Lack of Atorvastatin Protective Effect Against Atrial Fibrillation in
CETP TaqIB2B2 Genotype
Francesca Galati1, Antonio Galati2, Serafina Massari1
1Department of Biological and Environmental Sciences and Technologies - University of Salento, Lecce, Italy.2Department of Cardiology - “Card. G. Panico” Hospital, Tricase, Lecce, Italy.
There has been some evidence for a role of statins in reducing the risk of atrial fibrillation, but the response to statin treatment varies considerably due to environmental and genetic factors. One of these is related to CETP expression.
So we assessed whether CETP TaqIB polymorphism influences atrial fibrillation occurrence after treatment with statins.
200 unrelated dyslipidemic Caucasian patients (146 men and 54 women; mean age 75±8) from Salento (Southern Italy), assigned to atorvastatin treatment, and 158 normolipidemic subjects (119 men and 39 women; mean age 75±11), selected from the same ward, were enrolled. All patients were followed at six-month intervals. CETP TaqIB polymorphism was genotyped by RFLP-PCR.
During a mean follow-up time of 71±6 months, 64 patients (32%) of the group treated with atorvastatin and 70 subjects (44%) of the group without atorvastatin experienced at least one episode of AF, with a statistically significant difference (p = 0,0208) between the two groups. No significant differences were observed between the two groups with regard to demographic and echocardiographic data, to clinical history and pharmacological treatment. While in patients not assuming atorvastatin there was no significant difference (p = 1) between TaqIB genotype and atrial fibrillation occurence, in subjects treated with atorvastatin B2B2 genotype was more frequent in patients with atrial fibrillation (p = 0,0001). According to these data the subjects with the B2B2 genotype seem to be more susceptible to atrial fibrillation development (RR 2,74; IC 95% 1,92-3,90; p<0.025).
Our data seem to provide a further evidence for the hypothesis that statins may have adverse effect in subjects with genetically low CETP levels. Because statins reduce CETP activity up to 30%, we hypothesize that such CETP activity reduction by statins, in patients with low CETP levels induced by polymorphism, may counteract the beneficial effect of statins on atrial fibrillation.
Corresponding Address : Dr. Francesca GalatiDepartment of Biological and Environmental Sciences and Technologies, University of SalentoS.P. 6, Lecce-Monteroni Lecce, Italy.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and its prevalence increases with age. Although not acutely life threatening, because of haemodynamic compromise and associated increased risk of stroke, it can cause severe morbidity and mortality, especially among older people and those with heart failure. Therefore it leads to worsening of quality of life and causes a substantial burden to health services.
Recently, there has been some evidence for the protective role of statins in reducing the risk of this arrhythmia. In particular, one meta-analysis suggested that statins could reduce the risk of atrial fibrillation by 61%.1 A second meta-analysis, however, yielded a more modest (and non-significant) point estimate of 24%.2
There is a considerable variation in the response to statin treatment,3 due to environmental and genetic factors. One of these is related to expression of cholesteryl ester transfer protein (CETP), which plays a key role in lipid metabolism. In fact the statin efficacy may vary due to patients CETP genotype4,5 and CETP concentration.6
Several single nucleotide polymorphisms (SNPs) in the CETP gene have been identified. The most widely studied CETP variant is denoted TaqIB (rs708272), affecting the 279th nucleotide in the first intron of the gene.7
In the REGRESS study8 an interaction between this polimorphism and efficacy of statin therapy was observed, with TaqIB1 allele associated to a better response to statins. Carlquist also observed a pharmacogenetic interaction for coronary atherosclerotic events,9 but the observed effect was opposite, because cardiovascular event reduction by statin therapy is enhanced in the presence of TaqIB2 allele. Instead, an individual patient meta-analysis of 13677 patients10 failed to demonstrate an influence of this CETP variant on the response to pravastatin therapy.
High CETP activity, as seen in B1B1 patients, is classically known to increase the cholesterol component of atherogenic lipoprotein. Statins reduce CETP activity up to 30%11,12 and this reduction is associated with beneficial effects in subjects with high CETP concentrations, while these effects lack in B2B2 patients, with genetically determined low CETP activity. In fact, a critical concentration of CETP is required for normal reverse cholesterol transport.
Therefore, we conducted a prospective study to assess whether
CETP TaqIB polymorphism influences the occurrence of atrial
fibrillation in subjects treated with statins.
200 unrelated dyslipidemic Caucasian patients (146 men and 54
women; mean age 75±8) from Salento (Southern Italy) and 158
normolipidemic subjects (119 men and 39 women; mean age 75±11),
selected from the same ward, were enrolled between January 2007
and June 2009. Dyslipidemia was defined as elevated total (>240 mg/
dL) or low-density lipoprotein (LDL - >130 mg/dL) cholesterol
levels, or low levels of high-density lipoprotein cholesterol (HDL - <40 mg/dL) or elevated triglycerides levels (>150 mg/dL). All
subjects were on a stable medication regimen and diet for at least
4 weeks prior to study screening. Patients with a history of stroke,
renal disease, diabetes mellitus, heart failure (greater than grade
NYHA II), hyperthyroidism, moderate to severe valve disease and
lone AF were excluded. The dyslipidemic subjects were assigned to
atorvastatin treatment for at least 6 months. The dose of atorvastatin
(10-40 mg/day) was adjusted according to the National Cholesterol
Education Program Adult Treatment Panel III.13 All patients were
followed up in our outpatient clinic at six-month intervals.
The presence of AF was determined by ambulatory
electrocardiograms or 24 hours ECG monitoring. Transthoracic
echocardiogram was performed to asses left atrial and left ventricular
dimensions, atrial volume, left ventricular ejection fraction and to
detect significant valvular heart disease (at least moderate to severe).
The study was approved by the local ethics committee and
conducted in accordance with the guidelines of the declaration of
Helsinki. An informed consent prior to participation was obtained
from all subjects.
The urinary albumin excretion rate was measured as the mean
of two 24-h urine collections, and urinary albumin concentrations
were determined by nephelometry. Blood samples were collected
from subjects, after a 12- to 14-hour fast, into tubes containing 0.1%
EDTA. High-sensitive C-reactive protein (CRP) was determined by
nephelometry, interleukin-6 (IL-6) by immunochemioluminescence,
total serum cholesterol, HDL-cholesterol and triglycerides by
colorimetric/ spectrophotometric procedure, whereas LDLcholesterol
was calculated using the Friedewald equation.
DNA extraction was carried out on total blood using Archive Pure
DNA Blood Kit (5-PRIME, Hamburg, Germany) according to the
manufacturer’s recommended protocol. Subsequently, CETP TaqIB
(rs708272, G/A) genotyping was performed in all participants. Briefly,
a fragment of 1018 bp of the intron 1 of the gene was amplified by
PCR (polymerase chain reaction) with the use of primers designed
on the NCBI Reference Sequences NT_010498 (pos 10608262-
10610237) (forward 5’-GTGTGCCGCATCACCAAG-3’, reverse
5’-TCTCGCCGTGATATCTG-3’) followed by TaqI digestion.
The resulting DNA fragments were the 707 and 311 bp in length
corresponding to the wild type B1 allele, and the intact 1018-bp in
length corresponding to the uncut B2 allele.
Continuous data are expressed as mean ± standard deviation;
categorical data are expressed as a percentage. A goodness of fit test
for normality and a Brown-Forsythe or Levene test for homogeneity
of variances were used to assess the applicability of parametric tests.
Differences between mean data were compared by Student’s t-test
for the normally distributed continuous variables or by the Mann-
Whitney test for non-normally distributed variables. Differences
in genotype frequencies and other categorical data between cases and controls were compared with Fisher’s exact test (mid-p exact
p-value). Differences in baseline characteristics, inflammation and
lipid metabolism parameters between the three polymorphic forms
of the CETP gene were analyzed by ANOVA. The consistency of the
genotype frequencies with the Hardy-Weinberg equilibrium (HWE)
was tested using a chi-squared goodness-of-fit test on a contingency
table of observed versus expected genotypic frequencies in cases and
controls. Post-hoc evaluations, where necessary, were performed by
means of the Bonferroni correction. A two-sided p value <0.05 was
considered significant for all tests.
Table 1 provides a summary of the characteristics of our
population. The two groups appear to be homogeneous. No
differences exist with regard to demographic data, clinical history
and echocardiographic measurements, with the exception of higher
body mass index in the group assuming atorvastatin. Particularly
73,7% of the total population was hypertensive, but hypertension
was distributed in an uniform manner between the two groups (75%
vs 72%). No significant difference in pharmacological treatment
(beta-blockers, ACE-inhibitors, angiotensin receptor blockers,
antialdosterone, amiodarone, propafenone) was observed between
the groups. The average dosage of atorvastatin was similar in patients
with and without atrial fibrillation. The laboratory data concerning
inflammation (C-reactive protein, urinary albumin excretion and
interleukin 6) were not different between the two groups, while the
lipid metabolism data were higher in patients taking atorvastatin,
both before therapy and after the start of statin therapy (Table 2).
Table 1. Demographic data and clinical and echocardiographic features of the study population
| p value | Atorvastatin
n =200 | No atorvastatin
n = 158 |
---|
Demographic | Male sex, n (%) | 146 (73%) | 119 (75%) | 0,6298 |
| Age (years) | 75±8 | 75±11 | 1,0000 |
| BMI (kg/m2) | 28±3 | 27±4 | 0,0072 |
| Current smoking | 96 (48%) | 73 (46%) | 0,7501 |
Clinical history | NYHA class, n (%) | | | 0,9134 |
| I | 122 (61%) | 95 (60%) | |
| II | 78 (39%) | 63 (40%) | |
| |
---|
| IHD, n (%) | 99 (49%) | 79 (50%) | 1,0000 |
| Hypertension, n (%) | 151 (75%) | 113 (72%) | 0,4002 |
| COPD, n (%) | | | 0,9877 |
| Mild | 44 (22%) | 36 (23%) | |
| Moderate | 125 (62%) | 100 (63%) | |
| Severe | 24 (12%) | 17 (11%) | |
| |
---|
| Very severe | 7 (4%) | 5 (3%) | |
Echo | AP left atrial diameter, mm | 45,4±6,5 | 44,8±6,3 | 0,3800 |
| SI left atrial diameter, mm | 52,5±6,2 | 53,1±3,6 | 0,2805 |
| ML left atrial diameter, mm | 37,4±5,6 | 38,1±4,9 | 0,2157 |
| Atrial volume, cc | 47,0±1,2 | 46,7±2,5 | 0,1583 |
| LV EF, (%) | 56±7 | 55±4 | 0,1103 |
BMI, body mass index; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease; AP, antero-posterior; SI, supero-inferior; ML, medio-lateral; LV EF, left ventricular ejection fraction
Table 2. IL-6, interleukin 6
| Atorvastatin | No atorvastatin | p value |
---|
| Before therapy | After therapy | | |
C-reactive
protein, mg/dl | 1,12±2,10 | 0,99±3,21 | 1,02±1,83 | 0,6364* 0,9166# |
Urinary albumin
excretion, mg/L | 85,53±216,25 | 69,87±184,52 | 64,73±127,38 | 0,3361* 0,7656# |
IL-6, pg/ml | 14,48±56,62 | 16,67±58,97 | 16,35±41,02 | 0,7273* 0,9538# |
Total cholesterol,
mmol/L | 5,97±0,29 | 5,03±0,58 | 4,59±1,03 | 0,0001* 0,0001# |
Triglycerides,
mmol/L | 2,02±0,38 | 1,74±0,45 | 1,23±0,59 | 0,0001* 0,0001# |
HDL-cholesterol,
mmol/L | 1,00±0,21 | 1,30±0,32 | 1,47±0,40 | 0,0001* 0,0001# |
LDL-cholesterol,
mmol/L | 4,05±0,38 | 2,95±0,71 | 2,51±0,92 | 0,0001* 0,0001# |
IL-6, interleukin 6 * p value between pts on atorvastatin before therapy and pts not assuming atorvastatin; # p value between pts on atorvastatin after therapy and pts not assuming atorvastatin
The distribution of CETP TaqIB polymorphism in the whole
population and in the two groups is shown in Table 3. B1 and B2
were respectively used to denote the presence and the absence of
the restriction site for the enzyme TaqI in intron 1. No statistically
significant difference was evidenced between the two groups. Hardy-
Weinberg equilibrium was reached in the whole population as in the
two study groups.
Table 3. TaqIB polymorphism: genotype frequency
| Total population | Atorvastatin | No atorvastatin | p value |
---|
B2B2 | 62 (17%) | 33 (16%) | 29 (18%) | |
B1B2 | 164 (46%) | 87 (44%) | 77 (49%) | 0,3850 |
B1B1 | 132 (37%) | 80 (40%) | 52 (33%) | |
During a mean follow-up time of 71±6 months, 64 patients (32%;
95%CI 0,26-0,39) of the group treated with atorvastatin and 70
subjects (44%; 95%CI 0,37-0,52) of the group without atorvastatin
experienced at least one episode of AF, with a statistically significant
difference (p = 0,0208) between the two groups (Table 4):
administration of atorvastatin was associated with a lower frequency
of atrial fibrillation occurrence.
Table 4. Atrial fibrillation occurrence and statin therapy
| Atorvastatin | No atorvastatin | p value |
---|
| |
---|
Atrial fibrillation | 64 (32%) | 70 (44%) | 0,0208 |
No atrial fibrillation | 136 (68%) | 88 (56%) | |
The genotypic distribution of the polymorphism with respect to
arrhythmia occurrence is reported in Table 5 and 6. While in patients
not assuming atorvastatin there was no significant difference (p =
1) between TaqIB genotypes and atrial fibrillation occurence, in
subjects treated with atorvastatin B2B2 genotype was more frequent (p = 0,0001) in patients with atrial fibrillation, 23 subjects (36%;
95%CI 0,25-0,48) vs 11 subjects (8%; 95%CI 0,04-0,14). According
to these data the subjects with the B2B2 genotype seem to be more
susceptible to atrial fibrillation development (RR 2,74; IC 95% 1,92-
3,90; p<0.025).
Table 5. TaqIB polymorphism: genotype frequency in patients not assuming atorvastatin
| AF | No AF | p value |
---|
| |
---|
B2B2 | 13 (19%) | 16 (18%) | 1,0000 |
B1 carriers | 57 (81%) | 72 (82%) | |
Table 6. TaqIB polymorphism: genotype frequency in patients assuming atorvastatin
| AF | No AF | p value |
---|
| |
---|
B2B2 | 23 (36%) | 11 (8%) | 0,0001 |
B1 carriers | 41 (64%) | 125 (92%) | |
When analyzed by allele status (Table 7 and 8), there were no
significant differences in baseline clinical characteristics between
TaqIB2B2 patients and B1 carriers (B1/B2 plus B1/B1) in both
groups, with the exception of higher atrial volume (p = 0,0142) in B1
carriers assuming atorvastatin. With regard to laboratory data (Table 9 and 10) the only significant difference was represented by higher
total cholesterol levels in B2/B2 patients not assuming atorvastatin
(p = 0,0001). This was associated with higher HDL-C levels (p =
0,0378), while there was no difference regarding the LDL-C values
(p = 0,3706).
Table 7. Clinical characteristics and events stratified according to CETP allele status in patients not assuming atorvastatin
| CETP B2/B2
n = 29 | CETP B1 carriers
n = 129 | p value |
---|
Demographic | Male sex, n (%) | 22 (76%) | 97 (75%) | 1,0000 |
| Age (years) | 74±12 | 75±11 | 0,6642 |
| BMI (kg/m2) | 26±4 | 27±4 | 0,2258 |
| Current smoking | 13 (45%) | 62 (48%) | 0,8381 |
Clinical history | NYHA class, n (%) | | | 1,0000 |
| I | 18 (62%) | 77 (60%) | |
| II | 11 (38%) | 52 (40%) | |
| |
---|
| IHD, n (%) | 16 (55%) | 64 (50%) | 0,6824 |
| Hypertension, n (%) | 21 (72%) | 95 (74%) | 1,0000 |
| COPD, n (%) | | | 0,9792 |
| Mild | 7 (24%) | 29 (22%) | |
| Moderate | 18 (62%) | 82 (64%) | |
| Severe | 3 (10%) | 14 (11%) | |
| |
---|
| Very severe | 1 (4%) | 4 (3%) | |
Echo | AP left atrial diameter, mm | 44,7±6,5 | 46,1±5,8 | 0,2525 |
| SI left atrial diameter, mm | 52,1±6,5 | 52,6±5,2 | 0,6563 |
| ML left atrial diameter, mm | 37,0±5,1 | 37,7±5,8 | 0,5496 |
| Atrial volume, cc | 46,4±2,0 | 46,5±1,9 | 0,7072 |
| LV EF, (%) | 55±6 | 56±7 | 0,4773 |
BMI, body mass index; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease; AP, antero-posterior; SI, supero-inferior; ML, medio-lateral; LV EF, left ventricular ejection fraction
Table 8. Clinical characteristics and events stratified according to CETP allele status in patients assuming atorvastatin
| CETP B2/B2
n = 33 | CETP B1 carriers
n = 167 | p value |
---|
Demographic | Male sex, n (%) | 24 (73%) | 122 (73%) | 1,0000 |
| Age (years) | 76±5 | 74±8 | 0,1685 |
| BMI (kg/m2) | 27±3 | 28±3 | 0,0817 |
| Current smoking | 16 (48%) | 80 (48%) | 1,0000 |
Clinical history | NYHA class, n (%) | | | 1,0000 |
| I | 20 (61%) | 102 (61%) | |
| II | 13 (39%) | 65 (39%) | |
| |
---|
| IHD, n (%) | 16 (48%) | 85 (51%) | 0,2915 |
| Hypertension, n (%) | 26(79%) | 125 (75%) | 0,8249 |
| COPD, n (%) | | | 1,0000 |
| Mild | 7 (21%) | 37 (22%) | |
| Moderate | 21 (64%) | 104 (62%) | |
| Severe | 4 (12%) | 20 (12%) | |
| |
---|
| Very severe | 1 (3%) | 6 (4%) | |
Echo | AP left atrial diameter, mm | 44,8±6,3 | 46,5±5,3 | 0,1046 |
| SI left atrial diameter, mm | 51,9±5,1 | 53,6±6,5 | 0,1579 |
| ML left atrial diameter, mm | 36,8±5,1 | 38,3±4,8 | 0,1061 |
| Atrial volume, cc | 46,8±1,8 | 48,5±3,8 | 0,0142 |
| LV EF, (%) | 56±4 | 55±4 | 0,1909 |
BMI, body mass index; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease; AP, antero-posterior; SI, supero-inferior; ML, medio-lateral; LV EF, left ventricular ejection fraction
Table 9. Laboratory data stratified according to CETP allele status in patients assuming atorvastatin
| Before statin therapy | After statin therapy |
---|
| B2/B2
n = 33
| B1 carriers
n = 167
| p value | B2/B2
n = 33
| B1 carriers
n = 167
| p value |
---|
C-reactive protein, mg/dl | 1,01±2,0 | 1,18±2,6 | 0,7229 | 0,95±3,0 | 1,02±3,7 | 0,9187 |
Urinary albumin excretion, mg/L | 83,24±199,32 | 89,21±233,96 | 0,8912 | 68±194,26 | 72,47±183,21 | 0,8992 |
IL-6, pg/ml | 12,35±59,23 | 15,38±54,67 | 0,7745 | 14,99±62,21 | 16,79±57,11 | 0,8707 |
Total cholesterol, mmol/L | 6,04±0,26 | 5,96±0,29 | 0,1427 | 5,02±0,49 | 5,04±0,60 | 0,8574 |
Triglycerides, mmol/L | 2,02±0,42 | 2,02±0,38 | 1,0000 | 1,70±0,48 | 1,74±0,44 | 0,6388 |
HDL-cholesterol, mmol/L | 0,98±0,23 | 1,00±0,22 | 0,6363 | 1,30±0,33 | 1,30±0,32 | 1,0000 |
LDL-cholesterol, mmol/L | 4,13±0,38 | 4,04±0,38 | 0,2152 | 2,93±0,68 | 2,95±0,72 | 0,8832 |
IL-6, interleukin 6
Table 10. IL-6, interleukin 6
| B2/B2
n = 29 | B1 carriers
n = 129 | p value |
---|
C-reactive protein, mg/dl | 0,91±1,48 | 1,05±1,91 | 0,7117 |
Urinary albumin excretion, mg/L | 48,91±80,51 | 68,34±135,98 | 0,4606 |
IL-6, pg/ml | 15,7±24,5 | 16,5±43,7 | 0,9243 |
Total cholesterol, mmol/L | 4,81±1,10 | 4,54±1,00 | 0,0001 |
Triglycerides, mmol/L | 1,25±0,63 | 1,23±0,58 | 0,8690 |
HDL-cholesterol, mmol/L | 1,61±0,37 | 1,44±0,40 | 0,0378 |
LDL-cholesterol, mmol/L | 2,64±0,88 | 2,47±0,93 | 0.3706 |
IL-6, interleukin 6
We assessed whether CETP TaqIB polymorphism modified the
onset of atrial fibrillation in subjects treated with atorvastatin. Indeed
statins seem to have a protective effect on atrial fibrillation onset. Such
beneficial action was also documented in our population: patients
assuming atorvastatin had a significant lower occurrence of atrial
fibrillation. But there is consisting evidence that genetic markers,
such as single nucleotide polymorphisms, related to candidate genes
which impact metabolisms, enzymes, transport systems, may modify
the response to statin therapy. CETP plays a major role in modifying
lipoprotein particles and CETP TaqIB polymorphism, associated
with changes in CETP activity and mass, seems to modulate the
plasma lipid profile and the risk of cardiovascular events in subjects
taking statins. In our study we did not measured CETP mass or
activity across genotype subgroups, but previous studies, conducted
in hyperlipidaemic and normolipidaemic subjects, confirmed that
CETP activity and mass were lower in B2B2 genotype compared
with the others (B1B1 and B1B2).14,15,16
The frequency of the TaqIB polymorphism in our study cohort was
similar to that reported in other populations16,17 suggesting that our
subjects are not genetically different from others.
Our data show that this polymorphism seems to cancel the
protective role of statins in reducing the risk of atrial fibrillation.
Many studies are being conducted all over the world to determine
the differential responses to lipid lowering treatment as a function
of CETP TaqIB genotype. In one such a study, the influence of
CETP TaqIB/−629C/A genotypes on atorvastatin treatment in type
2 Diabetes Mellitus was studied and B1B1/CC carriers have been
found to have more atherogenic lipid profile, including low HDL-C
levels, but they were found to be better responders to statin therapy.5
In REGRESS study, pravastatin therapy slowed the progression of
coronary atherosclerosis in B1B1 carriers but not in B2B2.4 In our
study we also confirmed an interaction between statins and TaqIB
polymorphism, for the first time in patients with atrial fibrillation,
in which we found a higher percentage of B2B2 genotype. Thus
the benefit of statin therapy seems to be restricted to B1 patients.
Instead, in patients not taking atorvastatin we did not observe any difference between the various genotypes regarding the occurrence
of atrial fibrillation. This does not conflict with what we affirmed in
a previous work,18 in which we documented a higher risk of atrial
fibrillation in patients with B2B2 genotype, as this was only true for
the female subjects, while the population object of our study is made
for 3/4 of male subjects. The high frequency of appearance of atrial
fibrillation can be explained by old age of our population and the
high percentage of patients with hypertension.
We should expect the B2B2 genotype would impair statins ability
to reduce CRP or the impact on the LDL-C lowering effect. But
our data are not consistent with that. In fact, in subjects assuming
atorvastatin, lipid parameters among CETP TaqIB genotypes were
not different, though our patients with B2B2 genotype had a higher
event risk compared to B1 carriers.
CETP simultaneously affects the concentration and composition
of both antiatherogenic and atherogenic lipoproteins. So we must
take into account the net effect of CETP activity, likely dependent on the metabolic, genetic, and environmental context. CETP also
regulates the cholesterol traffic directly at cellular level, plays a role
in macrophage cholesterol homeostasis,19 contributes to the genesis
of small preβ-HDL, which stimulate cellular cholesterol efflux from
macrophages and fibroblasts. Furthermore, cholesterol can change
opening/closure state of voltage-dependent ion channels forming
functional units with lipids in close proximity.2
We do not assume a negative effect of the polymorphism on
statins, but we hypothesize particularly low CETP levels arising from
a “double inhibition” of CETP (by statins and by polymorphism).
Whereas in subjects with defective apoB-lipoprotein clearance
CETP might be harmful, instead in those with highly effective
apoB-lipoprotein clearance (such in patients on statins) CETP
action seems to be advantageous. But the important reduction in
CETP levels, resulting from the combined action of polymorphism
and statins, might delete these positive effects, promoting the onset
of atrial fibrillation. Data from CETP inhibitors trials (with all patients receiving statin treatment) seem to support our hypothesis,
as, despite a substantial increase in HDL cholesterol levels, no net
benefits or harm was evident.21,22,23
Clearly, the relationship between plasma HDL and atherosclerosis
is a more complex one than merely ‘high levels are good’.
A limitation of our study may be represented by the low number
of the enrolled patients. Despite this, our work was performed
on patients from a well-defined geographical area and in these
association studies the genetic background is particularly important.
Our study seems to show an interaction among CETP genotypes,
statins and occurrence of atrial fibrillation. We hypothesize that
further CETP suppression by statins in subjects with already
intrinsically low CETP levels, induced by polymorphism, could have
a deleterious effect on clinical outcome (i.e. atrial fibrillation).
However, to better define the associations observed in our work,
further studies are required in larger populations, also belonging to
other geographical areas.