Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury

Alex Helkin, David Bruch, David R. Wilson, Angelika C Gruessner, Rebecca R. Bader, Kristopher G. Maier, Vivian Gahtan

Research output: Contribution to journalArticle

Abstract

Introduction: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid–polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. Methods: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy—intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the –intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. Results: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. Conclusions: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

Original languageEnglish (US)
JournalVascular and endovascular surgery
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Tunica Intima
Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperplasia
Micelles
Wounds and Injuries
Vascular Smooth Muscle
Smooth Muscle Myocytes
Chemotaxis
Gels
Poloxamer
Therapeutics
Cell Proliferation
Endovascular Procedures
Drug Carriers
Common Carotid Artery
Platelet-Derived Growth Factor
Hyaluronic Acid
Drug Delivery Systems
Cell Movement

Keywords

  • arterial disease
  • balloon injury
  • intimal hyperplasia
  • micelles
  • statin

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury. / Helkin, Alex; Bruch, David; Wilson, David R.; Gruessner, Angelika C; Bader, Rebecca R.; Maier, Kristopher G.; Gahtan, Vivian.

In: Vascular and endovascular surgery, 01.01.2019.

Research output: Contribution to journalArticle

Helkin, Alex ; Bruch, David ; Wilson, David R. ; Gruessner, Angelika C ; Bader, Rebecca R. ; Maier, Kristopher G. ; Gahtan, Vivian. / Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury. In: Vascular and endovascular surgery. 2019.
@article{cc56294a11824365bc3a52a25798abc6,
title = "Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury",
abstract = "Introduction: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25{\%}. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid–polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. Methods: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy—intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the –intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. Results: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54{\%}-60{\%}). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. Conclusions: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.",
keywords = "arterial disease, balloon injury, intimal hyperplasia, micelles, statin",
author = "Alex Helkin and David Bruch and Wilson, {David R.} and Gruessner, {Angelika C} and Bader, {Rebecca R.} and Maier, {Kristopher G.} and Vivian Gahtan",
year = "2019",
month = "1",
day = "1",
doi = "10.1177/1538574419833224",
language = "English (US)",
journal = "Vascular and Endovascular Surgery",
issn = "1538-5744",
publisher = "SAGE Publications Inc.",

}

TY - JOUR

T1 - Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury

AU - Helkin, Alex

AU - Bruch, David

AU - Wilson, David R.

AU - Gruessner, Angelika C

AU - Bader, Rebecca R.

AU - Maier, Kristopher G.

AU - Gahtan, Vivian

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid–polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. Methods: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy—intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the –intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. Results: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. Conclusions: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

AB - Introduction: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid–polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. Methods: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy—intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the –intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. Results: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. Conclusions: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

KW - arterial disease

KW - balloon injury

KW - intimal hyperplasia

KW - micelles

KW - statin

UR - http://www.scopus.com/inward/record.url?scp=85064612987&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064612987&partnerID=8YFLogxK

U2 - 10.1177/1538574419833224

DO - 10.1177/1538574419833224

M3 - Article

JO - Vascular and Endovascular Surgery

JF - Vascular and Endovascular Surgery

SN - 1538-5744

ER -