Thermal Preconditioning Before Rat Arterial Balloon Injury

Limitation of Injury and Sustained Reduction of Intimal Thickening

From the Departments of Surgery (D.G.N., S.D.S., M.L.D., A.K.H., M.A.G.), Medicine (P.N.R., D.J.L., K.K., E.S.B.), and Pathology (J.E.T.), University of Pennsylvania Medical Center, Philadelphia, Pa.

Correspondence to Michael A. Golden, MD, Department of Surgery, Hospital of the University of Pennsylvania, 4 Silverstein Pavilion, 3400 Spruce St, Philadelphia, PA 19104. E-mail goldenm{at}mail.med.upenn.edu.

Abstract—Heat shock proteins (HSPs) are a family of highly conserved proteins, essential to cell survival, that are induced during times of physiological stress. These proteins, when induced, can provide tolerance to subsequent injury. Several studies have documented that HSPs play an important role in the response of vascular cells to injury or stress. Whether the vasculature itself can be effectively preconditioned before arterial injury is unknown. Vascular HSP induction by whole-body hyperthermia (WBH) was evaluated with regard to its effects on the vascular response to balloon injury. WBH treatment of Sprague-Dawley rats (colonic temperatures of 41 to 42°C for 15 minutes) resulted in maximal arterial HSP expression within 8 to 12 hours. Rats (male, 300 g, n=59) were randomly assigned to undergo either WBH or no treatment 8 hours before standard carotid balloon injury. At 14 (n=26) and 90 (n=21) days after balloon injury, histomorphometric analysis revealed a significant limitation of intimal accumulation in preconditioned arteries as compared to controls (intimal/medial area ratios±SEM: 14 days, 0.57±0.07 versus 0.86±0.08, P=0.01; 90 days, 0.78±0.12 versus 1.19±0.14, P<0.05). The medial cell proliferation index at 4 days (n=12) was significantly reduced in the treated group as well (3.6±0.9% versus 7.2±1.3%, P<0.05). Conversely, the mean total cell number in the media of heated arteries was higher (393±20 versus 328±17, P<0.05). Vascular preconditioning with brief WBH induces a heat shock response in the arterial wall that is associated with a significant and sustained reduction in intimal accumulation. This effect appears to be due in part to preservation of medial cell integrity and limitation of the proliferative response. These results suggest that thermal preconditioning of vascular tissue may be an effective strategy to improve long-term results after revascularization procedures.

Key Words: heat shock proteins • arteries • restenosis • smooth muscle • balloon

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