Potential Clinical Applications of Statins Targeting the Microvasculature

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Cardiovascular Disease

The pleiotropic actions of statins have been postulated to account for the impressive clinical benefits observed in atherosclerotic cardiovascular disease independent of cholesterol lowering. Improved microvascular function likely contributes to these benefits. Hypercholesterolemia, diabetes, and hypertension are all associated with impaired endothelium-dependent vasodilation, which is improved within days by statin therapy in humans. The stimulation of angiogenesis by these agents would be expected to promote the normal adaptive response of the microcirculation to chronic ischemia. In a murine model of hind limb ischemia, simvastatin at a dose of 0.1 mg/kg promoted new capillary formation and collateral flow. The microcirculation also plays an important role in the progression of large vessel plaques. The vasa vasorum of these arteries is the source of inflammatory cells that can promote plaque rupture. Statins may help to stabilize such lesions. Some investigators have speculated that the anti-angiogenic effects of high-dose statin therapy, by reducing plaque neovascularization, contributes to their clinical efficacy. The role of the anti-inflammatory effects of statins in atherosclerosis is suggested by the observation that these agents reduce C-reactive protein, an important risk factor for cardiovascular events.

Vascular smooth muscle cell hyperplasia and endothe-lial dysfunction are felt to underlie the pathogenesis of pulmonary hypertension. Statins attenuate and reverse experimental models of pulmonary hypertension.

Ischemia-ReperfUsion Injury (IRI)

An impairment of eNOS activity and increased ROS generation, followed by adherence of leukocytes and thrombosis within the microvasculature, are key events in the development of IRI. In multiple studies of cardiac IRI, pretreatment with statins reduces infarct size and left ventricular dysfunction. Significant protection has also been demonstrated in animal models of IRI in lung, brain, and kidney at physiologically relevant doses (e.g., 0.5mg/kg of simvastatin). In most studies, an important mechanism appears to be enhancement of NO activity, as NOS antagonists reversed the statin effect.

IRI is thought to underlie the pathogenesis of the multiple organ dysfunction syndrome complicating sepsis. A provocative retrospective study reported a mortality of 6 percent in bacteremic patients taking statins compared with 28 percent in nonusers of statins.

Neurologic Disease [10]

Statins inhibit the migration of lymphocytes across the blood-brain barrier and attenuate the severity of experimental autoimmune encephalomyelitis, a model of multiple sclerosis. A small clinical trial demonstrated a 45 percent reduction in the number of gadolinium-enhancing lesions on MRI. Alzheimer's dementia is becoming increasingly recognized as a disorder of the cerebral microcirculation. Epidemiologic data suggest a 70 percent reduction in the prevalence of dementia in statin users, and large trials are currently underway.

Transplant Rejection

The use of pravastatin in heart transplant recipients is associated with a significant reduction in acute rejection, as well as transplant coronary vasculopathy. A recent retrospective study reported a surprisingly lower incidence of acute rejection and obliterative bronchiolitis after lung transplantation. No reduction in renal allograft rejection has been observed with statin therapy, although statins may improve survival in these patients by reducing cardiovascular events.

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