Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice.

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.

A review of the effects of Transcendental Meditation on cardiovascular disease

Cardiovascular disease (CVD) is the single greatest cause of death in the United States, accounting for nearly 2400 deaths each day. It is estimated that 79.4 million American adults have some form of the disease, and CVD mortality rates are greater than those of cancer, chronic lower respiratory diseases, accidents and diabetes mellitus combined. Psychosocial stress is a nontraditional risk factor for CVD, and can contribute to the clustering of traditional risk factors as well as to vascular manifestations of the disease. The Transcendental Meditation (TM) technique has been researched as a cost effective intervention aimed at decreasing psychosocial stress. This literature review attempts to analyze randomized controlled clinical trials of TM on cardiovascular disease outcomes. Eleven studies met inclusion criteria and are described below, with statistically significant positive outcomes observed in each study. Studies are grouped by primary outcome reported in the categories of cardiovascular function, blood pressure, and exercise tolerance. The TM intervention significantly decreased insulin resistance, heart rate variability, and carotid intima media thickness and improved exercise tolerance compared to control groups. Seven studies also reported significant decreases in blood pressure among hypertensive and normotensive subjects. Five studies focused solely on African American subjects, a population that has disproportionately higher rates of CVD and hypertension, and found significant improvements in CVD outcomes. Further research is recommended to establish the efficacy of TM on CVD outcomes. Future trials should include larger sample populations, wider ethnic distributions of subjects, and longer follow-up to ascertain the impact of this particular stress reduction technique on cardiovascular disease.^