Increased Lipoprotein-associated phospholipase A2 activity portends an increased risk of resistant hypertension
Li et al. Lipids in Health and Disease
Increased Lipoprotein-associated phospholipase A2 activity portends an increased risk of resistant hypertension
Zhiming Li 1
Jingguang Liu 1
Yuansheng Shen 1
Fanfang Zeng 0
Dongdan Zheng 2
0 Department of Cardiology, Shenzhen Sun Yat-sen Cardiovascular Hospital , Shenzhen , China
1 Department of Cardiology, Huizhou Municipal Central Hospital , 41st Eling North RD, Huicheng District, Huizhou , China
2 Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
Background: To investigate the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and incidence of resistant hypertension (RH). Methods: This was a cross-sectional research. In essential, it was an observational design and collecting data on a population at a single point in time to evaluate the associations of studied variables. Totally 208 patients with arterial hypertension were enrolled. Baseline characteristics were collected and fasting venous blood were drawn for plasma Lp-PLA2 activity assessment. Twenty-four hour ambulatory blood pressure ambulatory (ABPM) was performed to diagnose RH. Initially, based on ABPM examination, all participants were divided into two groups, namely RH group and without RH group. And thereafter, in order to evaluate the effects of Lp-PLA2 activity on blood pressure, all participants were divided into low (< 225 nm/min/ml) and high (≥ 225 nm/min/ml) Lp-PLA2 activity groups based on the cut-off value of Lp-PLA2 activity. Comparisons were conducted between groups. Results: Forty two patients were diagnosed as RH. Compared to patients without RH, patients with RH were more elderly, had more males, smokers, longer duration of hypertension, higher plasma C-reactive protein (CRP) level and Lp-PLA2 activity (P < 0.05 for all comparisons). More RH patients treated with calcium channel blocker and diuretic, while less treated with angiotensin converting enzyme inhibitor, angiotensin receptor blocker and statins (P < 0.05 for all comparisons). Compared to low Lp-PLA2 group, the rate of RH was significantly higher in high Lp-PLA2 group (26.7 % versus 6.1 %, P < 0.05). Multivariate regression analysis revealed that after adjusted for age, gender, smoking, body mass index, hypertension duration, CRP, and anti-hypertensive drugs, association between Lp-PLA2 activity and RH remained significant, with odds ratio (OD) of 2.02 (95 % confidence interval, CI 1.85-2.06, P < 0.05). Nonetheless, the association was attenuated when further adjusted for statins, with OR of 1.81 (95 % CI 1.74-1.93, P < 0.05). Conclusion: Increased plasma Lp-PLA2 activity portends increased risk of RH, and statins may be beneficial to reduce incidence of RH in subjects with increased plasma Lp-PLA2 activity.
Lipoprotein-associated phospholipase A2; Resistant hypertension; Relationship
Arterial hypertension is a major modifiable risk factor
of cardiovascular diseases around the world [
And resistant hypertension (HR), which is defined as
blood pressure remains above 140/90 mm Hg despite
treatment on 3 different classes of anti-hypertensive drugs
(including one diuretic) at their optimal doses ,
significantly increases the risk of cardiovascular events such as
heart failure, renal dysfunction and ischemic stroke [
was previously reported that in patients with resistant
hypertension, plasma level of inflammatory cytokine such
as C-reactive protein (CRP) was considerably elevated
], and the underlying mechanisms operating in
these processes are not fully investigated yet.
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
is a serine-dependent lipase which circulates in blood
stream after released from inflammatory cells within
vascular atherosclerotic plaques [
]. Compared to CRP,
Lp-PLA2 is a more specific biomarker of vascular
]. A substantial amount of studies reveal that
vascular inflammation contributes to endothelial
dysfunction, which is reflected as decreased nitric oxide (NO)
generation and increased endothelin-1 (ET-1) production
]. The imbalance between NO and ET-1 generation
may lead to peripheral resistant vessels constriction and
blood pressure elevation. With respect to the potent
effects of Lp-PLA2 on promoting vascular inflammation, we
therefore hypothesized that increased plasma Lp-PLA2
activity might be associated with the incidence of resistant
hypertension. In our present cross-sectional research, we
compared plasma activity Lp-PLA2 between subjects with
and without RH. The major objective of present research
was to investigate whether increased Lp-PLA2 activity
was significantly and independently associated with the
incidence of resistant hypertension. We considered that
the results from our present research might shed insights
for further studies in investigating an effective therapy for
managing resistant hypertension.
Participants’ enrollment and studied protocol
In brief, in outpatient department, subjects previously
diagnosed as primary arterial hypertension or reported
taking anti-hypertensive drugs were enrolled after oral
informed consent was obtained. All recruited subjects
were clearly informed about the design of present study,
in terms of only laboratory examination and 24 h
ambulatory blood pressure monitoring (ABPM) would be
conducted and no intervention including blood
pressure managing would be conducted. Those with heart
failure, liver or renal dysfunction, cognitive impairment,
documented cancer and connective tissue disease,
secondary hypertension would be ruled out. Totally 208
patients with primary arterial hypertension were recruited.
Demographics and clinical characteristics were collected
by questionnaire. Present medications used such as
anti-hypertensive drugs, anti-platelet and statins were
recorded. Briefly, patients without RH had higher
percentage of statins treatment than those with RH. Fasting
venous blood were drawn for laboratory examination. In
brief, plasma Lp-PLA2 activity was measured by using an
automated Colorimetric Activity Method assay (diaDexus
Inc., South San Francisco, CA) using a Beckman Coulter
(Olympus) AU400e autoanalyzer. All procedures were
conducted in accordance to the manual’s instruction and
the inter-assay variation coefficient of Lp-PLA2 activity
assay was 4.0 %. Briefly, this is a cross-sectional research.
By definition, cross-sectional research is an observational
design, and collecting data on a population at a single
point in time to evaluate the associations of studied
Diagnosis of resistant hypertension
In order to reduce the incidence of “white-coat”
hypertension or masked hypertension, 24 h ABPM was performed
on top of official blood pressure examination. On the basis
of 24 h ABPM readings, patients with mean 24 h systolic
blood pressure (SBP) > 130 mm Hg or diastolic blood
pressure (DBP) > 80 mm Hg were diagnosed as resistant
hypertension, in spite of treatment on 3 different classes
of anti-hypertensive drugs at their optimal doses
(including one diuretic) [
]. And no change of anti-hypertensive
drugs would be conducted after enrolment.
Initially, based on 24 h ABPM examination, all
participants were divided into two groups, namely resistant
hypertension group and without resistant hypertension
group. And thereafter, in order to evaluate the effects of
Lp-PLA2 activity on blood pressure, all participants were
divided into low (< 225 nm/min/ml) and high (≥ 225 nm/
min/ml) Lp-PLA2 activity groups based on the cut-off
value of Lp-PLA2 activity [
Continuous data was presented as mean ± SD and was
compared by the Student’s t-test when data was normally
distributed, otherwise was compared by the Wilcoxon
rank-sum test. Categorical data was presented as
percentage and was compared by χ2 test. The relationship
between plasma Lp-PLA2 activity and resistant hypertension
was using multivariate regression analyses. All reported p
values were 2-sided, and a p value of < 0.05 was considered
statistically significant. All statistical analyses were
conducted with the SPSS statistical package for Windows
version 19.0 (SPSS Inc., Chicago, Illinois).
Baseline characteristics of all participants
Baseline characteristics of all participants were presented
in Table 1. The percentage of RH in our present
crosssectional research was nearly 20.2 %. Generally, as
compared to patients without RH, patients with RH were
more elderly (59.3 ± 10.1 years versus 53.2 ± 11.4 years,
P = 0.018), had higher percentages of male (76.2 % versus
62.7 %, P < 0.001) and smokers (64.3 % versus 60.2 %,
P = 0.037), longer duration of hypertension (6.5 ± 3.7 years
versus 4.0 ± 2.1 years, P = 0.022), higher CRP level (24.7 ±
5.0 mg/L versus 15.2 ± 5.4 mg/L, P < 0.001) and
LpPLA2 activity (254.2 ± 26.7 nmol/min/mL versus 228.1 ±
24.5 nmol/min/mL, P < 0.001). Briefly, most of these
variables have had been previously demonstrated as
significant risk factors of resistant hypertension.
Expectedly, compared to those without RH, office SBP (147.3 ±
3.6 mm Hg versus 132.4 ± 5.5 mm Hg, P < 0.001) and
DBP (94.4 ± 2.6 mm Hg versus 82.3 ± 4.4 mm Hg, P <
0.001), and 24 h mean SBP (137.7 ± 6.2 mm Hg versus
126.3 ± 4.9 mm Hg, P < 0.001) and DBP (86.5 ± 4.7 mm
Hg versus 76.8 ± 2.4 mm Hg, P < 0.001) were all
significantly higher in patients with RH. With respect to the
usage of anti-hypertensive medicines, more patients with
RH treatment on calcium channel blocker and diuretic,
and less treatment on angiotensin converting enzyme
inhibitor and angiotensin receptor blocker. Patients
without RH had higher percentage of statins treatment
than those with RH (38.1 % versus 53.6 %, P < 0.001).
Blood pressure comparisons between low and high
Lp-PLA2 activity groups
Blood pressure comparisons between low and high
Lp-PLA2 groups were conducted. As shown in Table 2,
patients with high Lp-PLA2 activity (≥ 225 nm/min/ml)
had significantly higher office SBP and DBP, and 24 h
mean SBP and DBP (P < 0.05 for all comparisons) as
compared to low Lp-PLA2 activity group (< 225 nm/min/ml).
Moreover, the percentage of RH (26.7 % versus 6.1 %,
P < 0.05) was also significantly higher in patients with
high Lp-PLA2 activity than those with low Lp-PLA 2
Relationship of Lp-PLA2 activity and incidence of resistant
Relationship of Lp-PLA2 activity and incidence of RH
was evaluated by multivariate regression analysis. In the
model 1, after adjusted for age and gender, odds ratio
(OR) for RH was 2.04 (95 % confidence interval, CI
1.87–2.08, P < 0.05) in the high Lp-PLA2 activity group
versus the low Lp-PLA2 activity group. And the strength
of this association remained similar after further adjusted
for body mass index (BMI), smoking, hypertension
duration, CRP, TC, LDL-C and anti-hypertensive drugs
(model 2), with OR of 2.02 (95 % CI 1.85–2.06, P < 0.05).
Nonetheless, the association was attenuated when further
adjusted for statins therapy (model 3), with OR of 1.81
(95 % CI 1.74-1.93, P < 0.05).
Our present cross-sectional research reveals that in
patients with primary arterial hypertension, the rate of
RH is nearly 20 % as diagnosed by 24 h ABPM. As
compared to patients without RH, those with RH have
more co-morbidities such as more elderly, larger
percentages of male patients and smokers, longer duration
of hypertension and have higher plasma CRP level. The
novel finding of our present research is that plasma
Lp-PLA2 activity in patients with RH is significantly
higher and increased Lp-PLA2 activity is independently
associated with the incidence of RH. Statins therapy may
be helpful to reduce the incidence of RH in subjects with
increased plasma Lp-PLA2 activity.
As is well known that arterial hypertension contributes
to a variety of CVD, and effectively lowering blood
pressure below 140/90 mm Hg could significantly reduce the
incidence and prevalence of heart failure, renal
dysfunction and ischemic stroke. Accordingly, the prevalence of
RH is between 10–20 % and the health burden
attributable to RH is substantial [
]. Therefore, it is clinically
important to decrease the incidence and prevalence of
RH. Previously, a substantial amount of studies revealed
that poor adherence, “white-coat” effect and unrecognized
co-morbidities such as obstructive sleep apnea and
primary hyper-aldosteronism were the underlying
mechanisms associated with pseudo-resistant hypertension
]. In addition, it was reported that plasma level of
inflammatory cytokine such as CRP in patients with RH
was also increased [
]. However, whether increased plasma
CRP level was independently associated with RH was
Compared to CRP (an unspecific inflammatory
biomarker), Lp-PLA2 is a highly specific marker of vascular
inflammation. It has been demonstrated that the higher
the plasma Lp-PLA2 activity, the more severe of
vascular inflammation and endothelial dysfunction [
Endothelial dysfunction is associated with peripheral
resistant vessels constriction and blood pressure
elevation. Therefore, we considered that increased Lp-PLA2
activity might be associated with the incidence of RH.
And data from our present study revealed that as
compared to patients without RH, Lp-PLA2 activity
in patients with RH was significantly higher (254.2 ±
26.7 nmol/min/mL versus 228.1 ± 24.5 nmol/min/mL,
P < 0.001). Moreover, on the basis of the U.S Food
and Drug Administration recommendation (which defines
Lp-PLA2 activity of more than ≥ 225 nm/min/ml is
beyond normal range) , all participants were divided into
two groups as indicated in Table 2. Comparisons of blood
pressure revealed that compared to those with low
LpPLA2 activity, patients with high Lp-PLA2 activity had
higher office SBP and DBP, and 24 h mean SBP and DBP,
and the incidence of RH was also significantly higher in
high Lp-PLA2 activity group (26.7 % versus 6.1 %, P <
0.001). We considered that the following aspects might
partially explain our findings. In the first place, as
mentioned above that vascular inflammation and endothelial
dysfunction induced by Lp-PLA2 played a critical role on
blood pressure elevation. Secondly, sympathetic nerve
activation triggered by chronic systemic inflammation might
also lead to catecholamine release and renin-angiotensin
axis activation. Both of these pathophysiological changes
could cause blood pressure elevation through peripheral
resistant vessels constriction and fluid retaining [
Although we haven’t measured plasma level of
catecholamine, heart rate in patient with RH was significantly
higher than those without RH might indirectly reflect the
activation of sympathetic nerve system. Last but not the
least, it was reported that in patients with coronary artery
disease, Lp-PLA2 was associated with arterial stiffness
]. Therefore, we postulated that through enhancing
arterial stiffness, Lp-PLA2 might directly increase blood
Finally, multivariate regression analysis revealed that
after extensively adjusted for potential confounding
factors including age, smoking, duration of hypertension,
CRP, BMI, and anti-hypertensive medicines, Lp-PLA2
activity was still significantly associated with RH.
Nonetheless, the relationship was attenuated by statins, and
the underlying mechanism we considered might be due
to improvement of vascular inflammation and
endothelium function by statins treatment, which was beneficial
for vessel dilation and blood pressure reduction [
There were some strengths and weaknesses of our
present research. To our best knowledge, this was the
first study to evaluate the relationship between Lp-PLA2
activity and the incidence of RH. In addition, 24 h ABPM
was used to diagnose RH which could avoid the
“whitecoat” hypertension or masked hypertension. Nonetheless,
since our present research was a cross-sectional research,
therefore, the causal relationship between Lp-PLA2
activity and the incidence of RH could not be drawn.
Moreover, despite we extensively adjusted for confounding
factors, inherent biases of cross-sectional research still
could not be avoided.
Data from our present study indicate that compared to
those without RH, plasma Lp-PLA2 activity in patients
with RH is significantly higher, suggesting that increased
plasma Lp-PLA2 activity is associated with the incidence
of RH. Lp-PLA2 activity may be used as a marker to
identify those who are at increased risk of RH. Future
studies are warranted to investigate whether Lp-PLA2
inhibitor or statins could be used to reduce the incidence
The authors declare that they have no competing interests.
ZL, JL, and YS performed this study, DZ performed statistic analyses, and FZ
designed this study and ZL wrote this article. All authors read and approved
the final manuscript.
We appreciate very much for the help Dr. Congwu Huang offered to us.
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