients, even when there is a reduction in weight. 
It is known that adipose tissue participates actively in the synthesis of cytokines and its 
constitutive role in metabolic phenotypes has been suggested. It is possible that the 

 
 
intrinsic mechanisms of adipose tissue participate in several benefits observed in 
morbidly obese patients who undergo anti-obesity surgery. Therefore, this study 
explores the participation of adipose tissue, as an active component, that can define 
metabolic phenotypes linked to the modification of cardiovascular risk after bariatric 
surgery. 
 
HYPOTHESIS 
 H1 Metabolic phenotypes based on basic mechanisms of adipose tissue are 
associated to the cardiovascular risk modification after bariatric surgery. 
 
 H0. Metabolic phenotypes based on basic mechanisms of adipose tissue are 
NOT associated to the cardiovascular risk modification after bariatric surgery. 
 
GENERAL OBJETIVE 
To evaluate the association of the cardiovascular benefit of the obese patient after bariatric 
surgery with the basic mechanisms of adipose tissue (metabolic profile) 
 
SPECIFIC OBJECTIVES 
a) Characterize the basal (pre-surgical) metabolic profile of adipose tissue. 
b) Evaluate post-surgical modification of cardiovascular prognosis 
c) Determine the association of the cardiovascular prognosis modification (risk subgroups) with 
the basal metabolic profile. 
 
DESIGN 
 
This is an OBSERVATIONAL study, of a prospective cohort follow-up. We will study morbidly 
obese patients who undergo bariatric surgery (this is not a proposal of the present protocol, it 
is routinely done as a treatment for morbid obesity in the CMN "20 de Noviembre", ISSSTE, and 
it would also be carried out although the patient does not participate in this study). It was 
considered that the independent variable is the change in cardiovascular risk after bariatric 
surgery and the dependent variable is the basal metabolic profile of adipose tissue. This order 
of variables was decided by methodological strategy, since it will be more convenient to 
determine and stratify based on the change in cardiovascular risk, than based on the basal 
metabolic profile of adipose tissue. 
 
where: 
n = sample size.                                                                                                                                                                                    Za/2 = Z-
value of the alpha error with a confidence of 95%, assigning alpha  = 0.05                                                                                       p = 
Expected population prevalence for the event under study (according to previous reports).                                              d 
=difference between the expected population prevalence value and the acceptable error. Considering the average difference in 
the modification of the basic mechanisms in adipose tissue associated with metabolic risk in similar studies 
 
 

 
 
           (1.96)2 (0.20 (1-0.20))                    0.614 
n = ___________________________ n = _________ = 36.3  
                    (0.13) 2                                 0.0169 
Additionally, for reasons of comparison and standardization of results, a C group would 
be considered: 10 non-obese patients undergoing non-bariatric surgery. 
 
Definition of the observation units. 
Patients with morbid obesity subjected to bariatric surgery, with significant modification 
of cardiovascular risk in the postoperative period. 
 
Definition of the control group 
Due to the observational design of the before-after evaluation (of bariatric surgery), the 
morbidly obese patient in the pre-surgical baseline is his own reference ("control") for 
the postoperative period. It is also considered non-obese subjects subjected to 
abdominal surgery eg. Hernioplasty, fundoplication etc. to know the "nomal" metabolic 
profile of adipose tissue. 
 
Inclusion criteria 
• Men and women. 
• Over 18 years. 
• With morbid obesity and candidates for bariatric surgery, under the routine of the 
treating service. 
• Signature of acceptance of your participation, through informed consent. 
 
Exclusion criteria. 
• Medication with potential effect on fatty tissue or cardiovascular risk in the last month. 
• Serious infections in the last month. 
• Clinically unstable conditions. 
 
Elimination criteria. 
• Desire not to continue in the study 
• Samples or insufficient information for an adequate analysis. 
 

 
 
Definition of variables and units of measurement. 
 
 
Definition of variables and units of measurement. 
Variable 
Dependent / 
Independent 
Type 
Units of measurement  
Total body fat, visceral 
and subcutaneous 
Dependent 
Discontinuous 
Quantitative 
Percentage 
Serum markers of 
inflammation PCR and IL-
6 
Dependent 
Quantitative continuous 
μUI / dL  
Serum adipokines: leptin 
and adiponectin  
Dependent 
 Quantitative continuous 
μUI / dL  
Differentiation and 
hypertrophy of 
adipocytes and 
angiogenesis  
Dependent 
Qualitative dichotomous 
Present or absent  
Pro-inflammatory 
markers at tissue level 
Dependent 
Qualitative dichotomous 
Present or absent 
Oxidative stress and 
tissue endoplasmic 
reticulum 
Dependent 
Qualitative dichotomous 
Present or absent 
Insulin sensitivity 
Dependent 
Qualitative dichotomous 
Sensitive or not sensitive 
HOMA 
Dependent 
Qualitative dichotomous 
Higher or lower than 15  
Prognostic scales 
mortality due to 
independent 
cardiovascular cause 
Independent 
Quantitative 
discontinuous  
Own rating 
Flow mediaded dilatation  
Independent 
Quantitative 
discontinuous  
Percentage 
Carotid intima media 
thickness 
Independent 
Quantitative 
discontinuous  
Millimeters 
 
 
 
Selection of sources, methods, techniques and procedures for collecting 
information 
 
With the acceptance of the Institutional Ethics, Research and Biosafety Committees, 
patients will be invited and included according to the selection criteria. 

 
 
Prior signature of informed consent, will include patients with morbid obesity, candidates 
for bariatric surgery and without additional modifiers of adipose tissue metabolism. 
Patients will be chosen in accordance with the criteria of the Bariatric Surgery Service, 
without modifying the routine procedures performed in this service. 
At the same time, a group of non-obese patients (obesity comparison group) scheduled 
and undergoing non-bariatric abdominal surgery (hernioplasty, cholecystectomy, 
appendectomy, etc.) will be included.In all groups, total body fat, subcutaneous and 
visceral fat will be determined non-invasively by computed tomography, with the support 
of the Department of Imaging (Dr. Julita Orozco and Dr. Mario Osorio) as described 
below: 
 
TOMOGRAPHIC MEASUREMENT OF SUBCUTANEOUS AND VISCERAL GREASE 
 
Subcutaneous fat: 
The thickness of adipose tissue will be measured, in the abdominal thickest site, at 
the level of the umbilical scar, with references from the skin to the muscular layer, 
either in vertical measurement (antero-posterior) or in lateral measurement. 
 
 
Visceral fat: 
Epicardial fat: The thickness of the adipose tissue will be measured 
epicardial level, in the thickest site. 
 
Preperitoneal fat:  
The thickness of adipose tissue will be measured, 
level of the umbilical scar; from the muscular layer (vertical measurement or ant-post) 
to the first visceral structure. 
 
Perirenal fat:  
The thickness of adipose tissue will be measured 
perirenal, in the thickest site. 
 
During the surgical act, a sample of 1-2 cubic cm of visceral and subcutaneous 
adipose tissue will be taken, in all groups, considering all aspects of patient Ethics 
and Biosafety described in the respective sections of this project. In patients with 
laboratorial evidence and image of progression to NAFLD, a sample of 1-2 cubic cm 
of liver tissue will be taken, in accordance with international guidelines for diagnosis 
and treatment, and with the study protocol established by the service. It will be 
guaranteed that the taking of biopsies will not affect the course of the surgery. The 
biological samples acquired will be properly identified, contained and stored for a 
maximum period of 1 year. Analysis and determinations will be made according to 
good laboratory practices. Subsequently, they will be treated and disposed of in 
appropriate bags for disposal. To comply with the provisions of section 6 of NOM-
087-ECOL-SSA1-2002 Biological-Infectious Waste. 
To study the characteristics of each metabolic profile, the following variables will be 
analyzed:  
 

 
 
a) Adipose tissue (visceral and subcutaneous) where the degree of differentiation 
and hypertrophy of adipocytes and angiogenesis will be determined by 
morphometric methods of histopathology; as well as markers of inflammation, 
oxidative stress, endoplasmic reticulum stress and adipose tissue dysfunction 
through immunohistochemistry and in vitro tests on isolated adipocytes.  
b) Liver tissue the degree of steatosis, steatohepatitis and fibrogenesis, considered 
as clinical progression of metabolic damage, will be determined. 
c)  Serum level, inflammation markers (TNFa, CRP and IL-6) and adipokines (leptin, 
adiponectin, resistin) will be determined by ELISA. 
 
Finally, in all groups, follow-up variables related to post-surgical modification of 
cardiovascular risk will be determined; through: 
Prognostic scales of cardiovascular mortality: They will be determined by Drs. Moises 
Ortíz and Juan Suárez Cuenca, based on probability calculation with variables such 
as age, gender, co-morbidities, etc. using Framingham or SCORE scales. Place: 
Clinical Research Division, CMN "November 20", ISSSTE. 
Determination of serum markers of endothelial dysfunction and ankle / arm index. 
They will be determined by Dr. Juan Suárez Cuenca and associated researchers, 
using commercially available ELISA kits and direct determination of systolic pressure 
in the ankle and arm, with the help of Doppler scan type Doptone, respectively. 
Place: Biomedical Research Laboratory and Clinical Research Division, CMN 
"November 20", ISSSTE. 
Determination of subclinical atherogenesis (thickness of the carotid intima media). It 
will be determined by the Department of Imaging, with the support of Dr. Toriz. The 
Doppler transducer will be placed in the neck and the common carotid artery will be 
located, then the thickness of the intimal vascular mean will be determined 1 cm from 
the carotid bifurcation. The determination will be made by two observers to estimate 
the inter-observer correlation. Place: Department of Imaging, CMN "November 20", 
ISSSTE. 
 
The determination of these variables of cardiovascular risk modification will be 
determined basally and periodically at 3, 6 and 9 months after bariatric surgery, in all 
groups. 
 
Definition of the processing plan and presentation of the information 
Data analysis will be done through descriptive statistics applied to demographic 
variables, and inferential statistics, which will include difference of averages, 
correlation, strength of association and relative risk, as well as multivariate logistic 
regression analysis to evaluate independent associations. With the variables most 
associated with the modification of cardiovascular risk, a metabolic profile will be 
established as a predictive model of the greatest cardiovascular benefit after bariatric 
surgery. Statistical significance will be considered with p <0.05 
 
ETHICAL CONSIDERATIONS 

 
 
This study is considered as minimal risk. Bariatric surgery (this procedure is not a 
proposal of the present protocol, it is routinely done as a treatment for morbid obesity in 
the CMN "20 de Noviembre", ISSSTE and would also be done if the patient does not 
participate in the study) will be performed according to the routine procedures of the 
Department of Bariatric Surgery. The project complies with the guidelines and 
recommendation of the Declaration of Helsinki. The protocol will be submitted to the 
Ethics and Institutional Research Committee. All patients will be asked to read and sign 
informed consent. 
 
BIOSECURITY CONSIDERATIONS. 
Bariatric surgery procedures are not part of this investigation. In any case, it is 
emphasized that this project does not alter the surgical procedure and routine 
biosecurity measures, which are based on the best clinical practice and international 
recommendations (Neff KJ, le Roux CW, Bariatric surgery: a best practice article. Pathol 
2013; 66: 90-8). Sampling during surgery will be done in accordance with the 
Regulation of the General Health Law on Health Research, respecting aspects of taking 
the appropriate measures to avoid any risk or damage to research subjects (includes 
adequate preoperative assessment). , biosecurity measures typical of an operating 
room and sampling by an experienced surgeon). In any case, the privacy of the 
individual subject of the investigation will be protected, and it will be sought to limit the 
likelihood that the subject will suffer any harm as a result of the study. 
The biological samples acquired will be properly identified, contained and stored for a 
maximum period of 1 year. Your analysis and determinations will be made according to 
good laboratory practices. Subsequently, they will be treated and disposed of in 
appropriate bags for disposal. To comply with the provisions of section 6 of NOM-087-
ECOL-SSA1-2002 Biological-Infectious Waste. 
The research is considered to be of minimal risk, since it is a common procedure with 
obtaining a minimum sample of visceral and subcutaneous adipose tissue. Likewise, the 
principal investigator will suspend the investigation upon noticing any risk or damage to 
the health of the subject in whom the investigation is carried out. All participants will 
read, understand and sign an informed consent. 
 
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