Clinical Biochemistry 45 (2012) 96–100
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Clinical Biochemistry
journal homepage: www.elsevier.com/locate/clinbiochem
The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of
cardiovascular disease in patients with familial hypercholesterolemia
Vladimír Soška a, b, Jiří Jarkovský c, Barbora Ravčuková d, Lukáš Tichý e,
Lenka Fajkusová e, f, Tomáš Freiberger d, f,⁎
a
Department of Biochemistry, Masaryk University, Brno, Czech Republic
2nd Clinic of Internal Medicine, Masaryk University, Brno, Czech Republic
Institute of Biostatistics and Analyses, Faculty of Medicine and Faculty of Science, Masaryk University, Brno, Czech Republic
d
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czech Republic
e
Center of Molecular Biology and Gene Therapy, University Hospital Brno, Jihlavska 20, 625 00 Brno, Czech Republic
f
Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
b
c
a r t i c l e
i n f o
Article history:
Received 2 May 2011
Received in revised form 2 November 2011
Accepted 8 November 2011
Available online 18 November 2011
Keywords:
Cardiovascular risk
Triglycerides/HDL-cholesterol ratio
Atherogenic index of plasma
Lipoprotein particle size
a b s t r a c t
Objectives: The aim of this study was to determine whether the atherogenic index of plasma (AIP = log
[triglycerides/HDL-cholesterol]) differs in heterozygous familial hypercholesterolemia (FH) patients with
and without a history of cardiovascular disease (CVD).
Design and methods: A total of 555 FH patients with known mutations in the LDL receptor or the
apolipoprotein B gene, of whom 53 had a history of CVD (CVD+ group), were retrospectively analyzed.
Results: Compared to patients without CVD (CVD− group), CVD+ patients showed significantly higher
fasting LDL-cholesterol, triglycerides and AIP as well as lower HDL-cholesterol. After both adjustment for age
and diabetes and using analysis based on age and sex matched groups, only the increase in triglycerides and
AIP in the CVD+ vs. the CVD− group remained significant.
Conclusion: The results of the present study indicate that AIP, which reflects the presence of atherogenic
small LDL and small HDL particles, may be connected to the risk of CVD in FH patients.
© 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction
Elevated low-density lipoprotein cholesterol (LDL-C) and decreased
high-density lipoprotein cholesterol (HDL-C) are important risk factors
for cardiovascular diseases (CVD), particularly for coronary artery disease (CAD) [1,2]. The size of lipoprotein particles also plays an important role in the atherogenic process. Small, dense LDL particles have
been associated with CAD in a number of studies [3–5]. They possess a
lower binding affinity for cellular LDL receptors and are more easily
oxidized compared with large LDL particles, which suggests that small
LDL particles are much more atherogenic [6–8]. Smaller LDL particles
Abbreviations: AIP, atherogenic index of plasma; APOB, apolipoprotein B gene; BMI,
body-mass index; BP, blood pressure; CAD, coronary artery disease; CETP, cholesterylester transfer protein; CVD, cardiovascular diseases; DM, diabetes mellitus; FER(HDL),
fractional esterification rate of cholesterol; FH, familial hypercholesterolemia; HDL,
high density lipoproteins; HDL-C, HDL-cholesterol; LCAT, lecithin:cholesterol acyltransferase; LDL, low density lipoproteins; LDL-C, LDL-cholesterol; LDLR, LDL receptor;
TC, total cholesterol; TG, triglycerides.
⁎ Corresponding author at: Molecular Genetics Laboratory, Centre for Cardiovascular
Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czech Republic. Fax: + 420
543211218.
E-mail address: [email protected] (T. Freiberger).
are predominant in a high proportion of CAD patients with normal
LDL-C levels [9]. In addition, HDL particles are known to be heterogeneous in the population regarding their size, density and physicochemical properties [10,11]. Particularly large and buoyant HDL particles
(HDL2) play a protective role against the development of atherosclerosis, whereas the effect of small, dense HDL (HDL3) particles on CVD risk
remains controversial [12–15]. However, there is some evidence that
small, dense HDL3 particles are associated with an increased CVD risk
[16–18]. LDL and HDL particle sizes are related to plasma levels of triglycerides (TG) [9,19]. The logarithm of the ratio TG/HDL-C correlates
well with the size of HDL and LDL particles and with the fractional
esterification rate of cholesterol by lecithin:cholesterol acyltransferase
(LCAT) in plasma [20–22]. The fractional esterification rate of cholesterol in plasma depleted of apoB-containing lipoproteins (FER[HDL])
reflects the reactivity of HDL to LCAT and shows a strong positive
correlation with plasma levels of small HDL3b,c particles and a strong
negative correlation with the level of large HDL2b particles [23,24].
Thus, FER(HDL) is the fastest in the smallest HDL particles, is slower
in larger HDL particles [25–27] and, together with LCAT activity, correlates with coronary atherosclerosis [22,28]. It has been established that the molar ratio of the concentration of TG/HDL-C is
significantly increased in patients who have experienced a myocardial
0009-9120/$ – see front matter © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.clinbiochem.2011.11.001
V. Soška et al. / Clinical Biochemistry 45 (2012) 96–100
infarction, compared with age- and sex-matched control subjects [29].
The measurement of the FER(HDL) or particle sizes (LDL and HDL)
is difficult to put into clinical practice, but it can be easily substituted
by calculating the atherogenic index of plasma (AIP) [30]. It has been
repeatedly shown that the AIP value (log[TG/HDL-C]) strongly correlates with FER(HDL) and with the size of the lipoprotein particles
[21,22]. Thus, the AIP value accurately reflects the presence of atherogenic small LDL particles and small HDL particles, and it is also a
sensitive predictor of coronary atherosclerosis and cardiovascular
risk [22,28,31,32].
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that is characterized by elevated LDL-C and premature atherosclerosis [33]. Previous FH studies have demonstrated smaller and
denser HDL and LDL particles in patients with heterozygous FH compared to healthy controls; a negative correlation between cholesterylester transfer protein (CETP) plasma levels and HDL and LDL particle
size in FH patients; and a trend toward an increased history of CVD
and increased IMT in the highest CETP concentration quartile compared
to the other CETP concentration quartiles in FH patients [34–36].
However, no study has yet investigated whether a relationship exists
between AIP and cardiovascular events in FH. The aim of this study
was therefore to establish whether AIP differs among heterozygous
FH patients with and without a history of CVD.
Materials and methods
Study design and study population
This was a retrospective, multicenter cohort study. We have maintained a MedPed (Make Early Diagnoses to Prevent Early Deaths in
medical pedigrees) national project database of FH subjects in the
Czech Republic, with the patients' demographics and clinical and laboratory data. To acquire the study population, the database was queried for patients with documented mutations in the LDL-receptor gene
(LDLR group) or mutation in the apolipoprotein B gene (APOB group),
who were at the time of entry into the database not undergoing hypolipidemic therapy and were at least 18 years old. This search returned
555 patients (378 unrelated and 177 related individuals; ratio 1.47
patients per affected family), of whom 53 had a history of CVD before
entry into the database. CVD was defined by the presence of at least
one of the following: a) coronary heart disease (myocardial infarction, angina pectoris, coronary artery bypass grafting or percutaneous
coronary intervention); b) ischemic stroke or transient ischemic
attack; or c) peripheral artery disease (peripheral arterial bypass
graft or peripheral percutaneous transluminal angioplasty). Age, sex,
body-mass index (BMI), systolic and diastolic blood pressure (BP),
cigarette-smoking habits and the presence of diabetes mellitus (DM)
were recorded.
Laboratory analysis
The results of the laboratory analysis were acquired from our patient databases; lipid analyses were performed in local certified laboratories with appropriate quality control, using the identical analytic
methods. Serum total cholesterol (TC) and TG levels were measured
using fully automated enzymatic methods, and HDL-C was determined with the same method after the precipitation of apolipoprotein
B-containing lipoproteins with polyanions. LDL-C was calculated using
the Friedewald formula, but only if TG levels were b4.5 mmol/L; when
TG levels exceeded 4.5 mmol/L, LDL-C values were considered missing
[37]. AIP was calculated as (log[TG/HDL-C]). All blood sampling was
performed after at least a 12-hour fast. Apolipoprotein B gene analysis
(detection of the p.Arg3527Gln mutation) was performed in all subjects, followed by LDL-receptor gene analysis in patients without
mutations in the apolipoprotein B gene, using the same stepwise approach described earlier [38].
97
Statistical analysis
Standard descriptive statistics were used for the description of
the dataset: the absolute and relative frequencies for categorical variables, arithmetic means for normally distributed variables and geometric means for log-normally distributed variables, accompanied
by a confidence interval for continuous data. (The confidence interval
has the same interpretation for the arithmetic and geometric means;
in the case of the geometric mean, the confidence interval is asymmetric.) Prior to analysis, the assumption of normality was tested
on continuous variables via histograms and a Kolmogorov–Smirnov
test. The data were log-transformed in the case of log-normal distribution. The transformed data were used in subsequent calculations.
Differences in the frequencies of the categorical data were tested
using Fisher's exact test. To test the differences between patients
with different diagnoses in continuous parameters, an unpaired ttest was adopted. A separate analysis was performed for the original
data, after adjustment for age and the effect of diabetes mellitus.
The purpose of the adjustment was to equalize influence of age and
diabetes on evaluated endpoints and to avoid artificially significant
results caused by age and diabetes differences among groups of patients. Linear regression, with age and diabetes mellitus status as
the explanatory variables, was used for adjusting. Additional analyses
based on age and sex matched groups are provided for unbiased estimates of plasma lipids and atherogenic index of plasma in CVD+ and
CVD− group. The matching of groups was computed using propensity score matching when for each CVD+ patient age and sex matching
CVD− patients were selected with 1-to-2 matching. Analysis was
performed with an IBM computer running SPSS Statistics 19.0.0 software (IBM Corporation, 2010) and R software with Nonrandom package (Susanne Stampf, 2011, Nonrandom: Stratification and matching
by the propensity score).
Results
A total of 555 FH patients (323 with mutations in the LDLR gene
and 232 in the APOB gene) from our MedPed database were eligible
for the present analysis. The basic characteristics of these populations
are shown in Table 1. The LDLR and APOB groups did not differ in
their age, sex, BMI, systolic and diastolic BP, cigarette smoking or
presence of DM. There were higher plasma TC, LDL-C, Tg and lower
HDL-C levels in LDLR group in comparison with APOB group (Table 1).
Fifty-three (42 with mutations in the LDLR gene and 11 in the
APOB gene) of 555 FH patients had a history of CVD before entry into
the database (CVD+ group): 49 had coronary heart disease, 3 had
stroke or transient ischemic attack and 1 had peripheral artery disease,
while 502 FH patients had no history of CVD (CVD− group). As
expected, FH patients in the CVD+ group were significantly older in
comparison with those in the CVD− group: 54.5 (51.2; 57.8) years vs.
39.6 (38.4; 40.8) years; P b 0.001. The two groups did not differ significantly in their sex distribution or smoking habits. As there were
more diabetics in the CVD + group compared to the CVD − group
(4 [7.55%] vs. 7 [1.39%], P = 0.015), BMI, BP, plasma lipids and AIP
were adjusted for age and DM effects. Age and DM-adjusted BMI
and systolic and diastolic BP did not differ significantly between
the CVD + and CVD − groups (Table 2).
Nonadjusted, age-adjusted and age-DM-adjusted plasma lipids
(TC, HDL-C, LDL-C and TG) and AIP in the CVD+ and CVD− groups
are shown in Table 3. Nonadjusted values of TC, LDL-C, TG and AIP
were significantly higher in the CVD+ group; the differences in
HDL-C were much smaller but significant, favoring higher HDL-C in
the CVD− group (P = 0.041). Age-DM-adjusted TG and HDL-C levels
were within the physiological ranges in both groups, but TG continued to be significantly higher (P b 0.001) and HDL-C significantly
lower (P = 0.017) in the CVD+ group. Conversely, age-DM-adjusted
TC and LDL-C did not differ between the CVD+ and CVD− groups.
98
V. Soška et al. / Clinical Biochemistry 45 (2012) 96–100
Table 1
Basic characteristics of the study population.
Total FH (N = 555)
Ageb
Maleb
Femaleb
Sexc
Malec
Femalec
Diabetesc
Smokingc
Systolic BPb (mm Hg)
Diastolic BPb (mm Hg)
BMIb (kg/m2)
Total cholesterol (mmol/L)d
LDL-cholesterol (mmol/L)d
Triglycerides (mmol/L)d
HDL-cholesterol (mmol/L)d
LDLR (N = 323)
41.0 (39.9; 42.2)
38.8 (37.0; 40.59)
42.4 (40.8; 43.9)
205
350
11
87
129.0
79.4
24.9
8.48
6.23
1.35
1.45
41.0 (39.5; 42.5)
38.2 (36.1; 40.4)
42.9 (40.9; 44.9)
(36.94%)
(63.06%)
(1.98%)
(15.68%)
(127.6; 130.5)
(78.5; 80.3)
(24.5; 25.3)
(8.33;8.63)
(6.09;6.38)
(1.30;1.41)
(1.42;1.48)
128
195
7
56
128.4
79.4
25.2
9.17
6.83
1.55
1.44
(39.63%)
(60.37%)
(2.17%)
(17.34%)
(126.4; 130.5)
(78.2; 80.7)
(24.7; 25.7)
(8.92;9.42)
(6.60;7.08)
(1.45;1.66)
(1.39;1.49)
Pa
APOB (N = 232)
41.1 (39.1; 43.0)
39.8 (36.6; 43.0)
41.7 (39.2; 44.2)
0.988
0.458
0.422
77 (33.19%)
155 (66.81%)
4 (1.72%)
31 (13.36%)
129.5 (127.4; 131.7)
79.5 (78.2; 80.9)
24.7 (24.0; 25.3)
7.97 (7.76;8.19)
5.76 (5.57;5.96)
1.20 (1.12;1.29)
1.52 (1.45;1.58)
0.130
0.769
0.237
0.565
0.914
0.335
b0.001
b0.001
b0.001
0.012
FH — familial hypercholesterolemia; LDLR — subjects with mutations in the LDL-receptor gene; APOB — subjects with mutation in the apolipoprotein B gene; BP — blood pressure;
BMI — body mass index.
a
Difference between LDLR and APOB groups.
b
Continuous variables are described by arithmetic means (95% CI), and statistical significance is assessed using a t-test.
c
Categorical data are described by the number of patients and percentage of category, and statistical significance is assessed using Fisher's exact test.
d
Geometric mean (CI); statistical significance tested by t-test on log-transformed data.
Adjusted AIP remained significantly higher in the CVD+ group
(P b 0.001) compared to the CVD− group.
Considering a substantial difference in the mean age between
CVD + and CVD − group we decided to perform independent supplementary analyses based on age and sex matched groups (using
propensity score matching) for unbiased estimates of plasma lipids
and atherogenic index of plasma in both CVD + and CVD − groups
(Supplementary table). These analyses confirmed significantly higher
AIP and triglycerides in the CVD+ group in comparison with CVD−
group (P = 0.042 and P = 0.040, respectively), while the difference in
HDL-C lost its statistical significance (P = 0.261). Again no differences
were found in TC or LDL-C between CVD+ and CVD− group (Table 4).
Table 2
Clinical characteristics of FH patients with a history of cardiovascular disease (CDV +
group) and without a history of cardiovascular disease (CVD − group).
CVD+ (N = 53)
Agea
Malea
Femalea
Sex
Maleb
Femaleb
Diabetesb
Smokingb
Systolic BPa (mm Hg)
Nonadjusted
Age-adjusted
Age-DM-adjusted
Diastolic BPa (mm Hg)
Nonadjusted
Age-adjusted
Age-DM-adjusted
BMIc (kg/m2)
Nonadjusted
Age-adjusted
Age-DM-adjusted
54.5 (51.2; 57.8)
52.8 (48.9; 56.7)
55.7 (50.6; 60.7)
22 (41.51%)
31 (58.49%)
4 (7.55%)
10 (18.87%)
CVD − (N = 502)
39.6 (38.4; 40.8)
37.1 (35.3; 4.9)
41.1 (39.5; 42.7)
183 (36.45%)
319 (63.55%)
7 (1.39%)
77 (15.34%)
P
b 0.001
b 0.001
b 0.001
0.459
0.015
0.550
132.9 (127.9; 137.8)
127.4 (122.8; 132.0)
127.4 (123.0; 131.9)
128.5 (127.0; 130.1)
129.0 (127.6; 130.4)
129.2 (127.8; 130.6)
0.097
0.488
0.406
79.3 (76.1; 82.5)
77.3 (74.1; 80.5)
77.4 (74.3; 80.5)
79.4 (78.4; 80.3)
79.6 (78.7; 80.5)
79.6 (78.7; 80.5)
0.952
0.177
0.118
25.3 (24.4; 26.3)
24.1 (23.2; 25.0)
24.0 (23.2; 24.8)
24.8 (24.4; 25.2)
25.0 (24.6; 25.4)
25.0 (24.6; 25.4)
0.369
0.069
0.075
FH — familial hypercholesterolemia; BP — blood pressure; BMI — body mass index;
DM — diabetes mellitus.
a
Arithmetic mean (95% CI), with statistical significance tested by t-test.
b
The number of patients and percentage of category, with statistical significance
tested by Fisher's exact test.
c
Geometric mean (95% CI), with statistical significance tested by t-test on logtransformed data.
Discussion
The present study investigated the connection between AIP (=log
[TG/HDL-C]) and CVD in a cohort of Czech FH patients. The results of
our study indicate that high AIP, which reflects the small size of HDL
and LDL particles, may be connected with the risk of CVD in heterozygous FH patients. FH is an autosomal dominant genetic disorder that
presents with premature atherosclerosis, primarily coronary heart
disease. It is commonly caused by mutations in the LDLR or APOB
gene [33,39]. The phenotype of patients with APOB gene mutation is
similar to the phenotype of patients with LDLR mutations, and these
entities are not clinically distinguishable [39]. Despite the hereditary
nature of the disease, FH shows great variability in phenotypic expression [40]. Typical laboratory findings include markedly elevated
Table 3
Nonadjusted, age-adjusted and age-DM-adjusted plasma lipids and atherogenic index of
plasma (=log[TG/HDL-C]) of FH patients with cardiovascular disease (CVD+ group)
and without cardiovascular disease (CVD− group).
Parameter
Total cholesterol (mmol/L)a
Nonadjusted (mmol/L)
Age-adjusted (mmol/L)
Age-DM-adjusted
Triglycerides (mmol/L)a
Nonadjusted (mmol/L)
Age-adjusted (mmol/L)
Age-DM-adjusted
HDL-cholesterol (mmol/L)a
Nonadjusted
Age-adjusted
Age-DM-adjusted
LDL-cholesterol (mmol/L)a
Nonadjusted
Age-adjusted
Age-DM-adjusted
AIPb
Nonadjusted
Age-adjusted
Age-DM-adjusted
CVD + (N = 53)
CVD− (N = 502)
P
9.17 (8.69; 9.68)
8.74 (8.25; 9.25)
8.71 (8.24; 9.20)
8.59 (8.42; 8.77)
8.45 (8.30; 8.61)
8.45 (8.30; 8.61)
0.003
0.273
0.328
1.79 (1.61; 2.00)
1.63 (1.47; 1.81)
1.62 (1.46; 1.80)
1.33 (1.27; 1.41)
1.33 (1.27; 1.39)
1.33 (1.27; 1.39)
b 0.001
0.001
0.006
1.36 (1.28; 1.45)
1.35 (1.27; 1.43)
1.35 (1.28; 1.43)
1.47 (1.43; 1.51)
1.46 (1.42; 1.50)
1.46 (1.43; 1.50)
0.041
0.017
0.048
6.82 (6.30; 7.38)
6.47 (5.97; 7.02)
6.45 (5.96; 6.97)
6.34 (6.17; 6.50)
6.21 (6.07; 6.36)
6.21 (6.07; 6.36)
0.013
0.328
0.334
0.12 (0.06; 0.18)
0.08 (0.02; 0.14)
0.08 (0.02; 0.13)
− 0.04 (− 0.07; − 0.01)
− 0.04 (− 0.07; − 0.02)
− 0.04 (− 0.07; − 0.02)
b 0.001
b 0.001
0.003
AIP — atherogenic index of plasma.
a
Geometric mean (95% CI), with statistical significance tested by t-test on logtransformed data.
b
Arithmetic mean (95% CI), with statistical significance tested by t-test.
V. Soška et al. / Clinical Biochemistry 45 (2012) 96–100
Table 4
Plasma lipids and atherogenic index of plasma (= log[TG/HDL-C]) of FH patients with
cardiovascular disease (CVD + group) and without cardiovascular disease (CVD −
group) in propensity score matched groups.
Parameter
a
Total cholesterol (mmol/L)
Triglycerides (mmol/L)a
HDL-cholesterol (mmol/L)a
LDL-cholesterol (mmol/L)a
AIPb
CVD + (N = 53)
CVD − (N = 106)
P
9.17
1.79
1.36
6.82
0.12
9.19
1.53
1.43
6.85
0.03
0.987
0.040
0.261
0.993
0.042
(8.69;
(1.61;
(1.28;
(6.30;
(0.06;
9.68)
2.00)
1.45)
7.38)
0.18)
(8.82; 9.58)
(1.38; 1.69)
(1.35; 1.51)
(6.49; 7.22)
(− 0.03; 0.09)
AIP — atherogenic index of plasma.
a
Log-normally distributed continuous data are described by geometric mean (95% CI);
Statistical significance of differences among groups is assessed using independent t-test.
b
Continuous variables are described by arithmetic mean (95% CI).
levels of TC and LDL-C, borderline HDL-C levels and normal or borderline TG [41–43]. The main risk factor for heterozygous FH patients is
high (2- to 3-fold elevated) plasma LDL-C levels, and the mean age
of onset of CVD in untreated FH subjects is between 40 and 45 years
old in male patients and approximately 10 years later in female patients [33,44]. Although high LDL-C is the main risk factor, the risk
of CVD in FH patients and its severity may vary not only be due to
LDL-C levels; expression of this disease may also be affected by other
risk factors, such as smoking, hypertension, BMI or DM [45–47]. The
risk of CVD in FH subjects may also be modified by other lipid and lipoprotein abnormalities [48,49]. It is documented that hypertriglyceridemia may be associated with a higher risk of premature CAD in FH
heterozygotes [46,50,51] and also that low HDL-C increases the risk of
CAD in FH patients [46,47,52]. In our study, FH subjects with a history
of CVD were older, and more of them had DM and had significantly
higher TC and LDL-C levels in comparison with those without CVD,
but age-DM-adjusted TC and LDL-C did not differ between the CVD+
and CVD− groups. Herewith, we found no significant differences in
BMI, systolic or diastolic BP or cigarette smoking between the CVD+
and CVD− groups, but there was a significantly higher incidence of
DM in the CVD+ group. TG levels were in the upper normal range in
the CVD+ group of our FH patients and were significantly higher in
comparison to the CVD− group. The differences in HDL-C were much
more subtle but still significant, favoring higher HDL-C in the CVD−
group, although the HDL-C levels were in the reference ranges in both
FH groups. Both differences in HDL-C and TG remained significant,
even after they were adjusted for age and for the presence of DM. It
has been previously published that triglyceride metabolism in FH
subjects seems to be impaired and may contribute to premature CVD
and that FH patients with disturbances in postprandial lipoprotein
metabolism have higher risks for coronary artery disease [51–53].
Hypertriglyceridemia also results in the formation of small, dense
LDL particles, low HDL concentrations and small, dense HDL particles
[19–21,54–56]. The size of the LDL and HDL particles is a very important factor affecting the degree of CAD risk [9,16,17,57,58]. Moreover, the size of lipoprotein particles correlates well with the AIP
value [21], and inverse correlations among the AIP value and the LDL
and HDL particle sizes and between the AIP value and the fractional
rate of cholesterol esterification have been shown [21,30].
In our study, we found a significantly increased value of AIP in FH
patients with established CVD compared to the CVD− group, even
after adjustments for age and DM effect. Although the adjustment
(for age) is a well accepted statistical approach to overcome differences between study and control populations, we decided to perform
additional analyses based on age and sex matched groups, particularly
due to a substantial age difference between CVD+ and CVD− group.
Notably, the identical result of a significantly higher AIP value in CVD+
group was achieved using this alternative approach. These findings
cannot be compared with any other results, as studies examining AIP
in FH patients with and without CVD have not been published before.
Hogue et al. showed that HDL particle size is significantly smaller in
99
FH patients compared to healthy controls, but they did not focus on its
association with the risk of CVD manifestation [35]. As the AIP value
can be easily determined, and it accurately reflects the presence of atherogenic small LDL particles and small HDL particles, based on our results, we assume that AIP should be considered (together with other
risk factors) as a predictor of future cardiovascular risk in heterozygous
FH patients. However, this hypothesis must be further tested, as our
study has a substantial limitation — it was designed as a retrospective
one, with relatively small number of FH subjects with CVD. Hence we
suppose that this work may provide the rationale for further large, prospective, age and sex matched studies.
Conclusion
The risk of premature CVD in FH patients that is driven by increased LDL-C levels may be further modified by other lipid abnormalities. The results of the present study indicate that AIP, which
reflects the presence of atherogenic small LDL particles and small
HDL particles, may be connected to the risk of CVD in heterozygous
FH patients.
Conflict of interest
The authors declare no conflicts of interest.
Contributions
V. Soska designed the study, prepared the draft of the manuscript
and helped with data collection. J. Jarkovsky performed the statistical
analysis. L. Fajkusova, B. Ravcukova and Lukas Tichy were responsible
for LDLR and APOB gene analyses, respectively, and helped with data
collection. T. Freiberger was responsible for the MedPed CZ database
and patients' data collection and participated in the genetic analysis
of FH patients and in manuscript preparation.
Supplementary materials related to this article can be found online at doi: 10.1016/j.clinbiochem.2011.11.001.
Acknowledgments
We would like to thank the following physicians from the regional
centers of the Czech MedPed project: V. Blaha, M. Budikova, J. Buryska,
R. Cifkova, R. Ceska, L. Dlouhy, L. Dostalova-Kopecna, H. Halamkova, J.
Hyanek, J. Hyjanek, Z. Krejsova, J. Machacek, S. Mala, J. Maly, V. Milacek,
J. Mracek, H. Podzimkova, D. Povalacova, H. Rosolova, E. Sipkova, F.
Stozicky, L. Toukalkova, Z. Urbanova, H. Vaverkova, M. Vrablík, S.
Zemek, A. Zak, and their co-workers. We thank also Marie Plotena for
the technical help.
The study was supported by the grant of MSMT CR No. 2B08060
and by the project CEITEC – Central European Institute of Technology
(CZ.1.05/1.1.00/02.0068).
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