Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A²²⁵) acetylates HIF-1, triggering its degradation, and thus may play a role in decreased expression of VEGFA.

We generated Apc^Min/+/mARD1A²²⁵ transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A²²⁵ were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A²²⁵ acetylation of Lys532 in HIF-1, we injected B16F10-mARD1A²²⁵ cell lines stably expressing mutant HIF-1/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.

Apc^Min/+/mARD1A²²⁵ transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc^Min/+ mice (n = 21) (number of intestinal polyps per mouse: Apc^Min/+ mice vs Apc^Min/+/mARD1A²²⁵ transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A²²⁵-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A²²⁵ decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc^Min/+ intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1 in B16F10-mARD1A²²⁵ cells prevented HIF-1 degradation and inhibited the antimetastatic effect of mARD1A²²⁵ (P < .001).

mARD1A²²⁵ may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.

Some studies have proposed that subclinical hypothyroidism (SCH) has adverse effects on the cardiovascular system, but little is known about the effect on patients undergoing cardiovascular operations. We examined the influence of preoperative SCH on postoperative outcome in patients undergoing coronary artery bypass grafting (CABG).

Among patients who underwent CABG between July 2005 and June 2007 at Seoul National University Bundang Hospital, 224 with normal thyroid function and 36 with SCH were enrolled. Preoperative risks and postoperative outcomes were evaluated prospectively without thyroid hormone replacement.

There were no significant differences in primary outcomes (major adverse cardiovascular events) and secondary outcomes such as wound problems, mediastinitis, leg infection, respiratory complications, delirium, or reoperation during the same hospitalization. However, patients with SCH had a higher incidence of postoperative atrial fibrillation than those with normal thyroid function after adjustment for age, gender, body mass index, and other independent variables such as emergency operation, the use of cardiopulmonary bypass, combined valvular operation, preoperative creatinine levels, left ventricular systolic dysfunction, and nonuse of β-blockers (45.5% vs 29%; odds ratio, 2.552; 95% confidence interval, 1.117 to 5.830; p = 0.026).

SCH appears to influence the postoperative outcome for patients by increasing the development of postoperative atrial fibrillation. However, it is still unproven whether preoperative thyroxine replacement therapy for patients with SCH might prevent postoperative atrial fibrillation after CABG.