María Josefa Fernández del Palacio

Mineralocorticoid Receptor Antagonists Modulate Galectin-3 and Interleukin-33/ST2 Signaling in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction

OBJECTIVES This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). BACKGROUND The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. METHODS MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined. RESULTS In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. CONCLUSIONS MRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling.

Modulation of IL‐33/ST2 system in postinfarction heart failure: correlation with cardiac remodelling markers

Interleukin (IL)‐33 and sST2 are molecules with an opposite pathophysiologic implications in the myocardial response after acute myocardial infarction (AMI). Both may be a target for therapeutic interventions. The kinetics of IL‐33 and sST2 expression in infarcted myocardium and their correlation with the ongoing processes of fibrosis, inflammation and apoptosis remains poorly defined.

Usefulness of Doppler ultrasonography to assess digital vascular dynamics in horses with systemic inflammatory response syndrome or laminitis

OBJECTIVE To evaluate the usefulness of Doppler ultrasonography as a method to assess changes in digital vascular dynamics in horses with systemic inflammatory response syndrome (SIRS) or laminitis. DESIGN Cross-sectional study. Animals-42 adult Andalusian horses. PROCEDURES Group 1 included 9 healthy horses, group 2 included 19 horses with SIRS without (n = 9) or with (10) a palpable increase in digital pulse intensity, and group 3 included 14 horses with laminitis without (8) or with (6) radiographic evidence of rotation or distal displacement (sinking) of the third phalanx. Qualitative spectrum characteristics and quantitative Doppler measurements of the lateral palmar digital artery were obtained for horses in each group. RESULTS 4 spectra, characterized by a positive systolic peak followed by several positive diastolic peaks, were observed in group 1 horses, group 2 horses, and group 3 horses that lacked radiographic changes. In the group 3 horses that had radiographic changes, laminar blood flow was detected. Diameter of the lateral palmar digital artery was significantly larger in the group 3 horses than in the group 2 horses; blood flow was significantly higher in the group 2 horses that had an increase in digital pulse intensity than in the group 2 horses without an increase in digital pulse intensity; velocity-time integral and acceleration time were significantly lower in group 3 horses, compared with group 2 horses. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that Doppler ultrasonography may be a useful complementary tool to detect digital blood flow changes of horses with SIRS, especially if they have a palpable increase in digital pulse intensity, or laminitis.

Alterations in the large peripheral circulation in dogs with heart failure.

The femoral artery is responsible for perfusion of a large muscular region that can be involved in the exercise intolerance shown by dogs with spontaneous heart failure. The objective of the present study was to evaluate blood flow in the femoral artery by transcutaneous duplex Doppler ultrasonography (TDU) in 50 healthy dogs and 50 dogs with spontaneous heart failure. The group of dogs with heart disease was divided according to the functional class of the heart failure. The TDU measurements were: peak systolic velocity (PSV), early retrograde (EDV) and end diastolic velocities (EnDV), mean velocity (MV), pulsatility index (PI), resistivity index (RI) and femoral flow volume (FFV). In healthy dogs, PSV and FFV were significantly higher than in dogs with heart disease. FFV was reduced mainly in patients with moderate and severe heart failure. TDU allowed for non-invasive detection and quantification of pathological alterations in peripheral hemodynamics.

Broncholithiasis in a cat: clinical findings, long-term evolution and histopathological features

A 14-year-old neutered male Persian cat was evaluated because of an acute exacerbation of a chronic cough of 2–3 years of duration. Physical examination was normal except for the auscultation of accentuated breath sounds and wheezes cranially on both sides of the chest. Complete blood count, biochemical parameters and urinalysis were normal. Thoracic radiographs showed a generalised nodular pattern with multiple mineral opacities. Oral prednisone and doxycycline were prescribed. Two weeks later, the frequency of the cough was significantly reduced. Terbutaline was recommended for relief of acute exacerbations. Three years later the cat was evaluated again due to a non-related disease that led to the euthanasia of the cat. Concerning its respiratory disease, the cat had experienced nearly asymptomatic periods of 3–6 weeks of duration punctuated by acute exacerbation periods of 7–10 days, during which terbutaline was useful to relieve the cough. Thoracic radiographs showed a mild increase in the size and extent of the pulmonary mineralisation. Histopathologically, mild bronchitis and bronchiectasis were evident, accompanied by calcified bronchial plugs and marked hyperplasia and hypertrophy of the seromucinous glands. Based on clinical and pathoanatomical findings, a final diagnosis of miliary broncholithiasis and bronchiectasis was made. Broncholithiasis should be considered in differential diagnosis of pulmonary mineralisation in cats. When no concomitant diseases are present, this rare disease appears to have a slowly progressive evolution that does not appear to carry a bad prognosis and may be satisfactorily managed with combinations of bronchodilators and corticosteroids.

International collaborative study to assess cardiovascular risk and evaluate long‐term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study

Background Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals One thousand seven hundred and thirty client‐owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long‐term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9‐15 years. Conclusions and Clinical Importance Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.

Traumatic pulmonary pseudocysts associated to pneumothorax and rib fractures in a dog

A two-year-old, 37 kg intact mixed-breed dog was presented with lameness of the left pelvic limb after being hit by a car three days ago. The physical examination revealed tachypnoea with an abdominal restrictive respiratory pattern. Based on history of the patient and imaging findings a presumptive diagnosis of pneumothorax, rib fractures and traumatic pulmonary pseudocysts (TPP) was made. The patient was treated conservatively. One month later, thoracic radiograph showed only a pulmonary small nodule. TPPs are an uncommon complication after blunt thorax trauma but should be included in the differential diagnosis when cavitary pulmonary lesions are seen on thoracic radiograph or CT.

Pharmacological inhibition of the mitochondrial NADPH oxidase 4/PKCα/Gal-3 pathway reduces left ventricular fibrosis following myocardial infarction

&NA; Although the initial reparative fibrosis after myocardial infarction (MI) is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental. Although metformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondrial NADPH oxidase 4 (mitoNox) and protein kinase C‐alpha (PKC&agr;) on the cardiac fibrosis and galectin 3 (Gal‐3) expression. Randomly rats underwent MI, received metformin or saline solution. A model of biomechanical strain and co‐culturewas used to enable cross talk between cardiomyocytes and fibroblasts. Long‐term metformin treatment after MIwas associated with (1) a reduction in myocardial fibrosis and Gal‐3 levels; (2) an increase in adenosine monophosphate‐activated protein kinase (AMPK) &agr;1/&agr;2 levels; and (3) an inhibition of both mRNA expression and enzymatic activities of mitoNox and PKC&agr;. These findings were replicated in the cellular model, where the silencing of AMPK expression blocked the ability of metformin to protect cardiomyocytes from strain. The use of specific inhibitors or small interference RNA provided evidence that PKC&agr; is downstream of mitoNox, and that the activation of this pathway results in Gal‐3 upregulation.The Gal‐3 secreted by cardiomyocytes has a paracrine effect on cardiac fibroblasts, inducing their activation. In conclusion, a metformin‐induced increase in AMPK improves myocardial remodeling post‐MI, which is related to the inhibition of the mitoNox/PKC&agr;/Gal‐3 pathway. Manipulation of this pathway might offer new therapeutic options against adverse cardiac remodeling, in terms of preventing the activation of the present fibroblast population.

Echocardiographic evaluation of the right ventricular dimension and systolic function in dogs with pulmonary hypertension

Background Right ventricular (RV) enlargement and dysfunction are associated with prognosis in humans with pulmonary hypertension (PH). Hypothesis/Objectives To assess RV size and systolic function in dogs with PH and to determine if they are associated with disease severity and right‐sided congestive heart failure (R‐CHF). Animals 89 dogs with PH and 74 healthy dogs. Methods Prospective observational study. PH was classified according to the tricuspid regurgitation pressure gradient. RV end‐diastolic area (RVEDA) index was calculated as RVEDA divided by body surface area. RV systolic function was assessed with the tricuspid annular plane systolic excursion (TAPSE) and the RV fractional area change (FAC) normalized for body weight (TAPSEn and FACn, respectively). Results RVEDA index was higher in dogs with moderate PH (10.8 cm2/m2; range, 6.2‐14.4 cm2/m2) and severe PH (12.4 cm2/m2; range, 7.7‐21.4 cm2/m2) than in those with mild PH (8.4 cm2/m2; range, 4.8‐11.6 cm2/m2) and control dogs (8.5 cm2/m2; range, 2.8‐11.6 cm2/m2; P < .001). RVEDA index was significantly higher in dogs with R‐CHF (13.7 cm2/m2; range, 11.0‐21.4 cm2/m2) than in dogs without R‐CHF (9.4 cm2/m2; range, 4.8‐17.1 cm2/m2; P < .001). The severity of tricuspid regurgitation (TR) was the only independent predictor of the RVEDA index (P < .001). TAPSEn and FACn were not significantly different among varying degrees of PH severity and between dogs with and without R‐CHF. Conclusions and Clinical Importance The RVEDA index can be used to evaluate RV size in dogs. It can provide additional information in dogs with PH and predict R‐CHF. Severity of TR is the main determinant of RV enlargement in dogs with PH.