Daniel Sherbet

Prevalence and management of coronary chronic total occlusions in a tertiary veterans affairs hospital

We sought to determine the contemporary prevalence and management of coronary chronic total occlusions (CTO) in a veteran population.

Profound Hypoglycemia in Starved, Ghrelin-deficient Mice Is Caused by Decreased Gluconeogenesis and Reversed by Lactate or Fatty Acids

Background: Calorie-restricted, fat-depleted Goat−/− mice develop profound hypoglycemia resulting from lack of ghrelin-mediated growth hormone release. Results: Hypoglycemia is caused by decreased gluconeogenesis and reversed by gluconeogenic precursors (lactate and alanine) or fatty acids. Conclusion: In absence of fatty acids, growth hormone maintains gluconeogenic precursors, allowing survival. Significance: Maintenance of blood glucose by ghrelin-growth hormone axis is crucial for evolutionary adaptation to starvation. When mice are subjected to 7-day calorie restriction (40% of normal food intake), body fat disappears, but blood glucose is maintained as long as the animals produce ghrelin, an octanoylated peptide that stimulates growth hormone secretion. Mice can be rendered ghrelin-deficient by knock-out of the gene encoding either ghrelin O-acyltransferase, which attaches the required octanoate, or ghrelin itself. Calorie-restricted, fat-depleted ghrelin O-acyltransferase or ghrelin knock-out mice fail to show the normal increase in growth hormone and become profoundly hypoglycemic when fasted for 18–23 h. Glucose production in Goat−/− mice was reduced by 60% when compared with similarly treated WT mice. Plasma lactate and pyruvate were also low. Injection of lactate, pyruvate, alanine, or a fatty acid restored blood glucose in Goat−/− mice. Thus, when body fat is reduced by calorie restriction, ghrelin stimulates growth hormone secretion, which allows maintenance of glucose production, even when food intake is eliminated. In humans with anorexia nervosa or kwashiorkor, ghrelin and growth hormone are known to be elevated, just as they are in fat-depleted mice. We suggest that these two hormones prolong survival in starved humans as they do in mice.

Optical coherence tomography findings after chronic total occlusion interventions: Insights from the “AngiographiC evaluation of the everolimus-eluting stent in chronic Total occlusions” (ACE-CTO) study (NCT01012869)

BACKGROUND There is limited information on optical coherence tomography (OCT) findings after percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). OCT allows high resolution imaging that can enhance understanding of the vascular response after stenting of chronically occluded vessels. METHODS The Angiographic Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study collected angiographic and clinical outcomes from 100 patients undergoing CTO PCI with the everolimus-eluting stent (EES). OCT was performed 8-months post stenting in 62 patients. Every third frame was analyzed throughout the course of the stented arterial segment. Lumen contours were semi-automatically traced and stent struts were manually delineated, with automatic measurement of the strut to lumen distance. Struts on the luminal side of the lumen contour were classified as malapposed if the distance to the lumen contour exceeded 0.108mm. RESULTS A total of 44,450 struts in 6047 frames were analyzed, of which 4113 9.3%, 95% confidence intervals [CI] 9.0% to 9.5%) were malapposed and 1230 (2.8%, 95% CI 2.6% to 2.9%) were uncovered. Fifty-five of 62 patients (88.7%, 95% CI 78.5% to 98.4%) had at least one malapposed stent strut and 50 patients (80.7%, 95% CI 69.2% to 88.6%) had at least one uncovered stent strut. Mean strut-intimal thickness of the apposed and malapposed struts was 0.126±0.140mm and -0.491±0.440mm, respectively. CONCLUSION High rates of stent strut malapposition and incomplete stent strut coverage were observed after CTO PCI using EES, highlighting unique challenges associated with stent implantation in CTOs.

Low-Density Lipoprotein Cholesterol: How Low Can We Go?

Elevated low-density lipoprotein cholesterol (LDL-C) is an established cause of cardiovascular disease and subsequent adverse events. The efficacy and safety of lowering plasma LDL-C to reduce the risk of coronary heart disease (CHD) and secondary event rates are now well established. What has not been established, however, is a plasma LDL-C lower threshold level of safety and efficacy. Here we review intensive plasma LDL-C-lowering with statins and argue that even further reductions of plasma LDL-C than current guideline targets is likely to safely reduce cardiovascular event rates. We discuss how to achieve very low levels of plasma LDL-C using both traditional and novel LDL-lowering therapies.

Peripheral Testosterone Metabolism

Testosterone is the principal androgen secreted by the human testis. Testosterone is carried by the circulation to target cells, where transactivation of the androgen receptor manifests its actions as a classical steroid hormone. Alternatively, the biological activity of testosterone might be increased, decreased, or categorically altered by enzymes in peripheral and target tissues. The 5α-reductase enzymes convert testosterone to more potent androgen, dihydrotestosterone (DHT), which is required for formation of the external genitalia in males. The biosynthesis of DHT also occurs in some species, including human beings, through an alternate pathway which does not utilize testosterone as an intermediate. Testosterone can be inactivated either through its conversion to androstenedione, mediated by 17β-hydroxysteroid dehydrogenase type 2, or through 5β-reduction. Testosterone, DHT, and their metabolites are subjected to glucuronidation and sulfation to facilitate excretion in the urine. Finally, some of the effects of testosterone are mediated through its aromatization to the potent estrogen, estradiol. This chapter discusses the peripheral metabolic pathways of testosterone, the key enzymes involved, and their physiology and genetics.

Surviving starvation: essential role of the ghrelin-growth hormone axis

Chronic starvation is a repeated threat to survival of animals of all species. Indeed, about 15% of the current human population is estimated to suffer from severe malnutrition, and one-half of all deaths in children less than 5 years of age (~6 million deaths per year) arise from malnutrition. Over the centuries, starvation has exerted profound evolutionary pressure that has selected for a variety of adaptive mechanisms to support life. Paramount among these mechanisms is the necessity to maintain blood sugar concentrations sufficient for brain function. The adaptive mechanisms are particularly strained when chronic starvation has depleted the body of its other source of energy – namely, fatty acids stored as triglycerides. Recently, our laboratory has begun to study the adaptation to chronic starvation, focusing on the essential roles of two peptide hormones, ghrelin and growth hormone. Ghrelin, a peptide hormone secreted by neuroendocrine cells in the stomach, was identified in 1999 by Kojima and Kangawa by its ability to stimulate release of growth hormone. In rodents and humans, plasma ghrelin rises before meals and declines after eating. Administration of excess ghrelin increases food intake, but knockout mice lacking ghrelin or its receptor have normal weight. Therefore, the true function of ghrelin has been enigmatic. Ghrelin is unique in that it requires a covalently attached 8-carbon fatty acid for activity, a modification conserved in all vertebrates. We identified ghrelin O-acyltransferase (GOAT), the enzyme that attaches octanoate to ghrelin. GOAT knockout mice cannot produce active ghrelin. Like ghrelin knockouts, GOAT knockouts have normal body weight. When these knockout mice are placed on a 60% calorie-restricted diet for 8 days, they are unable to maintain normal blood glucose and die. Restoration of ghrelin or growth hormone prevents death. Thus, ghrelin maintains blood glucose under conditions of severe calorie restriction, a function essential for survival in chronically starved rodents. Recent data on the mechanism by which the ghrelin-growth hormone axis preserves blood glucose will be presented.

SAFETY AND EFFECT ON HEALTHCARE EXPENSES WITH SAME VERSUS NEXT DAY DISCHARGE AFTER ELECTIVE TRANSRADIAL PERCUTANEOUS CORONARY INTERVENTION

Background: Transradial (TR) PCIs have been progressively increasing over the last decade in the US. Previous studies have shown that same-day discharge after elective PCI is associated with similar safety compared to overnight observation. This study sought to assess the clinical and financial

THE ‘ANGIOGRAPHIC EVALUATION OF THE EVEROLIMUS-ELUTING STENT IN CHRONIC TOTAL OCCLUSIONS’ (ACE-CTO) STUDY

BACKGROUND There are limited data on outcomes after implantation of second-generation drug-eluting stents in coronary chronic total occlusions (CTOs). We aimed to evaluate the frequency of angiographic restenosis and clinical outcomes after implantation of the everolimus-eluting stent (EES) in coronary CTOs. METHODS One hundred patients undergoing successful CTO percutaneous coronary intervention using EES at our institution between 2009 and 2012 were enrolled. The primary study endpoint was binary in-segment restenosis at 8-month follow-up quantitative coronary angiography. Secondary endpoints included death, myocardial infarction, target-lesion and target-vessel revascularization, and symptom improvement. RESULTS Mean age was 64 ± 7 years and 99% of the patients were men. The successful crossing technique was antegrade wiring in 51 patients, antegrade dissection/reentry in 24 patients, and retrograde in 25 patients. Binary angiographic restenosis occurred in 46% of the patients (95% confidence interval [CI], 35%-57%). The pattern of restenosis was focal, proliferative, and total occlusion in 19 lesions (46%), 14 lesions (34%), and 8 lesions (20%), respectively. At 12 months, the incidences of death, myocardial infarction, target-lesion revascularization, and target-vessel revascularization were 2%, 2%, 37%, and 39%, respectively. At 12 months, symptoms were improved, unchanged, or worse compared with baseline in 89 patients, 8 patients, and 1 patient, respectively (2 patients died before the 12-month follow-up). On multivariable analysis, smaller stent diameter was associated with higher risk for binary angiographic restenosis. CONCLUSION High rates of angiographic restenosis and repeat revascularization were observed among patients receiving EES in coronary CTOs, but most had significant symptom improvement.

The ghrelin-growth hormone axis preserves gluconeogenesis to maintain blood glucose levels during starvation

Background The octanoylated peptide ghrelin stimulates growth hormone (GH) secretion during severe calorie restriction in mice, which preserves fasting blood sugar after body fat has been depleted. Genetic deletion of ghrelin-O-acyltransferase (GOAT, which octanoylates ghrelin) renders mice ghrelin-deficient and abrogates the normal rise in GH after several days of calorie restriction, resulting in profound hypoglycemia. Administration of either ghrelin or GH to GOAT knockout mice restores the ability to maintain fasting blood sugar levels during prolonged calorie restriction. The mechanism of hypoglycemia in ghrelin-deficient mice has not been described previously.