1 high cholesterol, high blood pressure and raised

1       Introduction/Background of Study

diseases (NCDs) are diseases of long duration and generally slow progression.
The four main types of NCDs include cardiovascular diseases, cancer, chronic
respiratory diseases and diabetes. NCDs are by far the leading cause of death
in the world, representing 70% of all annual deaths that kill 40 million people
each year (WHO, 2017).

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In Malaysia, NCDs has contributed to an estimated 73% of total deaths
with cardiovascular diseases as the biggest contributor. An estimated 35% of
deaths occur in individuals aged less than 60 years old. According to the Second
Burden of Disease Study for Malaysia, published by the Institute for Public Health in 2012,
hypertension, diabetes, high cholesterol and
high Body Mass Index (BMI) are ranked as the biggest contributors to both Disability-Adjusted
Life Years (DALY) and deaths.

Previous data from National Health & Morbidity Survey (NHMS) showed
an increasing trend for all NCDs risk factors. An analysis of NHMS 2011 showed
that at least 63% of adults aged 18 years and above had at least one NCDs risk
factor (either overweight/obesity, high blood cholesterol, high blood pressure
or high blood sugar) (Institute for Public Health, 2015). This increasing trend is due to rapid ageing of the Malaysian
population, accompanied by changing lifestyles, nutritional transition (to high
calorie, low nutrition food), and declining physical activity (Atun, Berman, Hsiao, Myers, & Wei,

Metabolic Syndrome or insulin resistance syndrome is characterized by a
constellation of cardiovascular risk factors including abdominal obesity, high cholesterol,
high blood pressure and raised plasma glucose. It is approximated that around
20-25 % of the world’s adult population have metabolic syndrome and they are
twice as likely to die from and three times as prone to have myocardial
infarction (MI) or stroke in contrast to individuals without the syndrome (S. G. Alberti, Zimmet, Shaw, & Scott
M. Grundy, 2006). In Malaysia, metabolic syndrome is common where the prevalence of
metabolic syndrome in adult Malaysian is reported as high as 37.1% (Dr. Lim, C.H.,2016).

Metabolic syndrome is associated with a pro-inflammatory state, and the
role of visceral fat is thought to be central to this. Visceral fat leads to
alteration of the normal physiological balance of adipokines, insulin
resistance, endothelial dysfunction and a pro-atherogenic state (Ritchie & Connell, 2007).

Visceral adipose tissue (VAT) is closely related with adverse cardio metabolic
risk profile and is also known to be a strong predictive factor for severe
metabolic complications in adults. Consequently, the prevalence of the
metabolic syndrome is worrisome of the future increase of cardiovascular

To our knowledge, the association of visceral fat quantity with cardiovascular
risk factors has never been investigated among Malaysian population with metabolic
syndrome. Therefore, we sought to understand this condition in order to provide
better management to treatment plan for the patient.



Figure 1: Cardiovascular disease is the leading cause of death among
NCDs in Malaysia

Source: World Health Organization – Noncommunicable
Diseases (NCD) Country Profiles , 2014




2        Literature Review

2.1     Visceral Fat

Visceral fat which is also known as extra subcutaneous
fat or deep fat is stored within the abdominal cavity (Visceral Fat, 2018). It
is deposited around the vital body organs such as heart and abdominal organs due
to the extra intake of carbohydrate-rich foods, fewer exercises, and other
metabolic imbalances. 

The key
difference between the visceral fat and the subcutaneous fat is the
site of deposition. Visceral fat
is deposited around the vital organs whereas subcutaneous fat is deposited
under the skin (Samanthi, 2017).

Figure 2: White adipose distribution in the
body. White adipose falls under two major classifications: visceral, or
surrounding organs, and subcutaneous, under the skin. 

Source: Cook, A. and Cowan, C., Adipose (March 31, 2009)

Excess visceral fat is a central factor in the
pathogenesis of metabolic syndrome. It is the strongest risk for cardio metabolic
diseases compared to epicardial and subcutaneous fat (Sato et al.,
2017). An additional 500 increase in fat volume was associated in
higher incidence of metabolic syndrome. Most associations remained significant
even after additional adjustment for BMI change, waist circumference change, or
respective abdominal adipose tissue volumes (p ? 0.001) (Lee, Pedley,
Hoffmann, Massaro, & Fox, 2016).  

Obese individuals are at increased risk of
developing cardiovascular disease as a consequence of adipose tissue expansion
and subsequent dysfunction. In particular, the expansion of VAT is an
independent risk factor for cardiovascular morbidity and mortality. VAT
expansion results in local inflammation, characterized by hypertrophic
adipocytes and increased influx of proinflammatory macrophages and cytotoxic T
cells, contributing to elevated plasma levels of interleukin-6 (IL-6) and high
sensitive C-reactive protein (hsCRP). At the same time, expression of the
anti-inflammatory adipokine adiponectin is downregulated in adipocytes. The
inflammation leads to metabolic complications that predispose to the
development of CVD, including insulin resistance and development of the
metabolic syndrome and type 2 diabetes.

In 1012 patients with clinically manifest
vascular disease, visceral fat thickness was measured ultrasonographically. The
results showed that the average age of patients was 59 ± 10 years and 79% were
males. In total 18% of the patients was obese. Mean VAT thickness and waist
circumference (WC) were higher in males than females. Out of 51% of the
patients had metabolic syndrome, defined by the Adult Treatment Panel (ATP) III
criteria, there are 36% had central obesity, 94% were hypertensive, 39% had
hypertriglyceridemia, 29% had low HDL cholesterol levels and 63% had an
impaired fasting glucose (Kranendonk et
al., 2014).

Besides adults, there is statistically
significant associations of visceral fat and risk factors for metabolic
syndrome in children and adolescents. Adolescence is a time of emergence for
cardio metabolic disease, with metabolic syndrome occurring in 4% of all
adolescents and 28% of overweight adolescents. Adolescent cardio metabolic
health has been shown to predict cardiovascular health in adulthood  (Schwartz et
al., 2013). Visceral fat was found to be independently
associated with blood pressure (BP), blood triglyceride, blood high density
lipoprotein cholesterol (HDL-C) and fasting blood glucose (FBG). Thus,
screening tests for BP, cholesterol, fasting glucose and WC should be given in
clinics for children and adolescents so that metabolic syndrome can be detected
and its risk factors treated early (Kwon et al.,



2.2     Systems to Measure Visceral

There are many methods of measuring body
composition including hydrostatic weighing, skin fold thickness (SKF), air
displacement plethysmography (ADP) and dual-energy x-ray absorptiometry (DEXA).
However, all these methods are more expensive, require specific equipment and
training. Besides that, they are time consuming to use.  Overweight and obesity rates are rising fast
enough that practical, inexpensive, valid and reliable methods to track changes
in body composition are in high demand.

BIA is a method that is easy to use, non-invasive, inexpensive,
non-time consuming, reproducible and portable. It provides valid estimation of total body
water (TBW) and fat free mass (FFM) and thus can estimate percent body fat
(%BF) (Peterson,
Repovich, Eash, Notrica, & Hill, 2007). BIA is based on the principle of resistance
to the ?ow of electrical current due to differences in water content of fat and
lean tissue. Lean tissue contains large amounts of water and electrolytes and
is a good conductor of electrical current. On the other hand, fat tissue is
anhydrous and a poor conductor. Therefore, the larger the fat tissue, the
higher the resistance to electrical current and the higher the adiposity (Rutherford,
Diemer, & Eric D. Scott, 2010) .Some researchers recommend that BIA may be
a useful measurement tool for clinical and public health settings suggesting it
can be reliable to show percent body fat change over time.

In the current study, SKF had the highest
correlation but it cannot be done alone and require a skilled technician for
validity and reliability while BIA measures can be done alone. For reliability
when using SKF, the same technician should complete each measurement. If this
is not possible when repeated measurements are required, then BIA might still
be a better option (Peterson et
al., 2007).

Although performance of abdominal BIA in predicting
the metabolic syndrome is weak but it may be used in the follow-up of patients
with obesity and/or metabolic syndrome (Mousa et al.,




2.3     Cardiovascular Disease Risk

Cardiovascular disease risk factors are
divided into modifiable and non-modifiable risk factors. Among the modifiable
risk factors include hypertension, dyslipidaemia, diabetes mellitus and cardio
metabolic risk.

Epidemiological studies have shown that cardiovascular
risk rises as BP levels increases, starting at ?115/75 mmHg. The report on the
Global Burden of Disease 2015 states that there is about 54% of stroke worldwide
and coronary heart disease (CHD) were attributable to hypertension. It is a
major cause of deaths at about 20% and disability. In the Asia Pacific region,
up to 66% of some subtypes of cardiovascular disease can be attributed to
hypertension. Reduction in BP has consistently shown a reduction in
cardiovascular events in both primary and secondary prevention.

There is an association between elevated triglyceride
(TC), low density lipoprotein cholesterol (LDL- C) levels and cardiovascular
disease. Randomized controlled trials have shown that by lowering TC and LDL-C
levels, cardiovascular events and cardiovascular mortality can be reduced.

More than 70% of patients with type 2 diabetes
died of cardiovascular causes. Women with diabetes are 44% more likely to
develop CHD than men. They are also 50% more likely to have fatal CHD than men.
Cardiovascular risk in individuals who have diabetes of long duration (>10
years) is similar as in those with a prior cardiovascular event (MOH, 2017).


2.4     Prevalence of Cardiovascular Disease Risk
Factors in Malaysia

Cardiovascular disease is the main cause of global
mortality and a major contributor to disease related disability. In Malaysia,
cardiovascular has been the leading cause of morbidity and mortality for more
than a decade.

The Malaysian adult
population (?18 years) has high levels of cardiovascular risk factors. 63.6% of
men, and 64.5% of women are either overweight or obese. 43.5% of men, and 52.2%
of women have hypercholesterolemia. 30.8% of men, and 29.7% of women have
hypertension. 16.7% of men, and 18.3% of women have diabetes mellitus.


Data from NHMS V 2015
showed that the prevalence of these cardiovascular risk factors begin to
increase from the age of 30 years. The projected adult population (?18 years of
age) in this country for 2016, stands at 21.5 million, with 11 million men and
10.5 million women.

Clustering of these four
cardiovascular risk factors is common where 43.2% will had at least 2 of the
risk factors stated above. In the INTERHEART study, these 4 modifiable risk
factors (abnormal lipids, hypertension, diabetes and abdominal obesity)
contributed to about 80% of myocardial infarcts (MI) (MOH, 2017).


2.5     Metabolic Syndrome Criteria

Metabolic syndrome is one of a cluster of metabolic
risk factors that include central obesity, hyperglycaemia/ glucose intolerance,
hypertension, low HDL cholesterol levels, and high triglyceride levels.

The criteria for the definition of metabolic
syndrome are variable, since there are different definitions of metabolic
syndrome, depending on the respective health organizations, such as the World
Health Organization (WHO), the National Cholesterol Education Program Expert
Panel (NCEP) and Adult Treatment Panel III (ATP III), the International
Diabetes Federation (IDF) and the American Heart Association/National Heart,
Lung, and Blood Institute (AHA/NHLBI)  (Sulistiowati
& Sihombing, 2016).

WHO emphasized insulin resistance as the major
underlying risk factor and required evidence of insulin resistance for
diagnosis. ATP III criteria did not require
demonstration of insulin resistance. Instead, ATP III made the presence of 3 of
the following 5 factors the basis for establishing the diagnosis: abdominal
obesity (which is highly correlated with insulin resistance), elevated
triglyceride, reduced high-density lipoprotein cholesterol, elevated blood
pressure, and elevated fasting glucose (impaired fasting glucose or type 2
diabetes mellitus). In the absence of cardiovascular disease or diabetes, the
metabolic syndrome is a predictor of these conditions. Once cardiovascular
disease or diabetes develops, the metabolic syndrome is often present. The IDF
dropped the WHO requirement for insulin resistance but made abdominal obesity
necessary as 1 of 5 factors required in the diagnosis, with particular emphasis
on waist measurement as a simple screening tool. The AHA/NHLBI slightly modified
the ATP III criteria but did not mandate abdominal obesity as a required risk
factor. The remaining 4 risk factors were identical in definition to those of
the IDF. Recently, IDF and AHA/NHLBI representatives held discussions to
attempt to resolve the remaining differences between definitions of metabolic
syndrome. Both sides agreed that
abdominal obesity should not be a prerequisite for diagnosis but that it is 1
of 5 criteria, so that the presence of any 3 of 5 risk factors constitutes a
diagnosis of metabolic syndrome. Waist measurement should not be an obligatory
component but is recommended to continue to be a useful preliminary screening
tool (K. G. M. M.
Alberti et al., 2009).

In a study conducted in Kuala Lumpur, Malaysia, a
total of 1494 Malay employees participated in the study. Metabolic Syndrome was
diagnosed in 618 (41.4%) and 571 (38.2%) participants using the modified NCEP
and IDF criteria respectively. Participants who
were missed by the IDF criteria were mainly males (76.6%). However, there were no
participants who were diagnosed by IDF but missed by the modified NCEP
criteria. Metabolic Syndrome was highest among those aged 40- 49 years,
followed by those aged 50-59 years. The prevalence among those aged 60 years
and older was the lowest among all age groups. About 11% of the
participants diagnosed with Metabolic Syndrome were diabetics while 18% were
hypertensive. The study concluded that modified NCEP ATP
III criteria may be more
suitable in diagnosing Metabolic Syndrome in this cohort.

According to the definition provided by the modified
NCEP ATP III, for a person to be defined as having the metabolic syndrome, they
must have any three of the following five factors: abdominal obesity, hypertriglyceridemia (triglycerides ?1.7 mmol/L); low
HDL cholesterol (HDL cholesterol ?1.03 mmol/L for men and ?1.29 mmol/L for
women); elevated blood pressure (systolic blood pressure ?130 mmHg and/or
diastolic blood pressure ?85 mmHg or current use of antihypertensive drugs);
impaired fasting glucose (fasting plasma glucose ?5.6 mmol/L). The modified
NCEP ATP III criteria suggested the cut-off points of waist circumference
should be ethnic specific where individuals of Asian origin should use the
cut-off of 90 cm in men and 80 cm in women. For NCEP criteria, abdominal
obesity is a component of the syndrome but not a prerequisite for its diagnosis
(Moy &
Bulgiba, 2010).



2.6     Prevalence of Metabolic
Syndrome in Malaysia

Abdominal obesity showed the highest prevalence of
individual risk factors for metabolic syndrome based on IDF and Harmonized
criteria among Malaysian adults at 57.4% It was significantly higher in females
(64.2%), increased with age, and was highest in the Indian population (68.8%). Hypertension
was more prevalent in males than females (56.5% versus 50.0%), increased
significantly with age, and was highest in the Malay population (52.2%).
Elevated TG was most prevalent in the Chinese population (47.4%). It was also
noted that the prevalence of dyslipidaemia was higher in subjects from urban
areas, while hypertension was more prevalent in those from rural areas (Mohamud et
al., 2012)

There were four components identified for both men
and women i.e. anthropometric measurements, blood pressure, glycaemia and
dyslipidaemia. In anthropometric measures, BMI had the highest factor loading of
all 4 measurements. BMI is known to be related to insulin resistance, although
waist hip ratio explained more on central obesity. Women were found to have
higher BMI and hip circumference compared to men. However, other anthropometric
parameters, i.e. waist and neck circumference and waist –hip ratio were higher
in men. Men also found to have higher blood pressure reading. There are no significant
different of glucose and insulin parameters between both sexes (Azwany,
Mohamad, Bebakar, M, & Ismail, 2011)


3       Problem Statement

syndrome is not a disease but a cluster of metabolic
abnormalities that increased the likelihood of developing cardiovascular
disease. Metabolic syndrome is associated with a pro-inflammatory state, and
the role of visceral fat is thought to be central to this (Ritchie & Connell, 2007). In Malaysia, cardiovascular disease is the biggest contributor to the
total death of NCDs at 36% (WHO, 2014). The prevalence of metabolic syndrome in
adult Malaysian is reported as high as 37.1% (Dr. Lim, C.H.,2016). Therefore, this study is to
explore the degree to which the quantity of visceral fat is associated with
changes in cardiovascular risk factors such as metabolic syndrome. A healthy
group will be used as the control group for comparison be made to those with
existing metabolic syndrome.

4       Study Aim & Justification

purpose of this study is to investigate the association of visceral fat quantity with cardiovascular disease risk factors among Malaysian population with metabolic syndrome. The effect of
visceral fat quantity on metabolic syndrome has never been investigated among
Malaysian population and requires further studies.


5       Significance/Rational
of the study

The findings of the study will help to combat cardiovascular disease
which is the number one killer in Malaysia by serving an evidence-based
platform. If the results show that metabolic syndrome subgroup has higher
quantity of visceral fat as compared to healthy group, then Malaysian
population should be caution with their visceral fat quantity and take
prevention measures. This study can help
to provide further knowledge among Malaysian population as well as healthcare
provider to take primary prevention to intervene and overcome cardiovascular disease.


6       Objectives


6.1     Main

study the association of visceral fat quantity with changes in cardiovascular disease risk
factors such as metabolic syndrome in Malaysian population.


6.2     Specific Objectives

1.      To measure the quantity of visceral fat using
Bioelectrical Impedance Analysis (BIA).

2.      To compare the quantity of visceral fat
between individual with metabolic syndrome and healthy group.



7       Methodology

7.1     Study Design and setting

The study will be conducted as cross-sectional study
from 1st June 2018 to 31st December 2018 (7 months) in the medical
clinics of Hospital Serdang. A healthy group from the staffs of Hospital
Serdang will be used as the control group for comparison be made to those with
metabolic syndrome. 


7.2     Patient Selection

The following are inclusion and exclusion criteria for
individual eligible to be included in this study.


Inclusion criteria:

Any individual age 18 and
above with either three of the following criteria: abdominal obesity, raised
triglycerides, reduced HDL cholesterol, raised blood pressure or raised fasting
plasma glucose.


7.2.2      Exclusion criteria:

Any individual who is
currently a smoker

Any individual who eat/drink
2 hours before testing

Any individual who drink
alcohol 24 hours before testing

Any individual who take
caffeine 24 hours before testing

Any individual who
participate in moderate or vigorous exercise for 24 hours before testing

Any individual with
chronic kidney disease

Pregnant women

Cancer patient


7.3    Sampling
method & Sample size calculation                                                                                                          

Sample size is calculated using Cochran’s formula:

n =


n = Sample size

Z = Statistic for level of confidence (e.g.: 1.96 for 95% confidence

P = Expected prevalence (0.5 used for sample size needed)

d = precision (margin of error is 0.05)


Sample Size =  

                = 384.16


Corrected sample size for finite population:

New Sample Size =


                        = 131.75

                               ? 132 participants


7.4     Tools
and materials

7.4.1    Data Collection form

A self-structured data collection form (APPENDIX 1) will be used during
the data collection period to record the details from every subject. Patients’
demographic data and risk factors will be
obtained. This study will also evaluate the clinical aspects involving BMI, waist circumference, visceral fat quantity,
total cholesterol, fasting blood glucose and blood pressure. Every study population will have to undergo
these clinical measurements in order to access the criteria of modified NCEP
ATP III for metabolic syndrome.


7.4.2   Data

All statistical analyses will be performed using Statistical Package for
Social Sciences (SPSS) Version 23.0. The percentage of metabolic syndrome will
be analysed based on descriptive analyses such as mean of different age group,
mean of both genders, mean of different ethnicity, mean of visceral fat
quantity. T-test or Mann-Whitney test will be used to measure the effect of
visceral fat quantity on metabolic syndrome. Chi-square or Fischer’s exact test
will be used to compare between healthy group and metabolic syndrome subgroup.
The association between visceral fat quantity and cardiovascular risk factors
will be analysed using Pearson or Spearman’s test. The variable in this study
is the quantity of visceral fat. P value less than 0.05 is considered
statistically significant.


8       Ethical
approval of the study

All aspects of the study protocol will be reviewed and authorized by National
Medical Research Register (NMRR) and Clinical Research Centre (CRC) Hospital



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