No abstract

Objectives We sought to determine the contemporary prevalence and management of coronary chronic total occlusions (CTO) in a veteran population. Background The prevalence and management of CTOs in various populations has received limited study. Methods We collected clinical and angiographic data in consecutive patients that underwent coronary angiography at our institution between January 2011 and December 2012. Coronary artery disease (CAD) was defined as ≥50% diameter stenosis in ≥1 coronary artery. CTO was defined as total coronary artery occlusion of ≥3 month duration. Results Among 1,699 patients who underwent angiography during the study period, 20% did not have CAD, 20% had CAD and prior coronary artery bypass graft surgery (CABG) and 60% had CAD but no prior CABG. The prevalence of CTO among CAD patients with and without prior CABG was 89% and 31%, respectively. Compared to patients without CTO, CTO patients had more comorbidities, more extensive CAD and were more frequently referred for CABG. Percutaneous coronary intervention (PCI) to any vessel was performed with similar frequency in those with and without CTO (50% vs. 53%). CTO PCI was performed in 30% of patients without and 15% of patients with prior CABG with high technical (82% and 75%, respectively) and procedural success rates (80% and 73%, respectively). Conclusions In a contemporary veteran population, coronary CTOs are highly prevalent and are associated with more extensive comorbidities and higher likelihood for CABG referral. PCI was equally likely to be performed in patients with and without CTO.

Cytochrome p450c17 (CYP17) converts the C21 steroids pregnenolone and progesterone to the C19 androgen precursors dehydroepiandrosterone (DHEA) and androstenedione, respectively, via sequential 17alpha-hydroxylase and 17,20-lyase reactions. Disabling mutations in CYP17 cause combined 17alpha-hydroxylase/17,20-lyase deficiency, but rare missense mutations cause isolated loss of 17,20-lyase activity by disrupting interactions of redox partner proteins with CYP17. We studied an adolescent male with clinical and biochemical features of isolated 17,20-lyase deficiency, including micropenis, hypospadias, and gynecomastia, who is homozygous for CYP17 mutation E305G, which lies in the active site. When expressed in HEK-293 cells or Saccharomyces cerevisiae, mutation E305G retains 17alpha-hydroxylase activities, converting pregnenolone and progesterone to 17alpha-hydroxysteroids. However, mutation E305G lacks 17,20-lyase activity for the conversion of 17alpha-hydroxypregnenolone to DHEA, which is the dominant pathway to C19 steroids catalyzed by human CYP17 (the delta5-steroid pathway). In contrast, mutation E305G exhibits 11-fold greater catalytic efficiency (kcat/Km) for the cleavage of 17alpha-hydroxyprogesterone to androstenedione compared with wild-type CYP17. We conclude that mutation E305G selectively impairs 17,20-lyase activity for DHEA synthesis despite an increased capacity to form androstenedione. Mutation E305G provides genetic evidence that androstenedione formation from 17alpha-hydroxyprogesterone via the minor delta4-steroid pathway alone is not sufficient for complete formation of the male phenotype in humans.

After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at 60 mg/dL. In Goat 2/2 mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to 20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation.