María Jesús Delgado-Martos

Early regression of left ventricular hypertrophy after treatment with esmolol in an experimental rat model of primary hypertension

Certain β-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective β-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 μg kg−1 min−1). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower 18F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term β-blocker.

Short-term esmolol improves coronary artery remodeling in spontaneously hypertensive rats through increased nitric oxide bioavailability and superoxide dismutase activity

The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 μg/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P < 0.001), W/L (P < 0.05), and MCSA (P < 0.01) and improved endothelium-dependent relaxation (AUCSHR-E = 201.2 ± 33 versus AUCSHR = 97.5 ± 21, P < 0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10−6 to 10−4 mol/l) for SHR-E with respect to WKY. SOSA (P < 0.001) and nitrite (P < 0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR.

Severe hypoxaemia with a left ventricular assist device in a minipig model with an undiagnosed congenital cardiac disease

We describe the placement of a left ventricular assist device (LVAD) in a pig with spontaneously occurring atrial septal defect (ASD) (incidental finding) that created a right–left cardiac shunt, with subsequent severe hypoxaemia. Early diagnosis was critical in order to prevent end-organ damage due to hypoxaemia. Adequate monitoring alerted us to the deterioration in oxygenation, haemodynamics and cerebral oxygen metabolism. This forced us to change the level of assistance provided by the pump, and thus dramatically correct this impairment. Necropsy revealed an ostium secundum ASD. In conclusion, if hypoxaemia presents after implementation of an LVAD, the presence of a right–left shunt must be ruled out. The first step must be a judicious reduction in assist device flow to minimize intracardiac shunting. Subsequently, atrial septal closure of the defect should be considered. We report an experimental model of severe hypoxaemia after placement of an LVAD as part of a larger research project.

Does the epiphyseal cartilage of the long bones have one or two ossification fronts

Epiphyseal cartilage is hyaline cartilage tissue with a gelatinous texture, and it is responsible for the longitudinal growth of the long bones in birds and mammals. It is located between the epiphysis and the diaphysis. Epiphyseal cartilage also is called a growth plate or physis. It is protected by three bone components: the epiphysis, the bone bar of the perichondrial ring and the metaphysis. The epiphysis, which lies over the epiphyseal cartilage in the form a cupola, contains a juxtaposed bone plate that is near the epiphyseal cartilage and is in direct contact with the epiphyseal side of the epiphyseal cartilage. The germinal zone corresponds to a group of cells called chondrocytes. These chondrocytes belong to a group of chondral cells, which are distributed in rows and columns; this architecture is commonly known as a growth plate. The growth plate is responsible for endochondral bone growth. The aim of this study was to elucidate the causal relationship between the juxtaposed bone plate and epiphyseal cartilage in mammals. Our hypothesis is that cells from the germinal zone of the epiphyseal side of the epiphyseal cartilage are involved in forming a second ossification front that is responsible for the origin of the juxtaposed bone plate. We report the following: (a) The juxtaposed bone plate has a morphology and function that differs from that of the epiphyseal trabeculae; (b) on the epiphyseal edge of the epiphyseal cartilage, a new ossification front starts on the chondrocytes of the germinal area, which forms the juxtaposed bone plate. This ossification front is formed by chondrocytes from the germinal zone through a process of mineralisation and ossification, and (c) the process of mineralisation and ossification has a certain morphological analogy to the process of ossification in the metaphyseal cartilage of amphibians and differs from the endochondral ossification process in the metaphyseal side of the growth plate. The close relationship between the juxtaposed bone plate and the epiphyseal cartilage, in which the chondrocytes that migrate from the germinal area play an important role in the mineralisation and ossification process of the juxtaposed bone plate, supports the hypothesis of a new ossification front in the epiphyseal layer of the epiphyseal plate. This hypothesis has several implications: (a) epiphyseal cartilage is a morphological entity with two different ossification fronts and two different functions, (b) epiphyseal cartilage may be a morphological structure with three parts: perichondrial ring, metaphyseal ossification front or growth plate, and epiphyseal ossification front, (c) all disease (traumatic or dysplastic) that affects some of these parts can have an impact on the morphology of the epiphyseal region of the bone, (d) there is a certain analogy between metaphyseal cartilage in amphibians and mammalian epiphyseal cartilage, although the former is not responsible for bone growth, (e) comparative histological and anatomy studies are also warranted, to shed light on the phylogenetic study of epiphyseal cartilage throughout the changes that occur in the animal species.

Can 18F-FDG–PET show differences in myocardial metabolism between Wistar Kyoto rats and spontaneously hypertensive rats?

Positron emission tomography (PET) is useful for evaluating the cardiac metabolism of free fatty acid, glucose and oxygen both in human clinical practice and in experimental animal models. However, no data are available for such an evaluation in a model of stable compensated left ventricular hypertrophy in 14-month-old spontaneously hypertensive rats (SHRs). This study was designed to assess the metabolism of myocardial glucose in SHRs using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) using PET. The study was performed on 14-month-old male SHRs (n = 4) and age-matched Wistar Kyoto (WKY) rats (n = 4). PET scans were performed after the administration of anaesthesia with isoflurane and injection of a bolus of 39.37 ± 3.25 (mean ± SD) MBq (1.06 mCi) of 18F-FDG. The standardized uptake value (SUV) was used to evaluate 18F-FDG uptake by the heart. The analysis of SUV showed increased metabolism in the left ventricle of SHRs compared with WKY rats. Our results show that small animal PET using 18F-FDG can be performed in 14-month-old SHRs to evaluate new therapies in the regression of left ventricular hypertrophy in SHRs because pathological myocardial metabolism in the SHR differs from the normal metabolism of the WKY rat.

Evolutional patterns of articular cartilage following growth plate injury in rats

BackgroundNo study to date has analyzed the damage of the articular cartilage and its relation to growth plate injury. The purpose of this study was to test whether primary injury to the growth plate contributes to secondary damage to the articular cartilage in rats.MethodsA total of 109 two-week-old male Wistar rats were allocated to four lesional groups. In group I (controls) no surgery took place. In the remaining animals, an injury was caused in the proximal physis of the left tibia: group II, perichondrial ring injury; group III, direct injury to the growth plate; group IV, traumatic separation of the epiphysis where a Salter-Harris II-type injury was created. The results were assessed at 1 week, 6 weeks, and 6 months. A growth plate score was used. The stereological and histological changes in the articular cartilage were analyzed, and the results were subjected to statistical analysis.ResultsHistological studies showed discrete degenerative changes in the articular cartilage in the injured growth plate. Changes in the cell density, mean cell volume, and articular cartilage occurred in the injured growth plate. The changes appeared to be transient in groups II and III.ConclusionsPrimary injury to the growth plate contributes to secondary damage to the articular cartilage in young rats. Our data — extrapolated to the clinical view — suggests that a Salter-Harris type II injury does not seem to have impunity to subsequent joint degeneration.

Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats

Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 μg kg−1 min−1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose–response curves for 5-hydroxytryptamine (5-HT, 10−9–3 × 10−5 mol l−1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration–response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.

Short-term esmolol attenuates remodeling of the thoracic aorta in hypertensive rats by decreasing concentrations of ADMA down-regulated by oxidative stress

Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300μg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling.

Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs

The aim of this study was to assess the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device (LVAD). Ten healthy minipigs were divided into 2 groups (5 per group) according to the anesthetic received (sevoflurane or propofol). A Biomedicus centrifugal pump was implanted. Organ blood flow (measured using colored microspheres), markers of tissue injury, and hemodynamic parameters were assessed at baseline (pump off) and after 30 minutes of partial support. Blood flow was significantly higher in the brain (both frontal lobes), heart (both ventricles), and liver after 30 minutes in the sevoflurane group, although no significant differences were recorded for the lung, kidney, or ileum. Serum levels of alanine aminotransferase and total bilirubin were significantly higher after 30 minutes in the propofol group, although no significant differences were detected between the groups for other parameters of liver function, kidney function, or lactic acid levels. The hemodynamic parameters were similar in both groups. We demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of an LVAD under conditions of partial support.

Contribution to the initial pathodynamics of hip luxation in young rats.

Background: An anatomo-functional system has been described for the normal hip of some young mammals. This system includes the ligamentum teres, the transverse acetabular ligament, and the meniscoid of the hip. Purpose: This report analyzes morphologic changes in the anatomo-functional system of young rats in an experimental model of hip luxation, and on the initial pathodynamics of luxation produced experimentally. Methods: Hyperextension of the left knee was induced in 58 young rats through fixation of the tibia and femur with Kirschner wire. Radiographic, macroscopic, and microscopic parameters were analyzed for 3 study periods (group 1: 4 d, group 2: 1 wk, group 3: 2 wk), and macroscopic parameters were studied in a late group (group 4: 6 wk). Results: Breaks in the Shenton line were observed from group 1 (subluxation) onward (luxation). Hypertrophy of the round and transverse acetabular ligaments of the acetabulum and meniscoid, progressive elevation of the meniscoid, and fibrosis of the fibrofatty (pulvinar) tissue occurred from group 1 onward. Radiographic and morphometric studies showed triplane innominate bone deformation (anterior bending, lateral tilt, and rotation of the ischium), which resulted in decreased joint space. As time progressed, the increase in these injuries was accompanied by morphologic changes in the acetabulum, posterosuperior displacement and reorientation of the acetabulum and extrusion of the femoral head. Conclusions: Under the conditions of this study, the temporospatial morphologic changes in the acetabulum due to injury of the anatomo-functional system, and the triplane pelvic deformity in the initial period of the injury, produced femoral head extrusion of the acetabulum. Relevant Symptoms: These disorders may help us understand the pathogenic and clinical phenomena that appear in early stages of hip luxation disease.