mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques.

Statins are currently able to stabilize atherosclerotic plaques by lowering plasma cholesterol and pleiotropic effects, but a residual risk for atherosclerotic disease remains. Therefore, effective prevention of atherosclerosis and treatment of its complications is still a major clinical challenge. A large body of evidence indicates that mammalian target of rapamycin (mTOR) inhibitors such as rapamycin or everolimus have pleiotropic anti-atherosclerotic effects so that these drugs can be used as add-on therapy to prevent or delay the pathogenesis of atherosclerosis. Moreover, bioresorbable scaffolds eluting everolimus trigger a healing process in the vessel wall, both in pigs and humans, that results in late lumen enlargement and plaque regression. At present, this phenomenon of atheroregression is poorly understood. However, given that mTOR inhibitors suppress cell proliferation and trigger autophagy, a cellular survival pathway and a process linked to cholesterol efflux, we hypothesize that these compounds can inhibit (or reverse) the basic mechanisms that control plaque growth and destabilization. Unfortunately, adverse effects associated with mTOR inhibitors such as dyslipidemia and hyperglycemia have recently been identified. Dyslipidemia is manageable via statin treatment, while the anti-diabetic drug metformin would prevent hyperglycemia. Because metformin has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, both statins and metformin are known to inhibit mTOR via AMPK activation so that they would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis.

Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability.

OBJECTIVE: Matrix metalloproteinases (MMPs) form a large family of enzymes that collectively can degrade all components of the extracellular matrix, and there is widespread interest in developing MMP inhibitors for the prevention of atherosclerotic plaque rupture. We have therefore investigated the effects of a broad-spectrum MMP inhibitor, RS-130830, on plaque development and stability. This compound inhibits a wide range of MMPs at concentrations below 20 nmol/L. METHODS: Apolipoprotein E knockout mice were fed a Western diet. Dietary administration of RS-130830 commenced at the same time as fat-feeding and continued for 8, 12, 26 or 36 weeks. To investigate the effect of RS-130830 on established plaques, mice were fed high-fat diet for 16 weeks before initiation of drug treatment and were terminated 20 weeks after this. RESULTS: Broad-spectrum MMP inhibition was associated with a significant increase in plaque area, but there was no change in the incidence of plaque rupture. There were unfavourable changes in phenotypic characteristics associated with plaque instability, such as an increased lipid content and decreased collagen content. CONCLUSIONS: These data suggest that broad-spectrum MMP inhibition RS-130830 does not have a beneficial effect on atherosclerosis in the apolipoprotein E knockout mouse model, and indicate that more selective compounds would be preferable.

S18886, a selective TP receptor antagonist, inhibits development of atherosclerosis in rabbits.

OBJECTIVE: To investigate the effect of S18886, a novel TP (thromboxane A2 and prostaglandin endoperoxide) receptor antagonist, on the development of aortic fatty streaks and advanced lesions in a rabbit model of atherosclerosis and restenosis. METHODS AND RESULTS: The right iliac artery of 96 rabbits (8 groups, n=12/group) was balloon injured, then the animals were fed a cholesterol-enriched diet for 6 weeks. In Groups 1-4, concomitant oral administration of S18886 at 5 mg/kg/day over the 6-week-period reduced the intima to media ratio of lesions in the uninjured aorta and injured iliac artery, the accumulation of macrophages and the expression of ICAM-1 compared with 1 mg/kg/day S18886, 30 mg/kg/day aspirin and placebo, with no effect on body weight or plasma cholesterol levels. In Groups 5-8, 2 weeks of treatment with 5 mg/kg/day S18886 reduced the intima to media ratio of restenosing lesions when pre-formed iliac artery lesions underwent a second balloon injury at week 6. The smaller lesions resulting from S18886 treatment correlated with a significant decrease in the neointimal area occupied by macrophages, as well as in ICAM-1 expression, with no effect on the smooth muscle component. Aspirin treatment had no significant effect on the neointimal smooth muscle component, but partially inhibited macrophage infiltration, without inhibiting ICAM-1 expression. CONCLUSION: Inhibition of the TP receptor using S18886 causes a significant decrease in the recruitment of monocyte/macrophages within fatty streaks in the uninjured aorta and within primary and restenosing atherosclerotic lesions in the iliac artery of rabbits. Since TP receptor agonists, such as thromboxane A2, prostanoid endoperoxides and isoprostanes participate in vessel wall inflammation and are localized and increased in atherosclerotic plaques, treatment with S18886 may enhance atherosclerotic lesion stability by attenuating inflammatory processes that ultimately lead to plaque rupture.

Intra-arterial alcoholization of advanced hepatocellular carcinoma.

For the purpose of achieving emergency hemostasis of a ruptured hepatocellular carcinoma (HCC) or prevention of such rupture, we applied a new method of transcatheter therapy: intra-arterial alcoholization. Five patients with a ruptured HCC and 42 with an impending rupture were treated by intra-arterial injection of absolute ethanol mixed with an equal volume of iodized oil, Lipiodol (EtOH-Lp). The tumor size ranged from 4 to 26 cm (mean 7.8 cm) in diameter. The catheter tip was placed in the segmental branch or a more distal position of the hepatic artery, and 2-40 (mean 10.6) ml of EtOH-Lp was infused under fluoroscopic guidance. Infiltration of ethanol into the HCC mass was recognized as a dense deposition of Lipiodol on plain abdominal X-rays and computed-tomography. In all five cases of ruptured HCC, hemostasis was achieved. In all 42 cases of impending rupture, tumor rupture was prevented, and all except 3 patients could be discharged. No significant complication of the gastrointestinal tract or biliary tract was seen. The incidence and severity of postembolization syndrome was markedly lower than those seen in cases treated with Gelfoam embolization.