Changes in lipoproteins associated with lipid-lowering and antiplatelet strategies in patients with acute myocardial infarction

Zahra Lotfollahi, Ana P Q Mello, Francisco A H Fonseca, Luciene O Machado, Andressa F Mathias, Maria C Izar, Nagila R T Damasceno, Cristiano L P Oliveira, Antônio M F Neto, Zahra Lotfollahi, Ana P Q Mello, Francisco A H Fonseca, Luciene O Machado, Andressa F Mathias, Maria C Izar, Nagila R T Damasceno, Cristiano L P Oliveira, Antônio M F Neto

Abstract

Background: Despite lipid-lowering and antiplatelet therapy, the pattern of residual lipoproteins seems relevant to long-term cardiovascular outcomes. This study aims to evaluate the effects of combined therapies, commonly used in subjects with acute myocardial infarction, in the quality of low-density lipoprotein (LDL) particles.

Methods: Prospective, open-label trial, included patients with acute myocardial infarction. Patients were randomized to antiplatelet treatment (ticagrelor or clopidogrel) and subsequently to lipid-lowering therapy (rosuvastatin or simvastatin/ezetimibe) and were followed up for six months. Nonlinear optical properties of LDL samples were examined by Gaussian laser beam (Z-scan) to verify the oxidative state of these lipoproteins, small angle X-ray scattering (SAXS) to analyze structural changes on these particles, dynamic light scattering (DLS) to estimate the particle size distribution, ultra violet (UV)-visible spectroscopy to evaluate the absorbance at wavelength 484 nm (typical from carotenoids), and polyacrylamide gel electrophoresis (Lipoprint) to analyze the LDL subfractions.

Results: Simvastatin/ezetimibe with either clopidogrel or ticagrelor was associated with less oxidized LDL, and simvastatin/ezetimibe with ticagrelor to lower cholesterol content in the atherogenic subfractions of LDL, while rosuvastatin with ticagrelor was the only combination associated with increase in LDL size.

Conclusions: The quality of LDL particles was influenced by the antiplatelet/lipid-lowering strategy, with ticagrelor being associated with the best performance with both lipid-lowering therapies. Trial registration: NCT02428374.

Conflict of interest statement

I confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials. The study design, data collection, statistical analysis, or publications were not influenced by the sponsors and are the exclusive responsibility of the investigators.

Figures

Fig 1. Enrollment and flow of patients.
Fig 1. Enrollment and flow of patients.
From the total of 143 subjects assessed for eligibility, 14 were excluded due to inclusion or exclusion criteria and 6 did not complete the 6 months follow-up.
Fig 2. Graphical abstract.
Fig 2. Graphical abstract.
Fig 3. Box-plot for phase shift (θ)…
Fig 3. Box-plot for phase shift (θ) at baseline (T0) and after six months (T6).
(A) according to lipid-lowering and antiplatelet drugs; (B) for combined therapies. Simvastatin/ezetimibe (SIMVA/E), rosuvastatin (RSV), ticagrelor (TICA) and clopidogrel (CLOP). (*: significant difference, Wilcoxon signed rank test, **: significant difference, Mann-Whitney U test).
Fig 4. Correlations between absorbance at wavelength…
Fig 4. Correlations between absorbance at wavelength 484 nm and phase shift (θ) after six months of combined therapy (T6).
(A) rosuvastatin-clopidogrel (RSV-CLOP); (B) rosuvastatin-ticagrelor (RSV-TICA); (C) simvastatin/ezetimibe-clopidogrel (SIMVA/E-CLOP); (D) simvastatin/ezetimibe-ticagrelor (SIMVA/E-TICA). Significant correlations were observed for all the combined therapies at T6 (Spearman rank test).
Fig 5. Box-plots for combined therapies at…
Fig 5. Box-plots for combined therapies at baseline (T0) and after six months (T6).
(A) radius of the LDL particles RLDL; (B) relative electronic density contrast of the LDL particles |μLDL|. Simvastatin/ezetimibe (SIMVA/E), rosuvastatin (RSV), ticagrelor (TICA) and clopidogrel (CLOP). (*: significant difference, Wilcoxon signed rank test and **: significant difference, Kruskal-Wallis test with Dunn’s post-hoc test, p<0.05).
Fig 6. Classic lipid profile at baseline…
Fig 6. Classic lipid profile at baseline (T0) and after six months (T6).
(A) Total cholesterol at T0 and at T6 with combined therapy. Significant decrease was observed with all the combined therapies. For rosuvastatin-clopidogrel (p = 7.4E-9); for rosuvastatin-ticagrelor (p = 3.7E-9); for simvastatin/ezetimibe-clopidogrel (p = 1.4E-8); and for simvastatin/ezetimibe-ticagrelor (p = 1.8E-9). (B) LDL-C at T0 and at T6 with combined therapy. Significant decrease was observed with all the combined therapies. For rosuvastatin-clopidogrel (p = 1.8E-9); for rosuvastatin-ticagrelor (p = 3.7E-9); for simvastatin/ezetimibe-clopidogrel (p = 5.9E-8); and for simvastatin/ezetimibe-ticagrelor (p = 4.6E-10). (C) Non-HDL-C at T0 and at T6 with combined therapy. Significant decrease was observed with all the combined therapies. For rosuvastatin-clopidogrel (p = 2.9E-8); for rosuvastatin-ticagrelor (p = 3.4E-9); for simvastatin/ezetimibe-clopidogrel (p = 2.9E-8); and for simvastatin/ezetimibe-ticagrelor (p = 4.6E-10). (D) HDL-C at T0 and at T6 with combined therapy. None of the combined therapies significantly changed HDL-C. For rosuvastatin-clopidogrel (p = 0.1580); for rosuvastatin-ticagrelor (p = 0.9062); for simvastatin/ezetimibe-clopidogrel (p = 0.6402); and for simvastatin/ezetimibe-ticagrelor (p = 0.1750). (E) Triglycerides at T0 and at T6. Only the combined groups with ticagrelor showed significant decrease in triglycerides. For rosuvastatin-clopidogrel (p = 0.667); for rosuvastatin-ticagrelor (p = 0.020); for simvastatin/ezetimibe-clopidogrel (p = 0.640); and for simvastatin/ezetimibe-ticagrelor (p = 0.006). RSV–rosuvastatin; SIMVA/E–simvastatin/ezetimibe; CLOP–clopidogrel; TICA–ticagrelor. (*: significant difference, Wilcoxon signed rank test).
Fig 7. LDL subfractions at baseline (T0)…
Fig 7. LDL subfractions at baseline (T0) and after six months (T6).
(A) Group rosuvastatin-ticagrelor (RSV/TICA). The combined therapy decreased the cholesterol content of large and buoyant LDL particles (LDL1 and LDL 2) (p
All figures (7)

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