Adaptive-outward and maladaptive-inward arterial remodeling measured by intravascular ultrasound in hyperhomocysteinemia and diabetes.

BACKGROUND: Coronary artery remodeling implies structural changes in the vessel wall in response to various pathophysiologic conditions. However, the classification of remodeling is unclear. We hypothesized that the adaptive, positive-outward remodeling is a reactive and compensatory response to the stress. The maladaptive negative-inward constrictive remodeling is a passive atherosclerotic condition in which the vessel becomes stiffer. METHODS: Patients with atherosclerotic lesions underwent intravascular ultrasound (IVUS) scans. The size of the vessels distal to and proximal to plaques were analyzed by IVUS. Diabetes was created in mice by an intraperitoneal injection of alloxan (65 mg/kg). To reduce remodeling, mice received ciglitazone, an agonist of peroxisome proliferators activated receptor-gamma (PPARgamma) in drinking water. After 8 weeks, atherosclerotic vessels were analyzed for collagen and elastin. RESULTS: IVUS data suggest an adaptive coronary arterial remodeling was a positive compensatory response to various pathologic stimuli; for example, with the deposition of atherosclerotic plaque, coronary arterial segments enlarged to maintain luminal area. This phenomenon was commonly observed during the initial phases of the development of atherosclerosis. However, negative coronary artery remodeling, or a decrease in vessel area with the formation of atherosclerotic plaque, was maladaptive and was associated with smoking, hypertension, hyperhomocysteinemia, diabetes mellitus, and also after percutaneous coronary interventions (restenosis). In diabetic mice, there was increased collagen and decreased elastin contents; however, treatment with ciglitazone ameliorated the decrease in elastin contents. CONCLUSION: Global enlargement of the coronary vascular tree occurs during pressure and volume overload associated with ventricular hypertrophic states such as athletic conditioning, hypertensive heart disease, and dilated cardiomyopathy. On the other hand, maladaptive coronary arterial remodeling occurs in patients with severe deconditioning, diabetes mellitus, after coronary artery bypass surgery, and in some instances, postintervention.

Ischemic preconditioning of skeletal muscle: duration of late-phase protection.

BACKGROUND: The time course of the late phase of ischemic preconditioning (IPC) was determined in latissimus dorsi muscle (LDM) flaps using viability and function as the endpoints. MATERIALS AND METHODS: LDM flaps from Sprague-Dawley rats were allocated into 6 groups. LDMs were preconditioned with 2 30-minute periods of ischemia separated by 10 minutes of reperfusion and subjected to a 4-hour ischemic insult after 24, 48, 72, and 96 hours from IPC. LDMs were evaluated for percent necrosis and muscle contractile function and compared with controls. RESULTS: The late phase of IPC provides significant protection against necrosis up to 72 hours. Conversely, when the end point used was muscle contractile function, the protection only lasted 48 hours. CONCLUSION: The time course of late-phase protection in skeletal muscle is 2-3 days. Late phase IPC appears to protect muscle flaps during the most critical time period following elevation.

Late-phase ischemic preconditioning in skeletal muscle: is the phenomenon protective?

Reports in the literature on the effectiveness of late-phase Ischemic preconditioning (IPC) in skeletal muscle are controversial. The purpose of this study was to determine in the same muscle flap model the effectiveness of various IPC protocols in inducing late-phase protection. Rat latissimus dorsi muscle (LDM) flaps were preconditioned with either 30 or 60 min of total ischemia, divided as follows: single cycles of either 30 or 60 min, two cycles of 15 or 30 min, and three cycles of 10 or 20 min. Ischemia cycles were separated by 10 min of reperfusion. A day after IPC, flaps were elevated and challenged with 4 h of ischemia. Three days later, flaps were assessed for viability. We found that IPC protocols of different total durations and comprised of two or three cycles of ischemia elicited a protective effect against necrosis. We conclude that IPC induces late-phase protection against necrosis in skeletal muscle, and that the protection requires more than one ischemia/reperfusion cycle.

The use of end-to-side nerve grafts to reinnervate the paralyzed orbicularis oculi muscle.

Facial paralysis is a serious neurologic disorder, particularly when it affects the eye. Loss of the protective blink reflex may lead to corneal ulceration and, possibly, visual loss. The purpose of this study was to compare different nerve-grafting techniques to reanimate the paralyzed eyelid. Sixteen adult dogs (25 kg each) were allocated into four groups. Denervation of the left hemi-face was performed in all cases. One dog served as a control animal (group I). Group II dogs (n = 5) underwent end-to-side coaptation of the nerve graft to the intact palpebral branch and end-to-end coaptation to the denervated palpebral branch. Group III dogs (n = 5) underwent end-to-end coaptation of the nerve graft to the intact palpebral branch and end-to-end coaptation to the denervated palpebral branch. Group IV dogs (n = 5) underwent end-to-side coaptation of the nerve graft to the intact and denervated palpebral branches. The animals were monitored for 9 months after the surgical procedures, to allow adequate time for reinnervation. The dogs were postoperatively monitored with clinical observation, electrophysiologic testing, video motion analysis, and histologic assessments. Clinical observation and electrophysiologic testing demonstrated the production of an eye blink in the denervated hemi-face in all experimental groups. There was a trend toward increased speed of reinnervation for group III animals (end-to-end coaptations). It was concluded that end-to-side coaptation can produce a contralateral synchronous eye blink in a clinically relevant, large-animal model.

Preconditioning of latissimus dorsi muscle flaps with monophosphoryl lipid a.

The use of dynamic myoplasty to restore function to failing organs is an exciting new application of skeletal muscle flaps. A complication of large flap elevation that can compromise flap function is ischemia-induced necrosis; one approach to minimizing this is to pretreat tissues with ischemic preconditioning. The purpose of this study was to determine whether systemic administration of monophosphoryl lipid A, a drug known to mimic late-phase ischemic preconditioning in the heart, could reduce ischemia-induced necrosis in latissimus dorsi muscle flaps. Forty latissimus dorsi muscle flaps from 20 Sprague-Dawley rats were allocated into four groups. In group I (n = 10), flaps were not preconditioned and served as controls. In group II (n = 10), flaps received ischemic preconditioning with two 30-minute periods of ischemia interspersed by 10 minutes of reperfusion. In group III (n = 10), rats received an intravenous bolus of approximately 0.3 ml of monophosphoryl lipid A vehicle only. In group IV (n = 10), rats received an intravenous bolus of 450 microg/kg of monophosphoryl lipid A and vehicle. Twenty-four hours after treatment, all latissimus dorsi muscle flaps were elevated on a single neurovascular pedicle and subjected to 4 hours of ischemia. After 72 hours of reperfusion, latissimus dorsi muscles were harvested, weighed, stained with nitroblue tetrazolium, and assessed for percent necrosis using digitized images of muscle sections and computerized planimetry. The percent necrosis in ischemic preconditioning-treated flaps (group II) was significantly reduced by 57 percent (p < 0.05) compared with control flaps (group I). The percent necrosis in flaps treated with monophosphoryl lipid A (group IV) was significantly reduced by 58 percent (p < 0.05) compared with vehicle-control flaps (group III). There was no difference in mean percent necrosis between ischemic preconditioning (group II) and monophosphoryl lipid A-treated (group IV) flaps or between ischemic preconditioning-control (group I) and monophosphoryl lipid A vehicle-control (group III) flaps. Intravenous administration of systemic monophosphoryl lipid A mimics the late-phase protective effect of ischemic preconditioning in the authors' rat latissimus dorsi muscle flap model.

Targeting of glycosaminoglycan-cytokine interactions as a novel therapeutic approach in allotransplantation.

BACKGROUND: Glycosaminoglycans (GAGs) are heteropolysaccharides present as integral components of the extracellular matrix (ECM), cell and basement membranes. GAGs play an important role in immune and inflammatory responses because of their ability to interact with cytokines and chemokines, promoting the localization of these molecules onto the ECM or cell membranes at specific anatomical sites. The main goal of these studies was to test the hypothesis that interference with the binding of cytokines/chemokines to GAGs will interfere with a graft rejection response. METHODS: MC-2, a cationic peptide derived from the sequence of the heparin-binding domain of mouse interferon gamma, was used as an inhibitor of the binding of cytokines/chemokines to GAGs. The effects of this peptide were studied in an allogeneic transplantation model involving vascularized rat skin flaps. RESULTS: The MC-2 peptide was found to inhibit binding of interferon-gamma, as well as that of the chemokines, interleukin-8, interferon gamma inducible protein-10, and regulated on activation normal T cell expressed and secreted (RANTES), to GAGs in vitro. Direct administration of MC-2 in an allogeneic skin flap transplantation model resulted in a significantly delayed time of rejection, from 5.4 +/- 0.5 days (control; n=6) to 12.6 +/- 1.6 days (treated animals; n=10). Histopathologic analysis of the skin biopsies was consistent with the delayed rejection process in those animals receiving the peptide, showing only mild signs of rejection up to day 11 (in contrast, all control animals had rejected their flaps by day 6). CONCLUSIONS: These results are consistent with the idea that GAG-cytokine interactions constitute valid therapeutic targets and suggest the potential applicability of such an approach in the prevention of graft rejection.