Diferencias de género en la titulación de fármacos de pacientes con insuficiencia cardiaca y fracción de eyección reducida del ensayo ETIFIC / Gender differences in drug titration among heart failure patients with reduced ejection fraction in the ETIFIC trial

Introducción y objetivos El tratamiento óptimo disminuye la mortalidad y hospitalizaciones por insuficiencia cardiaca (IC) en pacientes con IC y fracción de eyección reducida. En los ensayos clínicos las mujeres estuvieron infrarrepresentadas y no fueron evaluadas específicamente. Este estudio buscó comparar la seguridad y efectividad de titulación (ajuste de dosis) de fármacos en mujeres y varones. Métodos Estudio post hoc de género del ensayo aleatorizado multicéntrico ETIFIC. Se incluyeron pacientes hospitalizados con IC de novo y fracción de eyección reducida. Proceso estructurado de titulación en unidades de IC. Objetivo principal: la dosis relativa media de bloqueadores beta (% de la dosis objetivo) alcanzada por mujeres frente a varones. Objetivos secundarios: dosis relativas medias de otros fármacos de IC, eventos adversos y resultados clínicos a 6 meses. Resultados Se incluyeron 320 pacientes, 83 (25,93%) mujeres y 237 (74,06%) varones. (76 frente a 213 analizados). Media±desviación estándar de dosis relativa de bloqueadores beta mujeres frente a varones: 62,08±30,72% frente a 64,4±32,77%; diferencia −2,32%; IC95%, −10,58-5,94; p=0,580, antagonistas del receptor de mineralocorticoides 79,85±27,72% comparado con 67,29±31,43%; p=0,003, sin diferencias significativas en dosificación de otros fármacos. El análisis multivariante no encontró diferencias significativas. Mortalidad cardiovascular 1 (1,20%) frente a 3 (1,26%), p=1 y 0 hospitalizaciones por IC (0,00%) frente a 10 (4,22%), p=0,125. Conclusiones En un análisis post hoc del ensayo ETIFIC de titulación en IC no encontramos diferencias de género significativas en dosificación, mortalidad cardiovascular y hospitalizaciones por IC (AU)

Introduction and objectives Optimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men. Methods This post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months. Results A total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean±standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08%±30.72% vs 64.4%±32.77%, with a difference of−2.32% (95%CI,−10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85%±27.72% vs 67.29%±31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P=1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P=.125. Conclusions In a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations (AU)

The epicardium as a source of mesenchyme for the developing heart.

The primitive epicardium of the vertebrate embryo has traditionally been regarded as a rather passive mesothelium, lining the embryonic myocardium and forming the adult visceral pericardium. However, in recent years, there is an increasing evidence that the primitive epicardium is a highly dynamic element which supplies cells to the developing heart through a process of epithelial-mesenchymal transition. This process seems to be more active at the atrioventricular canal and outflow tract, i.e. the cardiac segments where the endothelium transforms into mesenchyme. In this paper we review the current evidence which supports such epicardial-mesenchymal transition, namely: 1) morphological features, 2) colocalization of cytokeratin and vimentin in the epicardial and subepicardial mesenchymal cells, 3) presence of common antigens in the transforming epicardium and endocardial cushions (fibrillin-2/JB3, ES/130, Ets-1). Recendy, we have immunolocated the transcription factor Slug in the developing avian heart. Slug is a zinc-finger protein involved in the formation of the neural crest, a developmental event which implies an epithelial-mesenchymal transition. All cells of the primitive epicardium are Slug+ from their differentiation until the stage HH24. However, only a fraction of the endothelial cells from the endocardial cushions are Slug+. We speculate that the expression of Slug marks competence of the epicardial cells to transform into mesenchyme, although this transformation is only achieved where an inducing signal is produced. Regarding the developmental fate of the epicardial-derived cell population, there is strong evidence of its differentiation in fibroblasts and vascular smooth muscle cells, although a contribution to the coronary endothelium cannot be discarded.

[Urinary incontinence in patients with acute ictus]. / Incontinencia urinaria en el paciente con ictus agudo.

This project won the "Ausonia" Incontinence First Prize among those projects submitted during 1999. This article analyzes the prevalence of urinary incontinence among patients diagnosed as suffering acute ictus after 3 months, 6 months and 12 months. The authors also investigate those factors associated with acute ictus incontinence, how incontinence influences a patient's evolution, and how incontinence affects the environment where recuperation occurs, at home or in an institution, while the patient is recovering. The results confirm that acute urinary incontinence is a forecasting factor, independent of the poor middle and long range functional prognosis, and that the potential prognosis is superior than the seriousness of the neurological deficit at the moment a patient enters a hospital.

Immunolocalization of the transcription factor Slug in the developing avian heart.

Slug is a transcription factor involved in processes such as the formation of mesoderm and neural crest, two developmental events that imply a transition from an epithelial to a mesenchymal phenotype. During late cardiac morphogenesis, mesenchymal cells originate from two epithelia--epicardial mesothelium and cushion endocardium. We aimed to check if Slug is expressed in these systems of epithelial-mesenchymal transition. We have immuno-located the Slug protein in the heart of quail embryos between Hamburger and Hamilton stages HH16 and HH30. In the proepicardium (the epicardial primordium), Slug was detected in most cells, mesothelial as well as mesenchymal. Slug immunoreactivity was strong in the mesenchyme of the endocardial cushions and subepicardium from its inception until HH24, but the immunoreactivity disappeared in later embryos. Only a small portion of the endocardial cells located in the areas of epithelial-mesenchymal transition (atrioventricular groove and outflow tract) were immuno-labelled, mainly between HH16 and HH20. Endocardial cells from other cardiac segments were always negative, except for a transient, weak immunoreactivity that coincided with the development of the intertrabecular sinusoids of the ventricle. In contrast, virtually all cells of the epicardial mesothelium were immunoreactive until stage HH24. The mesenchymal cells that migrate to the heart through the spina vestibuli were also conspicuously immunoreactive. The myocardium was not labelled in the stages studied. Our results stress the involvement of Slug in the epithelial to mesenchymal transition. We suggest that Slug can constitute a reliable marker of the cardiac epithelial cells that are competent to transform into mesenchyme as well as a transient marker of the epithelial-derived mesenchymal cells in the developing heart.

Differentiation of hemangioblasts from embryonic mesothelial cells? A model on the origin of the vertebrate cardiovascular system.

The existence of the hemangioblast, a common progenitor of the endothelial and hematopoietic cell lineages, was proposed at the beginning of the century. Although recent findings seem to confirm its existence, it is still unknown when and how the hemangioblasts differentiate. We propose a hypothesis about the origin of hemangioblasts from the embryonic splanchnic mesothelium. The model is based on observations collected from the literature and from our own studies. These observations include: (1) the extensive population of the splanchnic mesoderm by mesothelial-derived cells coinciding with the emergence of the endothelial and hematopoietic progenitors; (2) the transient localization of cytokeratin, the main mesothelial intermediate filament protein, in some embryonic vessels and endothelial progenitors; (3) the possible origin of cardiac vessels from epicardial-derived cells; (4) the origin of endocardial cells from the splanchnic mesoderm when this mesoderm is an epithelium; (5) the evidence that mesothelial cells migrate to the hemogenic areas of the dorsal aorta. (6) Biochemical and antigenic similarities between mesothelial and endothelial cells. We suggest that the endothelium-lined vascular system arose as a specialization of the phylogenetically older coelomic cavities. The origin of the hematopoietic cells might be related to the differentiation, reported in some invertebrates, of coelomocytes from the coelomic epithelium. Some types of coelomocytes react against microbial invasion and other types transport respiratory pigments. We propose that this phylogenetic origin is recapitulated in the vertebrate ontogeny and explains the differentiation of endothelial and blood cells from a common mesothelial-derived progenitor.

Immunohistochemical evidence for a mesothelial contribution to the ventral wall of the avian aorta.

We report morphological and immunohistochemical evidence for a translocation of cells from the coelomic mesothelium to the aortic wall between the developmental stages HH16 and HH22 of the quail embryos. The coelomic mesothelial cells closest to the aorta showed, at these stages, increased mitotic activity, reduced intercellular adhesion, loss of tight junctions, and long basal cytoplasmic processes. Coinciding with these morphological traits, cytokeratin immunoreactivity was found in the mesothelium, in cells of the aortic wall and throughout the ventral periaortic mesenchyme (but not in the lateral and dorsal aortic regions). Vimentin immunoreactivity colocalized with cytokeratin in the mesothelial cells adjacent to the aorta. In the ventral aortic wall, cytokeratin colocalized with smooth muscle alpha-actin and with the 1E12 antigen (a smooth muscle-specific alpha-actinin isoform). We think that the morphological and immunolocalization data observed are compatible with an epithelial-mesenchymal transition by which mesothelial-derived cells contribute to the splanchnic mesoderm and aortic wall. The precise coincidence between the mesothelial contribution and the emergence of the aortic smooth muscle cells progenitors, as well as the immunolocalization data, suggest a potential relationship of the mesothelial-derived cells with this cell lineage. This may explain the observed ventrodorsal asymmetry in the distribution of smooth muscle cells progenitors in the aortic wall.

Immunolocalization of the vascular endothelial growth factor receptor-2 in the subepicardial mesenchyme of hamster embryos: identification of the coronary vessel precursors.

The earliest evidence of the development of the cardiac vessels in mammals is the emergence of subepicardial blood islands, which are thought to originate from mesenchymal progenitors. In order to identify these progenitor cells, we have studied the immunohistochemical localization in the heart of Syrian hamster embryos of the type 2 vascular endothelial growth factor receptor, the earliest molecule known to be expressed in the vasculogenic cell lineage. Only a few immunoreactive subepicardial mesenchymal cells were present by 10 days post coitum. By 11 days post coitum, the subepicardial mesenchymal cells became abundant at the dorsal part of the ventricle, the atrioventricular and the conoventricular grooves. About 20% of cells were labelled with the antibody. Immunoreactive cells were isolated or formed pairs, short cords, rounded clusters or ring-like structures at the subepicardium or, occasionally, within the ventricular myocardium. Other labelled cells were simultaneously cytokeratin immunoreactive. By 12 days post coitum, most immunoreactive mesenchymal cells have been replaced by a capillary network. We propose that an active process of vascular differentiation occurs between 10 and 12 days post coitum in the subepicardium of this species, and it might be a suitable model for the study of vasculogenetic mechanisms.

Immunoreactivity of the ets-1 transcription factor correlates with areas of epithelial-mesenchymal transition in the developing avian heart.

Cardiac morphogenesis involves substantial remodeling processes that include cell transdifferentiation and migration. The c-ets-1 protooncogene codes for a transcription factor that can transactivate a number of genes involved in developmental processes such as degradation of extracellular matrices and cell migration. We have immunolocated the ets-1 protein in the heart of quail and chick embryos between the Hamburger and Hamilton stages HH16 and HH37. In HH16-17 embryos, the ets-1 transcription factor was only detected in some endocardial cells and in most mesothelial and mesenchymal cells of the proepicardium. Ets-1 immunoreactivity increased markedly in the developing endocardial cushions, myocardium, epicardium and early subepicardial mesenchyme of HH18-19 embryos. By HH20-24 the immunoreactivity was found throughout the heart, with a stronger intensity in the areas of epithelial-mesenchymal transition of the endocardium and epicardium. In embryos between HH26 and HH33, ets-1 immunoreactivity increased in the cushion mesenchyme, atrioventricular endocardium, ventricular epicardium and subepicardial mesenchyme cells, but not in other areas of the heart. The immunoreactivity declined in the innermost part of the endocardial cushions. The subepicardial mesenchyme was particularly immunoreactive in these stages, coinciding with the development of the subepicardial vascular network. In fact, ets-1 colocalized with the quail vascular marker QH1 in the subepicardial mesenchymal cells. Ets-1-negative cells were abundant in the subepicardium and valvuloseptal tissue of the HH37 embryos. The results suggest that ets-1, probably through transactivation of genes such as urokinase-type plasminogen activator and matrix metalloproteinases, might play a crucial role in the differentiation of the cushion and subepicardial mesenchyme, the formation of the intratrabecular sinusoids and the early development of the cardiac vessels.

The origin of the subepicardial mesenchyme in the avian embryo: an immunohistochemical and quail-chick chimera study.

It has been proposed that the subepicardial mesenchymal cells (SEMC) originate from the primitive epicardium and also from migration of extracardiac mesenchyme from the liver area. We have studied the possibility of an origin of SEMC through transformation of the proepicardial mesothelium, as well as the potential of the early proepicardium to generate epicardium and SEMC in quail-chick chimeras. The study was carried out in quail and chick embryos between HH16 and HH29 stages. Most proepicardial cells, mesothelial as well as mesenchymal, were cytokeratin and vimentin immunoreactive, suggesting a cytoskeletal shift from the epithelial to the mesenchymal type. Furthermore, we immunolocated, in the proepicardial mesothelium, three proteins specifically expressed during the endothelial-mesenchymal transition of the endocardial cushions, namely the JB3/fibrillin-associated antigen, the ES/130 protein and the smooth muscle cell alpha-actin. Grafts of proepicardial tissue from HH16-17 quail embryos into chick embryos of the same age originated large areas of donor-derived epicardium, including mesothelial, mesenchymal, and vascular cells. The donor-derived primitive epicardium showed segment-specific features, being squamous and adhered to the myocardium on the atrial wall and showing morphological signs of ingression in the atrioventricular groove and outflow tract. These morphological traits together with the distribution of vimentin, the ES/130 protein, and the JB3/fibrillin-associated antigen suggested a localized transformation of some epicardial mesothelial cells into mesenchyme. Most of the donor-derived cells, mesothelial and mesenchymal, showed the vascular marker QH1, which frequently colocalized with cytokeratin. Heterotopic grafts of quail splanchnopleura into the pericardial cavity of chick embryos originated a squamous, epicardial-like, cytokeratin-immunoreactive cell layer on the heart surface, as well as a few QH1(+) subepicardial and intramyocardial cells. The results suggest that a substantial part of the subepicardial mesenchyme, including the progenitors of the cardiac vessels, originates from the transformation of proepicardial and epicardial mesothelial cells into mesenchyme, and that the epicardial transition could be driven by a segment-specific myocardial signal.

Contribution of the primitive epicardium to the subepicardial mesenchyme in hamster and chick embryos.

A study about the hypothetical contribution of the epicardial cells to the subepicardial mesenchyme was carried out in Syrian hamster embryos of 9-12 days post coitum (dpc) and chick embryos of 3-5 days of incubation. In the epicardium and subepicardium of these embryos we have immunolocated the proteins cytokeratin (CK), vimentin (VIM), fibronectin (FN), and two antigens related to the transformation of endocardial cells into valvuloseptal mesenchyme, ES/130 and JB3. In the hamster embryos, CK+ subepicardial mesenchymal cells (SEMC) were apparently migrating from the primitive epicardium from 9.5 dpc at the atrioventricular (AV) groove and proximal outflow tract (OFT). The morphological signs of delamination extended by 11 dpc to the epicardium of the interventricular groove and the dorsal part of the ventricle. The relative abundance of the CK+ SEMC decreased in embryos of 12 dpc. VIM colocalized with CK in most SEMC, and in some epicardial mesothelial cells, mainly at the areas of delamination. CK immunoreactivity was also found in some early subepicardial capillaries. Similar observations were made in the chick embryos studied. The immunoreactive patterns obtained at the subepicardium with anti-FN, ES/130, and JB3 antibodies were similar to those reported in the areas of endothelial transformation of the endocardial cushions. We suggest that these observations are compatible with an epithelial-mesenchymal transformation involving the epicardial mesothelium and originating at least a part of the SEMC.

Coronary arteriosclerosis in dogfish (Scyliorhinus canicula). An assessment of some potential risk factors.

Coronary myointimal lesions are described in the dogfish (Scyliorhinus canicula). These lesions are similar to those previously described in salmonids and are characterized by breaks in and disappearance of the inner elastic layer and intimal thickening as a result of inclusions of fibers and smooth muscle cells. Lesions are associated with all the branching points in the main subepicardial conal coronary arteries that supply the heart. Intimal thickenings were rare in other parts of these arteries. However, we found extensive lesions unassociated with branching points in two main intramyocardial ventricular arteries that supply the ventricular spongy myocardium. We carried out a statistical study of the incidence and severity of these intramyocardial lesions in relation to several potential risk factors. Intimal thickenings were present in 90.5% of the fish specimens and 40% of the histological sections. Sex, reproductive stage, plasma triacylglycerol, and cholesterol (total and related to high-density lipoproteins) were not significantly related to either the incidence or severity of lesions. Total fish length was significantly correlated with the lesion severity index (r = 0.33, p < 0.01). We also found significant differences in incidence related to the location of lesions. The middle areas of the intramyocardial branches, very close to the atrioventricular canal, were more affected than the cranial and caudal areas. The dorsal and ventral artery walls were also more affected than the lateral ones. The preferential location of the lesions in areas presumably subjected to mechanical stress because of a bifurcating bloodstream or the pulsatile flow throughout the atrioventricular canal suggests that coronary arteriosclerosis in dogfish is an age-related process, with hemodynamic factors playing a primary or secondary pathogenetic role. This disease seems not to be related to some factors suggested for salmonids, such as reproductive cycle, anadromous migration, river pollution, or plasma lipid concentration.

Anatomical studies of the coronary system in elasmobranchs: II. Coronary arteries in hexanchoid, squaloid, and carcharhinoid sharks.

Coronary artery anatomy was studied in 16 shark species belonging to 9 families of the orders Hexanchiformes, Squaliformes, and Carcharhiniformes. The study included 101 specimens and used an injection-corrosion technique that obtained internal casts of the main trunks and coronary arterial branches. The results showed 2 main patterns of coronary arterial arrangement: the dorsoventral coronary trunk pattern, shared by lamnoid and advanced carcharhinoid sharks, and the lateral coronary trunk pattern, shown by hexanchoid and squaloid sharks. Scyliorhinus and Galeus had intermediate arrangements of their vessels.

Coronary myointimal lesions in the dogfish shark Scyliorhinus canicula.

Proliferative lesions have been found in the coronary arteries of five specimens of dogfish shark (Scyliorhinus canicula). Three specimens lacked the internal elastic membrane and had a diffuse thickening of the intima obliterating most of the vascular lumen in several intramyocardial branches. Two specimens had intimal nodules in one of the main coronary conal trunks, where breaking and splitting of the internal elastic membrane and fibrosis of the tunica media were observed. These lesions appear similar to those described in salmonid fishes, but are less frequent. Although high concentrations of blood cholesterol and ApoB-containing lipoproteins have been related to the development of coronary lesions in these bony fishes, the dogfish sharks described in this paper showed low serum concentrations of both total cholesterol (0.33 to 1.64 mg per ml) and triglycerides (0.61 to 0.17 mg per ml).

Anatomical studies of the coronary system in elasmobranchs: I. Coronary arteries in lamnoid sharks.

A study of the anatomy of coronary arteries has been done in five shark species of the order Lamniformes: Isurus oxyrinchus, Isurus paucus, Lamna nasus, Alopias superciliosus, and Alopias vulpinus. The study, which included 26 specimens, was carried out with the injection-corrosion technique, obtaining internal casts of the main trunks and coronary arterial branches. The results have shown a high degree of constancy in the coronary patterns in all species and a number of general features common to all of them, except for Alopias vulpinus. In this species, a mesh-like ventricular pattern of intramyocardial vessels was found instead of subepicardial ventricular coronary branches with a definite pattern. It was also shown that there is a wide range of variation among the species regarding the relative importance of the dorsal and ventral coronary trunks. Thus, Isurus oxyrinchus showed a clear predominance of the ventral coronary trunk, whereas in Alopias superciliosus, most of the ventricle was supplied by branches derived from the dorsal coronary trunk.