articulo 3 equipo 4 genomica

8/13/2019 Articulo 3 Equipo 4 Genomica

1/10

O R I G I N A L A R T I C L E

Leptin, leptin gene and leptin receptor gene polymorphismin heart failure with preserved ejection fraction

Tarek A. Abd El-Aziz Randa H. Mohamed

Rasha H. Mohamed Heba F. Pasha

Received: 5 January 2011 / Accepted: 15 April 2011/ Published online: 17 May 2011

Springer 2011

Abstract Heart failure with a normal ejection fraction

(HFNEF) is common in obesity and coronary artery disease(CAD). Both ischemia and reperfusion induce leptin (LEP)

and leptin receptor (LEPR) gene expression. We aimed to

investigate the possible associations of serum leptin, leptin

gene and leptin receptor gene polymorphism with HFNEF

in patients with CAD. 100 Egyptian CAD patients with

HFNEF and 100 healthy subjects (the control group) were

genotyped for LEP and LEPR polymorphism. Leptin levels

were measured. Serum leptin levels were significantly

increased in patients compared to the control group. There

was a significant increase in the leptin gene (AA genotype)

and the leptin receptor gene (RR genotype) in HFNEF

patients compared to the control group. Leptin levels,

leptin gene (AA genotype) and LEPR (RR genotype) were

more associated with NYHA III than with NYHA I and II.

We thus concluded that HFNEF is associated with

increased serum leptin levels, and the LEP AA genotype or

LEPR RR genotype carries at least a threefold increased

risk of developing HFNEF.

Keywords Leptin Leptin receptor Polymorphism

Heart failure

Introduction

Nearly half of all patients with symptoms of heart failure

are found to have a normal left ventricular ejection frac-

tion. Such cases have been termed heart failure with a

normal ejection fraction (HFNEF) [1].

In a revealing study, Caruana et al. [2] found that one-

third of their patients who had HFNEF were obese, and one

half of them showed reduced respiratory function, while

many presented evidence of myocardial infarction or

ischemia.

Although the mechanisms for HFNEF are still not

completely understood, diastolic dysfunction is thought to

play a role. Another factor that may contribute to HFNEF

pathophysiology is abnormal ventriculararterial interac-

tion due to the stiffening of both systems [3].

Leptin has been demonstrated to regulate a variety of

cardiac and vascular effects, which include angiogenesis,

thrombosis, hemodynamics, and cardiac hypertrophy [4].

Both ischemia and reperfusion induce leptin (LEP) and

leptin receptor gene (LEPR) expression [5].

The leptin gene is located on chromosome 7q31.3 and

consists of three exons separated by two introns; it

expresses a 4.5 kb messenger RNA (mRNA) in adipose

tissue [6]. In humans, several polymorphisms have been

identified for the LEP G to A substitution at 2548 upstream

of the ATG start site in the LEP gene 5 0 promoter region [7].

Leptin exerts its physiological action through the LEPR.

LEPR was initially identified in the brain, which explains

its negative feedback mechanism for controlling food

intake and body weight [8]. However, the presence of the

T. A. Abd El-Aziz (&)Cardiology Department, Faculty of Medicine,

Zagazig University, 28-El-Galaa Street, Zagazig, Egypt

e-mail: [email protected]

R. H. Mohamed H. F. Pasha

Medical Biochemistry Department, Faculty of Medicine,

Zagazig University, Zagazig, Egypt

e-mail: [email protected]

R. H. Mohamed

Biochemistry Department, Faculty of Pharmacy,

Zagazig University, Zagazig, Egypt

1 3

Heart Vessels (2012) 27:271279

DOI 10.1007/s00380-011-0152-2
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


2/10


3/10

conditions used with the thermal cycler were as follows:

94C for 5 min, followed by 35 cycles at 94C for 30 s,

52C for 45 s and 72C for 45 s. A final extension step was

carried out at 72C for 5 min.

The PCR products (80 bp) were electrophoresed on a

3% agarose gel containing ethidium bromide to monitor

amplification and possible contamination. The 80 bp PCR

products were digested with MspI and analyzed on 4%agarose gels because of the small size of the DNA prod-

ucts. The presence of the MspI site was indicated by the

cleavage of the amplified product into two fragments of 57

and 23 bp. The two allelic forms of LEPR, corresponding

to the absence or the presence of the MspI site, are referred

to as 223Q and 223R, respectively. Quality control mea-

sures included blinded analyses and replicates of 10% of

the samples; also, positive controls (blood-derived DNA

from all known genotypes) and negative controls for con-

tamination (no DNA) were run routinely with patient

samples.

Echocardiography

A complete echocardiographic examination following a

standard protocolincluding a two-dimensional analysis

and the assessment of established Doppler parameters that

are commonly used to evaluate cardiac diastolic function

was performed. All of the examinations and measurements

were conducted using a Hewlett Packard (Anaheim, CA,

USA) Sonos 5500 with 2.5 MHz transducer. Two-dimen-

sional apical four- and two-chamber views were used to

calculate the left atrial volume (LAV) by the biplane area

length method and the left ventricular EF using the biplane

Simpson method.

Cardiac catheterization

All patients underwent left heart catheterization through

the femoral approach. LVEDP was measured using a 7Fr

pigtail fluid-filled catheter before angiography.

Statistical analysis

The results for continuous variables are expressed as the

mean SD. The means of the three genotype groups

were compared in a one-way analysis of variance.

Genotype frequencies in cases and controls were tested

for HardyWeinberg equilibrium, and any deviation

between the observed and expected frequencies was tested

for significance using the chi-square (v2) test. The cor-

relation coefficients were calculated using Spearman

correlation. The statistical significances of differences in

the frequencies of variants between the groups were tested

using the v2 test. In addition, the odds ratios (ORs) and

95% CIs were calculated as a measure of the association

of the LEP and LEPR genotypes with HFNEF. Multiple

regression analysis was performed, adjusted for clinical

variables (e.g., age, sex, history of hypertension, history

of diabetes, smoking, total cholesterol, triglycerides,

HDL, LDL). A difference was considered significant at

P\ 0.05. All data were evaluated using SPSS version

10.0 for Windows.

Results

Clinical characteristics of the study subjects

Levels of total cholesterol, triglycerides, LDL cholesterol

and leptin were significantly increased in HFNEF patients

compared to the control group (Table1). Furthermore,

levels of HDL cholesterol were significantly decreased in

HFNEF patients compared to the control group.

LEP and LEPR polymorphisms: genotype and allele

distributions

In the HFNEF group, the frequency of the LEPR RR

genotype was significantly increased compared to the

control group (17% versus 6%, P = 0.007) (Table2).

Subjects with the LEPR-RR genotype were significantly

more likely to develop HFNEF (OR = 3.7, 95%

CI = 1.410.3, P = 0.007). The frequency of the R allele

was also significantly increased in the HFNEF group

compared to the control group (36 vs 23%, P\ 0.001).

Carriers of the R allele were significantly more likely

to develop HFNEF (OR = 8.6, 95% CI = 4.516.2,

P\ 0.001). In the HFNEF group, the frequency of the LEP

AA genotype was significantly increased compared to

the control group (14 vs. 4%, P = 0.02). Subjects with the

LEP AA genotype were significantly more likely to develop

HFNEF (OR = 3.9, 95% CI = 1.212.6, P = 0.02).

In NYHA III patients, the frequency of the LEPR RR

genotype was significantly increased compared to NYHA I

and II patients (40 vs. 12.5%, P\ 0.001). Subjects with the

LEPR-RR genotype were significantly more likely to have

NYHA III (OR = 8.3, 95% CI= 3.718.6, P\ 0.001).

Frequencies of the R allele were significantly increased in

NYHA III patients compared to NYHA I and II (60 vs

29.38%), resulting in a significantly increased OR of sub-

jects bearing the R allele having NYHA III (OR = 3.6,

95% CI = 1.77.3, P \ 0.001). In patients with NYHA III,

the frequency of the LEP AA genotype was significantly

increased compared to NYHA I and II (40 vs. 11.25%,

P\ 0.001). Subjects with the LEP AA genotype were

significantly more likely to have NYHA III (OR = 7, 95%

CI = 3.215.6, P\ 0.001). The frequency of the A allele

Heart Vessels (2012) 27:271279 273

1 3
http://-/?-http://-/?-http://-/?-http://-/?-


4/10

was significantly increased in the NYHA III group com-

pared to the NYHA I and II groups (55 vs. 26.9%,

P\ 0.001), resulting in a significantly increased OR of

subjects bearing the A allele having NYHA III (OR = 3.9,

95% CI = 1.98, P\ 0.001) (Table3).

Association between LEP and LEPR polymorphism

genotypes and the clinical characteristics

of the study subjects

Levels of total cholesterol, triglycerides, and leptin were

significantly higher in LEP AA than in LEP GG (Table 4).Levels of HDL cholesterol were significantly lower in LEP

AA than in LEP GG. Also, levels of total cholesterol, tri-

glycerides, LDL cholesterol and leptin were significantly

higher in LEPR RR than in LEPR QQ. Levels of HDL

cholesterol were significantly lower in LEPR RR than in

LEPR QQ.

Leptin levels and LVEDP values according

to the NYHA classification

Leptin levels and LVEDP values were significantly

increased in NYHA III compared to NYHA I and II

(Table5).

Association of the study participants characteristics

with the severity of HFNEF

The difference in NYHA was tested for independence from

other variables by multiple regression analysis. The dif-

ference in NYHA was found to be dependent on leptin

(P = 0.001), triglycerides (P = 0.01), HDL (P = 0.02),

Table 1 Clinical, biochemical, and echocardiographic characteristics

of the study participants

Parameter (n) Controls

(100)

HFNEF

(100)

P

Age (years) 50.7 9.5 55.5 8.1

Sex (male/female) 72/28 74/26

Hypertension 57Systolic blood pressure

(mmHg)

120 13.8 143 22 \0.001

Diastolic blood pressure

(mmHg)

74 8 84 11 \0.001

Diabetes 41

Body mass index (kg/m2) 25.7 2 26.2 1.9 [0.05

Cholesterol (mg/dl) 185.9 8.4 240.5 27.4 \0.001

Triglycerides (mg/dl) 132 14.4 175.7 13.9 \0.001

HDL (mg/dl) 54.7 3.2 41.8 4.2 \0.001

LDL (mg/dl) 106.2 6.2 163.3 26.6 \0.001

Leptin (ng/ml) 15.7 3.3 26.1 6.2 \0.001

Echocardiography

Left atrial volume (ml/m2) 27.2 2.9 49.3 20.6 \0.001

Ejection fraction (%) 68.5 6.4 60.3 7.6 \0.001

Trans-mitral flow

Mitral Evelocity (cm/s) 80.2 8.3 51.3 11.5 \0.001

Mitral A velocity (cm/s) 64.6 12.8 73.8 11.1 \0.001

E/A ratio 1.3 0.096 0.67 0.095 \0.001

Deceleration time (ms) 183.7 15.5 255 58.9 \0.001

E/E0 ratio 9.6 1.03 16.1 1.1 \0.001

E Early diastolic LV filling velocity, A late diastolic LV filling

velocity, E0 early diastolic myocardial velocity

Table 2 Distribution frequencies of the genotypes and alleles of the

LEPR and LEP polymorphisms in the patients and controls

Gene Controls (100) HFNEF (100) OR 95% CI P

n % n %

LEPR Q223R

Q/Q 60 60 45 45 1

Q/R 34 34 38 38 0.67 0.41.2 0.2

R/R 6, 6 17 17 3.7 1.410.3 0.007

R allele 46 23 72 36 8.6 4.516.2 \

0.001LEP G2548A

G/G 56 56 50 50 1

G/A 40 40 36* 36 1.01 0.61.8 0.9

A/A 4*,# 4 14* 14 3.9 1.212.6 0.02

A allele 48 24 64 32 1.5 0.92.6 0.095

Significant difference from QQ

Significant difference from QR

*Significant difference from GG# Significant difference from GA

Table 3 Distribution frequencies of the genotypes and alleles of the

LEPR and LEP polymorphisms in the patients, as classified according

to the NYHA classification

Gene NYHA I and II

(80)

NYHA III

(20)

OR 95% CI P

n % n %

LEPR Q223RQ/Q 43 53.75 4 20 1

Q/R 27 33.75 8 40 3.2 (1.66.3) 0.001

R/R 10 12.5 8 40 8.3 (3.718.6) \0.001

R allele 47 29.38 24 60 3.6 (1.77.3) \0.001

LEP G2548A

G/G 46 57.5 6 30 1

G/A 25 31.25 6 30 0.5 (0.31) 0.06

A/A 9 11.25 8 40 7 (3.215.6) \0.001

A allele 43 26.9 22 55 3.9 (1.98) \0.001

274 Heart Vessels (2012) 27:271279

1 3
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


5/10

and LEP G2548A gene polymorphism (P = 0.03)

(Table6).

Correlation between leptin levels

and lipid profile parameters

Leptin had significant positive correlations with total cho-

lesterol, triglycerides and LDL cholesterol, and a signifi-

cant negative correlation with HDL cholesterol (Table7).

Association of the study participants characteristics

with leptin as well as LEP and LEPR polymorphisms

The leptin level was tested for independence from other

variables by multiple regression analysis (Table 8). The

leptin level was found to be dependent on LEP G2548A

polymorphism.

Discussion

Association of leptin with HFNEF

The novel finding from this study is that in Egyptian CAD

patients who had heart failure with a normal ejection

fraction, serum leptin levels were significantly increased

compared to the control group. Moreover, leptin levels and

LVEDP were related to exercise intolerance. They showed

Table 4 Characteristics of the study participants, classified according to the LEPR and LEP genotypes

LEPR Q223R LEP G2548A

Genotype (n) Q/Q (105) Q/R (72) R/R (23) G/G (106) G/A (76) A/A (18)

Hypertension, n (%) 29 (27.6) 31 (43) 14 (60.8) 28 (26.4) 38 (50) 110 (55.6)

Diabetes, n (%) 25 (23.8) 19 (26.4) 9 (39.1) 24 (22.6) 21 (27.6) 8 (44.4)

Cholesterol (mg/dl) 217 34 219 35 239 37, 217 33 222 38 233 36*

Triglycerides (mg/dl) 152 26 162 18 185 20, 154 25 161 22 184 21*,#

HDL (mg/dl) 47 7.8 49 6.4 41 6.3, 46 7.3 49 7* 41 6.8*,#

LDL (mg/dl) 139 34 140 35 161 39,

142 38 140 33 155 39

Leptin (ng/ml) 19 5.5 22.7 5.1 33 5.9,

18.9 5.5 23.6 5.2* 33.7 6.4*,#

Significant difference from QQ

Significant difference from QR

*Significant difference from GG# Significant difference from GA

Table 5 Mean leptin levels and LVEDP in patients classified

according to the NYHA classification

NYHA I (23) NYHA II (57) NYHA III (20)

Leptin 26.4 5 24.4 5.2 30.9 7.1

LVEDP 17.2 1.9 20.7 4.7 26.4 5.6

Significant difference from NYHA III

Table 6 Association of the

study participants

characteristics with the severity

of HFNEF

Variable Unstandardized coefficients Standardized

coefficients

95% CI t P

B SE b

Age 3.02 9 10-3 0.003 0.055 -0.003 to 0.009 0.97 0.34

Sex 3.8 9 10-2 0.08 0.04 -0.12 to 0.2 0.502 0.61

Hypertension -2.4 9 10-2 0.06 -0.025 -0.14 to 0.09 -0.42 0.68

Diabetes -7.8 9 10-2 0.07 -0.07 -0.22 to 0.06 -1.15 0.26

Smoker -7.7 9 10-2 0.06 -0.08 -0.2 to 0.05 -1.3 0.2

Cholesterol 7.4 9 10-3 0.006 0.513 -0.005 to 0.02 1.2 0.24

Triglycerides 5.9 9 10-3 0.002 0.301 0.001 to 0.01 2.6 0.012

HDL -2.1 9 10-2 0.008 -0.308 -0.04 to -0.003 -2.4 0.02

LDL -5.3 9 10-3 0.006 -0.369 -0.02 to 0.008 -0.8 0.42

Leptin 2.7 9 10-2 0.007 0.395 0.012 to 0.04 3.704 0.001

LEPR Q223R 1.9 9 10-2 0.08 0.029 -0.14 to 0.2 0.25 0.803

LEP G2548A 0.21 0.09 0.295 0.02 to 0.4 2.2 0.03

Heart Vessels (2012) 27:271279 275

1 3
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


6/10

a significant increase in patients with NYHA III compared

to those with NYHA classes I and II. Interestingly, these

findings were associated with significant increases in the

leptin gene (AA genotype) and the leptin receptor gene

(RR genotype) in HFNEF patients compared to the control

group. We found that subjects carrying LEP AA or LEPR

RR had at least a threefold greater risk of developing

HFNEF.In addition, the leptin gene (AA genotype) was more

associated with NYHA III than with NYHA I and II

(OR = 7, P\ 0.001). Also, LEPR (RR genotype) was

more associated with NYHA III than with NYHA I and II

(OR = 8.3, P\ 0.001).

In accordance with our data, Schulze et al. [15] found

that patients with CHF have increased serum levels of

leptin as compared to healthy controls. Furthermore,

patients with CHF and severe exercise intolerance have

significantly higher serum concentrations of leptin than

patients with moderate exercise intolerance or healthy

controls.Leyva et al. [21] showed that compared to controls who

had been matched for both total and regional body fat,

patients with congestive heart failure are relatively hyper-

leptinemic. However, in a study by Toth et al. [22], no

difference in plasma leptin concentrations was found

between patients with congestive heart failure and healthy

controls. This variability in results arose because Toth

et al.s study included some cachectic patients, whose

plasma leptin concentrations tended to be lower than those

in noncachectic patients.The results of our study showed that the frequency of the

LEPR R allele in the Egyptian population was 23%, which

is lower than the figures reported in Japanese (85%),

Caucasian (45%), and Pima Indian (32%) [10] populations.

With respect to LEP polymorphism, the G allele frequency

was higher than the A allele frequency in our study. This is

in accordance with the frequencies found in other studies

[23,24], except for one population from Taiwan, where the

G allele frequency was somewhat lower than that of the A

allele [25].

van der Vleuten et al. [26] found that, in patients with

the Q223R polymorphism within the leptin receptor gene,the carriers of one or two R alleles had an increased risk of

CHF compared to subjects who were homozygous for the

Q allele (OR = 1.6; 95% CI= 1.02.4). It has been

reported that there is a relationship between increased

leptin levels and progressive functional impairment in

advanced CHF, so hyperleptinemia represents a negative

prognostic factor in CHF patients [4].

Effect of the G-2548A LEP variant on leptin

A sequence variation in the gene encoding leptin may

affect the expression of this hormone. Although a variation

within the coding region of LEP is exceedingly rare in the

Table 7 Correlations between leptin levels and lipid profile

parameters

Leptin

R P

Cholesterol 0.361 \0.001

Triglycerides 0.533 \0.0001

HDL -0.46 \0.0001

LDL 0.375 \0.001

Table 8 Association of the

study participants

characteristics with leptin as

well as LEP and LEPR

polymorphisms

Variable Leptin LEPR Q223R LEP G2548A

Standardized

coefficient

P Standardized

coefficient

P Standardized

coefficient

P

Age -0.12 0.4 0.078 0.4 -0.13 0.06

Sex -0.01 0.9 -0.02 0.8 -0.04 0.6

Hypertension -0.04 0.8 -0.004 0.9 -0.06 0.4

Diabetes -0.015 0.9 -0.089 0.3 0.06 0.4

Smoker 0.079 0.6 0.103 0.3 -0.05 0.4

NYHA 0.001 0.9 -0.012 0.89 0.003 0.9

Cholesterol 0.54 0.6 -0.14 0.89 0.02 0.8

Triglycerides -0.16 0.3 -0.03 0.75 -0.09 0.3

HDL -0.2 0.2 -0.08 0.37 -0.04 0.6

LDL -0.035 0.8 0.03 0.78 -0.7 0.5

Leptin -0.037 0.78 -0.8 0.04

LEPR Q223R -0.09 0.8 0.6 0.001

LEP G2548A -0.8 0.04 0.6 0.001

276 Heart Vessels (2012) 27:271279

1 3
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


7/10

general population, several common polymorphisms in the

50 regulatory regionG2548A and A19Gshow associa-

tions with LEP levels [27]. Lucantoni et al. [28] showed

that the A19G variant present in the untranslated exon 1 of

the leptin gene is not associated with any significant dif-

ference in leptin levels.

The potential effect of the G-2548A LEP variant on

leptin expression has been assessed; however, there havebeen conflicting reports. The present study demonstrates

that the leptin level was significantly higher in LEP AA

than in LEP GG.

In accordance with our data, Mammes et al. [19] found

that the AA genotype was associated with increased plasma

leptin levels in men from a French cohort. This finding was

confirmed by a Swedish study, which showed that the

-2548A allele of this variant was associated with

increased leptin mRNA levels and increased adipose tissue

leptin secretion rates [29]. However, in the Taiwanese

population, no association was found between this LEP

polymorphism and plasma leptin concentrations [25].Conversely, a relationship between the AA genotype and

lower plasma leptin concentrations was described in heal-

thy individuals from Greece, in morbidly obese French

patients, and recently in obese Brazilian women [3032].

Effect of LEPR Q223R polymorphism on leptin

The relationship between leptin level and the LEPR Q223R

polymorphism is unclear. The present study demonstrates

that the leptin level was significantly higher in LEPR RR

than in LEPR QQ. In accordance with our data,

Yiannakouris et al. [33] found that carriers of the LEPR

223R allele had significantly higher leptin levels than

noncarriers. In contrast, Quinton et al. [11] indicated that

the LEPR 223R allele was associated with a lower circu-

lating leptin level. van Rossum et al. [34] demonstrated that

R allele carriers have higher leptin levels than people with

the homozygotic Q/Q genotype. The LEPR polymorphism

leading to a change in charge could considerably impair the

ability of leptin to bind to its receptor, and thus provide a

phenotype for leptin resistance with inadequate leptin sig-

naling. Other allelic variations in coding and noncoding

sequences of the LEPR gene have also been reported, some

of which result in silent changes or represent rare mutations

[35]. These were not studied here because they are unlikely

to have any functional significance.

Association of the LEP and LEPR polymorphisms

with the lipid profile

In this study we demonstrated that levels of total choles-

terol, triglycerides, and leptin were significantly increased

in the LEP AA genotype. Also, levels of total cholesterol,

triglycerides, LDL cholesterol and leptin were significantly

increased in the LEPR RR genotype. Recent studies have

reported that the LEPR gene polymorphism influences

serum lipid levels [26,36]. Patients with the RR genotype

had significantly higher total cholesterol levels and lower

high-density lipoprotein cholesterol levels than those with

the QQ genotype [37]. Chui et al. [38] have reported that

the presence of the R allele correlated with an increasedlevel of total cholesterol, LDL, and the phenomenon of

insulin resistance. Leptin or the R allele of the LEPR gene

may contribute to low plasma levels of HDL-C by modi-

fying hepatic lipase, phospholipid transfer protein, cho-

lesteryl ester transfer protein, or lipoprotein lipase [39].

Pathophysiological effects of leptin on heart failure

Leptin is correlated with markers of inflammation such as

TNF-a9 [15] and CRP [40], which have been associated

with worse outcomes in patients with CAD [41] and CHF

[42]. In the setting of CHF, serum levels of leptin arecorrelated to altered metabolic, cardiovascular and respi-

ratory parameters, which all contribute to the progression

of the underlying disease. While increasing sympathetic

nervous outflow through the stimulation of hypothalamic

receptors, leptin participates in neurohumoral activation

during heart failure. The metabolic effects of leptin include

increased energy expenditure [22], reduced insulin signal-

ing in muscle [43], impaired fatty acid oxidation, and

reduced energy storage. Further, its direct action in the

heart involves enhanced levels of reactive oxygen species

and prohypertrophic mechanisms, which together increase

cardiac energy consumption, attenuate cardiac contractil-

ity, and reduce cardiac efficiency.

Singhal et al. [16] found a marked influence of leptin on

arterial distensibility. The association of arterial distensi-

bility with leptin was independent of fat mass and meta-

bolic and inflammatory markers. Arterial stiffness is

increased in patients with CAD, and represents an inde-

pendent predictor of CAD. It has been shown that as the

stiffnesses of large arteries such as the aorta increase,

cardiovascular morbidity and mortality also increase [44].

In fact, cross-sectional studies have reported a relation

between arterial stiffness and LV diastolic function [45].

Arterial stiffness could influence diastole by elevating the

systolic load in order to prolong relaxation, compromise

filling, and raise LVEDP [3].

Lieb et al. [46] stated that it is, however, unclear whe-

ther leptin contributes to the development of heart failure,

or if the higher leptin levels are secondary responses to

cardiac damage.

The results of our study support the suggestion that

leptin contributes to the development of heart failure with

normal ejection fraction in CAD patients. This conclusion

Heart Vessels (2012) 27:271279 277

1 3
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


8/10

is based on the observation that, in our study, elevated

leptin levels in patients with HFNEF are associated with

increased frequencies of LEP AA and LEPR RR genotype.

Thus, the increase in leptin levels is due to genetic causes,

because these genotypes have been shown to be accom-

panied by increased levels of leptin [19,29,33,34].

Study limitation

Our sample may be considered relatively small. Further-

more, the generalizability of our results is limited given the

lack of ethnic and racial diversity, because all patients and

controls were Egyptians. Lastly, the absence of measure-

ments of fat mass and body fat distribution prevented the

correction of leptin levels for total and regional body fat.

Conclusion

Heart failure with a normal ejection fraction is associatedwith an increased serum leptin level. The LEP AA geno-

type and LEPR RR genotype carries at least a threefold

greater risk to develop HFNEF. Increased serum levels of

leptin, the LEP AA genotype and the LEPR RR genotype

are associated with increased exercise intolerance. Dysli-

pidemia is associated with increased serum leptin levels, as

well as the LEP AA genotype and the LEPR RR genotype.

References

1. Sanderson JE (2007) Heart failure with normal ejection fraction.

Heart 93:155158

2. Caruana L, Petrie MC, Davie AP, McMurray JJV (2000) Do

patients with suspected heart failure and preserved left ventricular

systolic function suffer from diastolic heart failure or from

misdiagnosis? A prospective descriptive study. BMJ 321:215

219

3. Kawaguchi M, Hay I, Fetics B, Kass DA (2003) Combined

ventricular systolic and arterial stiffening in patients with heart

failure and preserved ejection fraction implications for systolic

and diastolic reserve limitations. Circulation 107:714720

4. Schulze PC, Kratzsch J (2005) Leptin as a new diagnostic tool in

chronic heart failure. Clin Chim Acta 362(12):111

5. Matsui H, Motooka M, Koike H, Inoue M, Iwasaki T, Suzuki T,

Kurabayashi M, Yokoyama T (2007) Ischemia/reperfusion in ratheart induces leptin and leptin receptor gene expression. Life Sci

80(7):672680

6. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto

M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, Jingami H,

Kawada T, Nakao K (1995) Human obese gene expression:

adipocyte-specific expression and regional differences in the

adipose tissue. Diabetes 44:855858

7. Mammes O, Betoulle D, Aubert R, Giraud V, Tuzet S, Petiet A

(1998) Novel polymorphisms in the 50 region of the LEP gene:

association with leptin levels and response to low-calorie diet in

human obesity. Diabetes 47:487489

8. Malik KF, Young WS 3rd (1996) Localization of binding sites in

the central nervous system for leptin (OB protein) in normal,

obese (ob/ob), and diabetic (db/db) C57BL/6J mice. Endocri-

nology 137:14971500

9. Tartaglia LA, Wold LE, Relling DP, Duan J, Norby FL, Ren J

(2002) Abrogated leptin-induced cardiac contractile response in

ventricular myocytes under spontaneous hypertension: role of

Jak/STAT pathway. Hypertension 39:6974

10. Paracchini V, Pedotti P, Taiol E (2005) Genetics of leptin and

obesity: a HuGE review. Am J Epidemiol 162:101114

11. Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI (2001) A

single nucleotide polymorphism SNP in the leptin receptor is

associated with BMI, fat mass and leptin levels in postmeno-

pausal Caucasian women. Hum Genet 108:233236

12. Ahima RS, Flier JS (2000) Leptin. Annu Rev Physiol 62:413437

13. Schols AMWJ, Creutzberg EC, Buurman WA, Campfield LA,

Saris WHM, Wouters EFM (1999) Plasma leptin is related to

proinflammatory status and dietary intake in patients with chronic

obstructive pulmonary disease. Am J Respir Crit Care Med

160:12201226

14. Koh KK, Park SM, Quon MJ (2008) Leptin and cardiovascular

disease. Response to therapeutic intervention. Circulation

117:32383249

15. Schulzea PC, Kratzschc J, Linke A, Schoene N, Adamsa V,

Gielena S (2003) Elevated serum levels of leptin and soluble

leptin receptor in patients with advanced chronic heart failure.

Eur J Heart Fail 5:3340

16. Singhal A, Farooqi S, Cole TJ, ORahilly S, Fewtrell M,

Kattenhorn M, Lucas A, Deanfield J (2002) Influence of leptin on

arterial distensibility. A novel link between obesity and cardio-

vascular disease? Circulation 106:19191924

17. Frieldewald WT, Levy RI, Fredrickson DS (1972) Estimation of

the concentration of low-density lipoprotein cholesterol in

plasma, without use of the preparative ultracentrifuge. Clin Chem

18:499502

18. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens

TW, Nyce MR, Ohannesian JP, Marco CC (1996) Serum

immunoreactive-leptin concentrations in normal-weight and

obese humans. N Engl J Med 334:292295

19. Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron

F (2000) Association of the G-2548A polymorphism in the 50

region of the LEP gene with overweight. Ann Hum Genet

64(5):391394

20. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL,

Strosberg AD, McKeigue PM, Scott J, Aitman TJ (1997) Leptin

receptor gene variation and obesity; lack of association in a white

British male population. Hum Mol Genet 6:869876

21. Leyva F, Anker SD, Egerer K, Stevenson C, Kox WJ, Coats AJS

(1998) Hyperleptinaemia in chronic heart failure. Relationships

with insulin. Eur Heart J 19:15471551

22. Toth MJ, Gottlieb SS, Fisher ML, Ryan AS, Nicklas B, Poehlman

E (1997) Plasma leptin concetrations and energy expenditure in

heart failure patients. Metabolism 46:450453

23. Skibola CF, Holly EA, Forrest MS, Hubbard A, Bracci PM,Skibola DR, Hegedus C, Smith MT (2004) Body mass index,

leptin and leptin receptor polymorphisms, and non-Hodgkin

lymphoma. Cancer Epidemiol Biomark Prev 13:779786

24. Snoussi K, Strosberg AD, Bouaouina N, Ahmed SB, Helal AN,

Chouchane L (2006) Leptin and leptin receptor polymorphisms

are associated with increased risk and poor prognosis of breast

carcinoma. BM Cancer 6:3847

25. Wang TN, Huang MC, Chang WT, Ko AM, Tsai EM, Liu CS,

Lee CH, Ko YC (2006) G-2548A polymorphism of the leptin

gene is correlated with extreme obesity in Taiwanese aborigines.

Obesity 14:183187

278 Heart Vessels (2012) 27:271279

1 3
http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


9/10

26. Van der Vleuten GM, Kluijtmans LA, Hijmans A, Blom HJ,

Stalenhoef AF, de Graaf J (2006) The Gln223Arg polymorphism

in the leptin receptor is associated with familial combined

hyperlipidemia. Int J Obes 30(6):892898

27. Jiang Y, Wilk JB, Borecki I, Williamson S, DeStefano AL, Xu G,

Liu J, Ellison RC, Province M, Myers RH (2004) Common

variants in the 50 region of the leptin gene are associated with

body mass index in Men from the National Heart, Lung, and

Blood Institute Family Heart Study. Am J Hum Genet

75:220230

28. Lucantoni R, Ponti E, Berselli ME, Savia G, Minocci A, Calo G,

de Medici C, Liuzzi A, Di Blasio AM (2000) The A19G poly-

morphism in the 50 untranslated region of the human obese gene

does not affect leptin levels in severely obese patients. J Clin

Endocrinol Metab 85:35893591

29. Hoffsted J, Eriksson P, Mottagui-Tabar S, Arner P (2002) A

polymorphism in the leptin gene promotor region (-2548 G/A)

influences gene expression and adipose tissue secretion of leptin.

Horm Metab Res 34:355359

30. Yiannakouris N, Melistas L, Yannakoulia M, Mungal K, Mant-

zoros CS (2003) The -2548G/A polymorphism in the human

leptin gene promoter region is associated with plasma free leptin

levels; interaction with adiposity and gender in healthy subjects.

Hormones 2:229236

31. Poitou C, Lacorte JM, Coupaye M, Bertrais S, Bedel JF, Lafon N

(2005) Relationship between single nucleotide polymorphisms in

leptin, IL6 and adiponectin genes and their circulating product in

morbidly obese subjects before and after gastric banding surgery.

Obes Surg 15:1123

32. Hinuy HM, Hirata MH, Forti N, Diament J, Sampaio MF, Ar-

maganijan D, Salazar LA, Hirata RDC (2008) Leptin G-2548A

promoter polymorphism is associated with increased plasma

leptin and BMI in Brazilian women. Arq Bras Endocrinol Met-

abol 52:611616

33. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-

Zacas D, Mantrozos CS (2001) The Q223R polymorphism of the

leptin receptor gene is significantly associated with obesity and

predicts a small percentage of body weight and body composition

variability. J Clin Endocrinol Metab 86:44344439

34. Van Rossum CTM, Hoebee B, Van Baak MA, Mars M, Saris

WHM (2003) Genetic variation in the leptin receptor gene, leptin,

and weight gain in young Dutch adults. Obes Res 11:377386

35. Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma

Z, Sothern M, Udall JN, Kahle B, Leibel RL (1997) Exonic and

intronic sequence variation in the human leptin receptor gene

LEPR. Diabetes 46(9):15091511

36. Winiarska M, Gorecka D, Sliwinski P, Demkow U (2007) Fre-

quency of distribution of leptin receptor gene polymorphism in

obstructive sleep apnea patients. J Physiol Pharmacol 58:551561

37. Sun YM, Wang LF, Li J, Li ZQ, Pan W (2009) The 223A[G

polymorphism of the leptin receptor gene and lipid-lowering

efficacy of simvastatin in Chinese patients with coronary heart

disease. Eur J Clin Pharmacol 65(2):157161

38. Chui KC, Chu A, Chuang LM, Saad M (2004) Association of

leptin receptor polymorphism with insulin resistance. Eur J

Endocrinol 150:725729

39. Soro A, Jauhiainen M, Ehnholm C, Taskinen MR (2003) Deter-

minants of low HDL levels in familial combined hyperlipidemia.

J Lipid Res 44:15361544

40. Shamsuzzaman ASM, Winnicki M, Wolk R, Svatikova A, Phil-

lips BG, Berger PB, Somers VK (2004) Independent association

between plasma leptin and C-reactive protein in healthy humans.

Circulation 109:21812185

41. Ridker PM, Hennekens CH, Buring JE, Rifai N (2000) C-reactive

protein and other markers of inflammation in the prediction of

cardiovascular disease in women. N Engl J Med 342:836843

42. Levine B, Kalman J, Mayer L, Fillit HM, Packer MP (1990)

Elevated circulating levels of tumor necrosis factor in severe

chronic heart failure. N Engl J Med 323:236241

43. Doehner W, Rauchhaus M, Godsland IF, Davos CH, Proudler AJ,

Bolger AP (2002) Insulin resistance in moderate chronic heart

failure is related to hyperleptinaemia, but not to norepinephrine or

TNF-alpha. Int J Cardiol 83:7381

44. Triantafyllidi H, Rizos I, Rallidis L, Tsikrikas S, Triantafyllis A,

Ikonomidis I, Panou F, Rigopoulos A, Kremastinos DT (2010)

Aortic distensibility associates with increased ascending thoracic

aorta diameter and left ventricular diastolic dysfunction in

patients with coronary artery ectasia. Heart Vessels 25:187194

45. Hsu PC, Lin TH, Lee CS, Lee HC, Chu CY, Su HM, Voon WC,

Lai WT, Sheu SH (2010) Mismatch between arterial stiffness

increase and left ventricular diastolic dysfunction. Heart Vessels

25:485492

46. Lieb W, Sullivan LM, Aragam J, Harris TB, Roubenoff R,

Benjamin EJ, Vasan RS (2009) Relation of serum leptin with

cardiac mass and left atrial dimension in individuals[70 years of

age. Am J Cardiol 104:602605

Heart Vessels (2012) 27:271279 279

1 3


10/10

Reproducedwithpermissionof thecopyrightowner. Further reproductionprohibitedwithoutpermission.

articulo 3 equipo 4 genomica

Documents