Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Modulating the nitric oxide - cyclic GMP pathway in the pressure-overloaded left ventricle and group II pulmonary hypertension.

Group II pulmonary hypertension (PH) commonly occurs in the setting of a pressure-overloaded left ventricle (LV) which is also conducive to the development of heart failure with preserved ejection fraction. Population trends and a high prevalence of underlying causative conditions, such as essential hypertension or aortic stenosis, have increased the awareness of the pressure-overloaded LV and associated group II pulmonary hypertension. Patients often exhibit poor exercise tolerance and signs of heart failure indistinguishable from systolic heart failure; but effective medical treatments in this area have been lacking. Recent preclinical work has shed light on how the down-regulated nitric oxide - cyclic GMP pathway (within the myocardium and pulmonary vasculature) contributes to the pathophysiology of these associated conditions. This article will discuss the impact of the nitric oxide - cyclic GMP pathway on the pathogenesis of the pressure-overloaded LV and group II pulmonary hypertension, and will also introduce the potential therapeutic value of modulating this pathway.

Relaxation of pig coronary arteries by new and potent cGMP analogs that selectively activate type I alpha, compared with type I beta, cGMP-dependent protein kinase.

Smooth muscle preparations of human aorta or pig coronary arteries contain nearly equal amounts of cGMP-dependent protein kinase isozymes (cGMP kinase I alpha and I beta). In order to understand the roles of these isozymes in relaxing vascular smooth muscle, several new cGMP analogs were synthesized and tested for potencies in activating each enzyme and in relaxing pig coronary arteries. Analogs modified with a derivatized phenylthio group at the 8-position were as much as 72-fold more potent in activating purified cGMP kinase I alpha than cGMP kinase I beta. Electron-donating substituents, such as hydroxy, amino, and methoxy, on the phenyl ring enhanced the potencies of these analogs in activating cGMP kinase I alpha. The most potent of these cGMP analogs [8-(4-hydroxyphenylthio)-cGMP] was 17 times more potent (EC50 = 1.1 microM) as a muscle relaxant than the most efficacious analog tested previously. Among derivatives with an 8-halo group, 8-iodo-cGMP was the most potent compound (Ka = 9 nM for I alpha and 122 nM for I beta) for both I alpha and I beta. Analogs modified at the 1,N2-position or at both the 1,N2-and 8-positions of cGMP were highly potent for activating both isozymes. Within this group, 8-I-beta-phenyl-1,N2-etheno-cGMP had Ka values of 22 nM and 17 nM for cGMP kinase I alpha and I beta, respectively, whereas the Ka values of cGMP were 110 nM and 250 nM for the two isozymes. 8-I-beta-phenyl-1,N2-etheno-cGMP was the most potent muscle relaxant tested, with EC50 of 0.4 microM. For all cGMP analogs tested, there was a positive correlation between potency for activation of cGMP kinase I alpha and that for relaxation of pig coronary arteries. Assuming that the kinase assay conditions yielded a cyclic nucleotide specificity similar to that which would exist in intact cells, it was concluded that the cGMP kinase I alpha isozyme mediates the relaxation of pig coronary artery smooth muscle caused by cGMP elevation. However, an additional role for cGMP kinase I beta in the relaxation process could not be ruled out.

Acute and subacute effects of naturally occurring estrogens on luteinizing hormone secretion in the ovariectomized rat: Part 2.

Acute intravenous administration of the phytoestrogen genistein (G) blocks the gonadotropin-releasing hormone-(GnRH)-induced rise of luteinizing hormone (LH) in ovariectomized rats. The present experiments were performed to determine whether subacute administration of G or the mycoestrogens zearalenone and zearalenol would affect GnRH-induced or progesterone-induced LH secretion in ovariectomized rats. Charles River CD rats were ovariectomized and used 2 to 5 weeks later. Blood samples were obtained either via decapitation or via intraatrial cannulae three days after compounds were injected subcutaneously in sesame oil or corn oil vehicle. LH was measured by RIA. Pretreatment with estradiol benzoate suppressed LH levels at 1200 h, while G had no effect. Challenge with progesterone (8 mg/kg BW, sc) evoked LH release at 1600 h in rats pretreated with estradiol benzoate, but LH levels did not change in rats pretreated with G, zearalenone, or zearalenol. While GnRH-induced LH secretion was preserved in rats pretreated with estradiol, no LH response was detected in rats pretreated with the higher dose of G (8 mg/kg BW) or either dose of zearalenol (0.8 mg/kg BW or 8 mg/kg BW). We conclude that in the ovariectomized rat 1) subacute administration of G, zearalenone, or zearalenol do not inhibit tonic LH secretion, 2) G, zearalenone, and zearalenol do not provide "estrogenic priming" for progesterone-induced LH secretion; however, 3) G and zearalenol do block GnRH-induced LH secretion. The seemingly selective neuroendocrine effects of these naturally-occurring dietary estrogens emphasize that actions of each putative estrogen must be characterized for each "estrogenic" endpoint.