Effect of Pravastatin on Malondialdehyde-Modified Low-Density Lipoprotein Levels and Coronary Plaque Regression as Determined by Three-Dimensional Intravascular Ultrasound

doi:10.1016/j.amjcard.2005.05.069

The American Journal of Cardiology

Volume 96, Issue 8, 15 October 2005, Pages 1089-1094

https://doi.org/10.1016/j.amjcard.2005.05.069 Get rights and content

We hypothesized that a reduction in atherogenic malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels, which may antagonize the action of atheroprotective high-density lipoprotein cholesterol, leads to coronary plaque regression. This study investigated the effects of pravastatin on the serum levels of MDA-LDL and coronary atherosclerosis. In a 6-month prospective study, 75 patients with stable coronary artery disease were randomly assigned to a pravastatin-treatment group (n = 52) or a control group (n = 23). Volumetric analyses were performed in matched coronary artery segments by 3-dimensional intravascular ultrasound. Pravastatin therapy for 6 months resulted in a decrease in coronary plaque volume (14.4%, p <0.0001) and a corresponding reduction in serum MDA-LDL levels (12.7%, p = 0.0001). In the pravastatin treatment group, the percentage of change in plaque volume correlated with changes in the MDA-LDL and high-density lipoprotein cholesterol levels (r = 0.52 and −0.55, respectively, p <0.0001) but not with the changes in any other lipid levels. Multivariate regression analysis revealed that a reduced MDA-LDL level is an independent predictor of plaque regression, as was an increase in high-density lipoprotein cholesterol. In conclusion, these results suggest that the reduction in the MDA-LDL levels induced by pravastatin may serve as a novel marker of coronary atherosclerosis regression.

Section snippets

Study design

The present study was a prospective, single-center, randomized, open trial of pravastatin therapy versus control on coronary plaque regression with serial volumetric intravascular ultrasound (IVUS) examination. Patients with a stable coronary artery were randomized in a 2:1 ratio to either the pravastatin treatment group or the control group. We enrolled patients with stable coronary artery disease who had undergone percutaneous coronary intervention after IVUS examination in the study. We

Patient characteristics

No significant differences were found between the 2 study groups with respect to gender, age, body mass index, serum lipid levels, coronary risk factors (prevalence of diabetes, hypertension, and smoking), or the use of concomitant drugs. The baseline characteristics of the 2 groups were well matched (Table 1). A total of 82 patients were eligible for the study and were randomized in a 2:1 ratio to the pravastatin treatment group or the control group. Five patients in the control group withdrew

Discussion

In this study, we have demonstrated that a decrease in the serum levels of MDA-LDL induced by pravastatin is associated with coronary atherosclerosis regression. Several studies have demonstrated that lipid-lowering therapy with statins can prevent progression and achieve regression of coronary atherosclerosis.10, 14, 15, 16, 17, 18 However, unlike previous studies, this is the first study to show the relation between coronary atherosclerosis regression and circulating MDA-LDL levels, as a

References (26)

T. Gordon et al.
High density lipoprotein as a protective factor against coronary heart disease
Am J Med
(1977)
S. Tani et al.
Aberrant antibody responses to oxidized LDL and increased intimal thickening in apoE−/− mice exposed to cigarette smoke
Atherosclerosis
(2004)
S.C. Smith et al.
AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease2001 update
J Am Coll Cardiol
(2001)
J. Kobayashi et al.
Singe LDL apheresis improves serum remnant-like particle-cholesterol, C-reactive protein, and malondialdehyde-modified-low-density lipoprotein concentrations in Japanese hypercholesterolemic subjects
Clin Chim Acta
(2002)
K. Ishikawa et al.
Effect of pravastatin on coronary plaque volume
Am J Cardiol
(2003)
H.R. Arntz et al.
Beneficial effects of pravastatin (+/−colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study)
Am J Cardiol
(2000)
T. Vasankari et al.
Oxidized LDL and thickness of carotid intima-media are associated with coronary atherosclerosis in middle-aged menlower levels of oxidized LDL with statin therapy
Atherosclerosis
(2001)
B. Cercek et al.
Nuclear factor-kappaB activity and arterial response to balloon injury
Atherosclerosis
(1997)
S. Tsimikas et al.
Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes
J Am Coll Cardiol
(2003)
H.B. Rubins et al.
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol
N Engl J Med
(1999)

J.J. Badimon et al.

High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits

Lab Invest

(1989)

A. Mertens et al.

Oxidized LDL and HDLantagonists in atherothrombosis

FASEB J

(2001)

P. Liuba et al.

Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media

Eur Heart J

(2003)

Cited by (59)

Atherosclerotic coronary plaque regression from lipid-lowering therapies: A meta-analysis and meta-regression
2024, American Journal of Preventive Cardiology
Studies reporting collective and comprehensive data on plaque regression of different lipid-lowering therapies (LLTs) are limited.
We evaluated plaque regression of LLTs based on multiple markers and performed subgroup analyses based on LLT type and post-treatment LDL-C levels
A literature search was performed to identify studies assessing plaque regression from LLTs. The following LLTs groups were included: High-intensity statin (HIS), HIS+ eicosapentaenoic acid (EPA), HIS + ezetimibe, Low-intensity statin (LIS), LIS + EPA, LIS + Ezetimibe, and PCSK9 inhibitors. Our primary outcomes were change in percent atheroma volume (PAV). Secondary outcomes included mean differences in total atheroma volume (TAV), lumen, plaque, and vessel volumes, fibrous cap thickness (FCT), and lipid arc (LA). Subgroup analyses were performed on LLT type and post-treatment LDL-C levels. Meta-regression was performed to control for covariates.
We identified 51 studies with 9,113 adults (22 % females). LLTs reduced PAV levels (-1.10 % [-1.63, -0.56], p < 0.01), with significant reduction observed with HIS, LIS + ezetimibe, LIS + EPA, and PCSK9 inhibitors. LLTs reduced TAV levels (-5.84 mm3 [-8.64 to -3.04] p < 0.01), mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). LLTs reduced plaque volume and LA and increased FCT.
The plaque regression associated with LLTs is observed to be mainly driven by HIS, reducing both TAV and PAV. This suggest that HIS is the most effective LLT for plaque regression
We evaluated plaque regression of LLTs from 51 studies. We found that while reduction of PAV (-1.10 % [-1.63, -0.56], p < 0.01) were present across different LLT types, reduction of TAV (-5.84 mm3 [-8.64 to -3.04] p < 0.01) was mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). These results suggest that HIS is the most effective LLT for plaque regression.
The association of circulating inflammatory and oxidative stress biomarker levels with diagonal earlobe crease in patients with atherosclerotic diseases
2016, Journal of Cardiology
Earlobe creases (ELC) are frequently observed in patients with atherosclerosis. Atherosclerosis is considered to be a systemic vascular inflammatory disease, and oxidative stress is known to be a contributor to vascular inflammation. It is well known that inflammatory biomarkers [high-sensitivity C-reactive protein (hs-CRP), pentraxin3 (PTX3)] and oxidative stress markers [malondialdehyde low-density lipoprotein (MDA-LDL)] are associated with atherosclerotic changes. This study was designed to test the hypothesis that biomarkers of inflammation and oxidative stress are increased in patients with ELC.
A total of 223 consecutive patients with atherosclerotic risk factors were enrolled and divided into two groups. One group consisted of patients with ELC (ELC group, n = 134) and the other was without ELC (non-ELC group, n = 89). Medical information and biomarker levels related to atherosclerosis were acquired from these patients.
The male ratio, prevalence of hypertension, diabetes mellitus, and MDA-LDL, hs-CRP, and PTX3 levels were found to be higher in the ELC group, compared with the non-ELC group. A multiple logistic regression analysis showed that PTX3 levels, rather than hs-CRP, constituted the strongest predictive factor for the appearance of ELC.
Vascular inflammation and oxidative stress are associated with the presence of ELC.
Investigation of MDA-LDL (malondialdehyde-modified low-density lipoprotein) as a prognostic marker for coronary artery disease in patients with type 2 diabetes mellitus
2015, Clinica Chimica Acta
Although increased circulating levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL) are associated with coronary artery disease (CAD), there is no direct evidence that increased MDA-LDL is a prognostic factor for CAD.
Forty-two patients (20 diabetic and 22 non-diabetic patients) who underwent percutaneous coronary intervention (PCI) were enrolled, and their baseline MDA-LDL levels were determined by immunoassay. Follow-up coronary angiography was performed at 2 to 7 months post-PCI. The patients were then divided into 2 groups, with in-stent restenosis (ISR) (n = 13) and without ISR (n = 29), and the baseline MDA-LDL levels were compared. We also studied 34 diabetics with CAD for up to 57 months until the onset of the next coronary event.
In the diabetic patients, the mean MDA-LDL level was significantly higher in those with ISR than in those without ISR (151 +/− 61 vs. 90 +/− 26 U/l, p = 0.010). A baseline MDA-LDL value of 110 U/l for differentiating between diabetics with and without ISR was defined as the cut-off value. Kaplan–Meier analysis demonstrated that a circulating MDA-LDL of ≥ 110 U/l correlated significantly with a higher prevalence of cardiac events than MDA-LDL < 110 U/l (p = 0.032).
Circulating MDA-LDL is a useful prognostic marker for future cardiac event in diabetic patients with CAD.
A systematic review of the time course of atherosclerotic plaque regression
2014, Atherosclerosis
We sought to determine the time required for lipid treatment to produce regression of atherosclerotic plaques.
The cholesterol content of atherosclerotic plaques contributes to their instability, and most acute cardiac events including myocardial infarction and sudden death are produced by coronary plaque disruption. We systematically reviewed the literature on atherosclerosis regression to identify the time required for cholesterol egress, plaque regression, and possible plaque stabilization. Such information may help decide when patients with statin side effects or other reasons for statin discontinuation could consider a reduction in the intensity of treatment.
We performed a PubMed search to identify English language articles reporting atherosclerotic regression. Articles pertinent to the topic were reviewed in detail.
We identified 189 articles, 50 of which provided sufficient information to establish a rate of regression and 31 of which demonstrated plaque regression with statin therapy in the carotid (n = 11), coronary (n = 16), and aortic (n = 4) vascular beds. Plaque regression occurred after an average of 19.7 months of treatment.
Regression of atherosclerotic plaque using statin therapy in those studies documenting regression occurred after an average time of 19.7 months. This suggests that patients should undergo approximately two years of aggressive lipid reduction before considering a reduction of statin therapy.
Atorvastatin 10mg plus ezetimibe 10mg compared with atorvastatin 20mg: Impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease
2012, Journal of Cardiology
Citation Excerpt :
Oxidised LDL cholesterol (including MDA-LDL) is a relatively new marker of oxidative stress, which has been reported to be a stronger predictor of cardiovascular risk than standard lipid parameters [17,18]. In particular, the plasma level of MDA-LDL is related to atherogenic processes such as foam cell formation, endothelial dysfunction, and vascular inflammation [17–19]. Although combination therapy with ezetimibe and a statin has been shown to reduce atherogenic oxidized LDL cholesterol in addition to lowering LDL cholesterol [20], a clinical trial has not been performed to investigate the differential effects of these drugs.
Oxidized low-density lipoprotein (LDL) cholesterol is a sensitive lipid marker for predicting atherosclerosis. Ezetimibe and statins are reported to decrease both LDL cholesterol and oxidized LDL cholesterol. This prospective randomized open-label crossover study compared combination therapy with atorvastatin plus ezetimibe versus high-dose atorvastatin monotherapy. Changes in serum lipids, including malondialdehyde-modified LDL (MDA-LDL) as a representative form of oxidized LDL cholesterol, and glucose metabolism were assessed.
The subjects were 39 Japanese patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance who were taking 10 mg/day of atorvastatin (30 men and 9 women with a mean age of 67.8 years). They were randomized to a group that first received add-on ezetimibe (10 mg/day) or a group that first received atorvastatin monotherapy at a higher dose of 20 mg/day. Both treatments were given for 12 weeks each in a crossover fashion. Add-on ezetimibe significantly decreased MDA-LDL (109.0 ± 31.9 mg/dl to 87.7 ± 29.4 mg/dl, p = 0.0009), while up-titration of atorvastatin did not. The decrease with add-on ezetimibe was significantly greater than with up-titration of atorvastatin (p = 0.0006). Total cholesterol and LDL cholesterol were significantly decreased by both treatments, but the percent reduction with add-on ezetimibe was significantly greater (p < 0.05). High-density lipoprotein cholesterol was significantly increased by both treatments and there was no significant difference between them. The apolipoprotein B/apolipoprotein A-I ratio and remnant-like particle cholesterol were only significantly decreased by add-on ezetimibe. Both treatments caused similar elevation of hemoglobin A_1c.
In Japanese patients with type 2 diabetes or impaired glucose tolerance and coronary artery disease, adding ezetimibe (10 mg/day) to atorvastatin (10 mg/day) significantly improved the lipid profile compared with atorvastatin monotherapy at 20 mg/day.
Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk
2022, International Journal of Molecular Sciences

View all citing articles on Scopus

View full text

Coronary artery diseaseEffect of Pravastatin on Malondialdehyde-Modified Low-Density Lipoprotein Levels and Coronary Plaque Regression as Determined by Three-Dimensional Intravascular Ultrasound

Section snippets

Study design

Patient characteristics

Discussion

Am J Med

Atherosclerosis

J Am Coll Cardiol

Clin Chim Acta

Am J Cardiol

Am J Cardiol

Atherosclerosis

Atherosclerosis

J Am Coll Cardiol

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol

N Engl J Med

High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits

Lab Invest

Oxidized LDL and HDLantagonists in atherothrombosis

FASEB J

Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media

Eur Heart J

Coronary artery disease
Effect of Pravastatin on Malondialdehyde-Modified Low-Density Lipoprotein Levels and Coronary Plaque Regression as Determined by Three-Dimensional Intravascular Ultrasound