Archief Roodbont

Question
What is the role of statins in the treatment of pulmonary hypertension (PH)?

The HMG-CoA reductase inhibitors (statins) are known to provide antiproliferative and anti-inflammatory cardiovascular benefits. During the past few years, more evidence has been gathered that statins can reduce various forms of pulmonary hypertension (PH). Different animal models of PH have been developed ranging from the hypoxic to the monocrotaline model. The exact pathway in which the statins can potentially improve PH, however, is not well understood.

The Rho-kinase activation is noted in models of PH. PH develops in rats exposed to hypoxia for 2 weeks. This chronic hypoxic PH injury can then be reversed with 2 weeks of therapy with simvastatin. The expression of Rho-kinase-1 and 2 was markedly diminished in the rats treated with simvastatin. The activity of Rho-kinase increased threefold under hypoxic conditions and normalized with simvastatin treatment. Thus, the inhibition of Rho-kinase expression and activity maybe important in the statin effect seen in hypoxic PH in rats.^[1] Similarly, the hypoxia-induced p38 MAP kinase activation and proliferation of pulmonary fibroblasts can be inhibited by statins.^[2]

Using the monocrotaline model of PH, PH develops in the male Sprague-Dawley rat. After exposure to monocrotaline, atorvastatin given daily for 4 weeks reduced the development of PH and reduced the levels of serotonin transporter protein in the pulmonary vasculature.^[3] Similarly, PH develops in Wistar male rats injected with monocrotaline. Pravastatin but not atorvastatin was able to significantly reduce PH and restore endothelium-dependent relaxation. Both agents, however, are able to restore endothelial nitric oxide synthetase expression, prevent apoptosis, and improve medial wall thickening. Thus, potentially, different members of the statin family may have different effects on PH.^[4]

Mutations in the bone morphogenetic protein receptor II (BMPR2) have been identified in patients with familial PH. The use of simvastatin seems to induce BMPR2 expression and improve the BMP-BMPR2 signaling, enhancing endothelial differentiation and function.^[5]

Because of the benefits seen in animal models, an open-label observational study was performed at Stanford University Medical Center.^[6] Sixteen patients who had PAH with different WHO functional class 1 through 4 were treated with simvastatin 20-80 mg/day. Individual patients demonstrated improvements in 6-minute walk and cardiac output or decreases in right ventricular systolic pressure. It was felt by the investigator that these improvements might be associated with simvastatin treatment.

These observations have led physicians to believe that the use of simvastatin may be beneficial for the treatment of pulmonary arterial hypertension. During the past few years different human trials have been designed and are in the process of recruiting patients to answer that question. Results of these trials will probably be reported in the next few years. Currently, the American College of Chest Physicians and the World Health Organization have no recommendation for using statins in the treatment of PH.