Chronic Hypersecretion of Luteinizing Hormone in Transgenic Mice Selectively Alters Responsiveness of the α-Subunit Gene to Gonadotropin-Releasing Hormone and Estrogens

Steroid hormones can act either at the level of the hypothalamus or the pituitary to regulate gonadotropin subunit gene expression. However, their exact site of action remains controversial. Using the bovine gonadotropin α-subunit promoter linked to an expression cassette encoding the β-subunit of LH, we have developed a transgenic mouse model where hypersecretion of LH occurs despite the presence of elevated ovarian steroids. We used this model to determine how hypersecretion of LH could occur when steroid levels are pathological. During transition from the neonatal period to adulthood, the endogenous LHβ subunit gene becomes completely silent in these mice, whereas the α-directed transgene and endogenous α-subunit gene remain active. Interestingly, gonadectomy stimulates expression of the endogenous α and LHβ subunit genes as well as the transgene; however, only the endogenous LHβ gene retains responsiveness to 17β-estradiol and GnRH. In contrast, LH levels remain responsive to negative regulation by androgen. Thus, α-subunit gene expression, as reflected by both the transgene and the endogenous gene, has become independent of GnRH regulation and, as a result, unresponsive to estradiol-negative feedback. This process is accompanied by a decrease in estrogen receptor α gene expression as well as an increase in the expression of transcription factors known to regulate the α-subunit promoter, such as cJun and P-LIM. These studies provide in vivo evidence that estrogen-negative feedback on α and LHβ subunit gene expression requires GnRH input, reflecting an indirect mechanism of action of the steroid. In contrast, androgen suppressesα -subunit expression in both transgenic and nontransgenic mice. This suggests that androgens must regulate α-subunit promoter activity independently of GnRH. In addition to allowing the assessment of site of action of sex steroids on α-subunit gene expression, these studies also indicate that chronic exposure of the pituitary to LH-dependent ovarian hyperstimulation leads to a heretofore-undescribed pathological condition, whereby normal regulation of α, but not LHβ, subunit gene expression becomes compromised

Pediatric SubQ-ICD implantation, a single center review of the inter-muscular technique.

INTRODUCTION: Pediatric patients with cardiomyopathies are at risk for sudden death and may need implantable cardioverter defibrillators (ICDs), but given their small size and duration of use, children are at increased risk for complications associated with ICD use. The subcutaneous ICD presents a favorable option for children without pacing indications. Unfortunately, initial pediatric studies have demonstrated a high complication rate, likely due to the 3-incision technique employed. MATERIAL AND METHODS: Patients with ICD but no pacing indication were retrospectively reviewed after implantation of subcutaneous ICD via the two-incision technique. In half of the patients, 10-J impedance test was also performed to compare with impedance obtained after defibrillation threshold testing with 65-J. RESULTS: Twelve patients were included. The median age was 14 years (range 10-16 years) with eight males included (72.7%). The median weight was 55 kg (range 29 kg-75.1 kg). Follow-up had a median of 11.5 months (range 2-27 months). The median body mass index was 18.4 kg/m squared (range 15.5-27.9 kg/m squared). One patient suffered a minor complication after tearing off the incisional adhesive strips early and required a non-invasive repair in clinic. Shock impedance had a median of 55 J (range 48-68 J). There was one appropriate shock/charge and no inappropriate shocks during follow-up. CONCLUSION: The two-incision, intermuscular technique appears to have a lower acute complication rate than prior reports, in our cohort of 12 pediatric patients

Eisenmenger Syndrome: JACC State-of-the-Art Review

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension–targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond