Community-based statins and advanced carotid plaque: Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque

Fumiyuki Otsuka, Xiao Qing Zhao, Hugh H. Trout, Ye Qiao, Bruce A Wasserman, Masataka Nakano, Colin H. Macphee, Martin Brandt, Sue Krug-Gourley, Liang Guo, Elena R. Ladich, Qi Cheng, Harry R. Davis, Aloke V. Finn, Renu Virmani, Frank D. Kolodgie

Research output: Contribution to journalArticle

Abstract

Background and aims Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. Methods Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). Results Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. Conclusions Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.

Original languageEnglish (US)
Pages (from-to)78-89
Number of pages12
JournalAtherosclerosis
Volume267
DOIs
StatePublished - Dec 1 2017

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1-Alkyl-2-acetylglycerophosphocholine Esterase
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Atherosclerotic Plaques
Macrophages
Cell Death
Apoptosis
Inflammation
Endarterectomy
LDL Cholesterol
Lipoproteins
Fluorescent Antibody Technique
Monocytes
Pathologic Constriction
Anti-Inflammatory Agents
Cardiovascular Diseases
Therapeutics
Biomarkers
History
Myocardial Infarction
Staining and Labeling

Keywords

  • Carotid artery
  • Lipoprotein-associated phospholipase A
  • Macrophage
  • Pathology
  • Statin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Community-based statins and advanced carotid plaque : Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque. / Otsuka, Fumiyuki; Zhao, Xiao Qing; Trout, Hugh H.; Qiao, Ye; Wasserman, Bruce A; Nakano, Masataka; Macphee, Colin H.; Brandt, Martin; Krug-Gourley, Sue; Guo, Liang; Ladich, Elena R.; Cheng, Qi; Davis, Harry R.; Finn, Aloke V.; Virmani, Renu; Kolodgie, Frank D.

In: Atherosclerosis, Vol. 267, 01.12.2017, p. 78-89.

Research output: Contribution to journalArticle

Otsuka, F, Zhao, XQ, Trout, HH, Qiao, Y, Wasserman, BA, Nakano, M, Macphee, CH, Brandt, M, Krug-Gourley, S, Guo, L, Ladich, ER, Cheng, Q, Davis, HR, Finn, AV, Virmani, R & Kolodgie, FD 2017, 'Community-based statins and advanced carotid plaque: Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque', Atherosclerosis, vol. 267, pp. 78-89. https://doi.org/10.1016/j.atherosclerosis.2017.10.014
Otsuka, Fumiyuki ; Zhao, Xiao Qing ; Trout, Hugh H. ; Qiao, Ye ; Wasserman, Bruce A ; Nakano, Masataka ; Macphee, Colin H. ; Brandt, Martin ; Krug-Gourley, Sue ; Guo, Liang ; Ladich, Elena R. ; Cheng, Qi ; Davis, Harry R. ; Finn, Aloke V. ; Virmani, Renu ; Kolodgie, Frank D. / Community-based statins and advanced carotid plaque : Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque. In: Atherosclerosis. 2017 ; Vol. 267. pp. 78-89.
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abstract = "Background and aims Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. Methods Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). Results Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin na{\"i}ve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. Conclusions Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.",
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T1 - Community-based statins and advanced carotid plaque

T2 - Role of CD163 positive macrophages in lipoprotein-associated phospholipase A2 activity in atherosclerotic plaque

AU - Otsuka, Fumiyuki

AU - Zhao, Xiao Qing

AU - Trout, Hugh H.

AU - Qiao, Ye

AU - Wasserman, Bruce A

AU - Nakano, Masataka

AU - Macphee, Colin H.

AU - Brandt, Martin

AU - Krug-Gourley, Sue

AU - Guo, Liang

AU - Ladich, Elena R.

AU - Cheng, Qi

AU - Davis, Harry R.

AU - Finn, Aloke V.

AU - Virmani, Renu

AU - Kolodgie, Frank D.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background and aims Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. Methods Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). Results Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. Conclusions Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.

AB - Background and aims Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. Methods Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). Results Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. Conclusions Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.

KW - Carotid artery

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KW - Pathology

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