Background—: Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell–cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results—: We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4 -deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4 -deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4 -deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions—: These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.

Objective—To determine the prevalence of Doppler echocardiography–derived evidence of pulmonary arterial hypertension (DEE-PAH) in dogs with mitral valve disease (MVD) classified according to the International Small Animal Cardiac Health Council (ISACHC) heart failure classification scheme and various echocardiographic and Doppler indices of MVD severity. Design—Retrospective case series. Animals—617 dogs examined from 2001 to 2005 with MVD in ISACHC classes I to III. Procedures—Dogs were examined echocardiographically. Criteria used for systolic and diastolic DEE-PAH were detection of high tricuspid (≥ 2.5 m/s) and telediastolic pulmonic (≥ 2.0 m/s) valvular peak regurgitant jet velocities, respectively, by use of continuous-wave Doppler echocardiography. Results—86 (13.9%) dogs with MVD had a diagnosis of DEE-PAH. Severity and prevalence of DEE-PAH increased with ISACHC class (3.0%, 16.9%, 26.7%, and 72.2% prevalences for ISACHC classes Ia, Ib, II, and III, respectively). A significant correlation between systolic or diastolic pulmonary arterial pressure and left atrial-to-aortic diameter ratio (LA/Ao) was detected. Doppler echocardiography–derived evidence of pulmonary arterial hypertension was detected in 18 dogs with values of LA/Ao within reference range, all of which had moderate (n = 2 dogs) or severe (16) mitral valve regurgitation on color Doppler imaging. Conclusions and Clinical Relevance—The prevalence and degree of DEE-PAH were related to the severity of MVD. Changes associated with DEEPAH may be detected in early stages of the disease, but only in dogs with severe mitral valve regurgitation.

Objective—To determine left ventricular free wall (LVFW) radial and longitudinal myocardial contraction velocities in healthy dogs via quantitative 2-dimensional color tissue Doppler imaging (TDI). Animals—100 dogs. Procedure—TDI was used by a single trained observer to measure radial and longitudinal myocardial movement in the LVFW. Radial myocardial velocities were recorded in segments in the endocardial and epicardial layers of the LVFW, and longitudinal velocities were recorded in segments at 3 levels (basal, middle, apical) of the LVFW. Results—LVFW velocities were higher in the endocardial layers than in the epicardial layers. Left ventricular free wall velocities were higher in the basal segments than in the middle and apical segments. Radial myocardial velocity gradients, defined as the difference between endocardial and epicardial velocities, were (mean ± SD) 2.5 ± 0.8 cm/s, 3.8 ± 1.5 cm/s, and 2.3 ± 0.9 cm/s in systole, early diastole, and late diastole, respectively. Longitudinal myocardial velocity gradients, defined as the difference between basal and apical velocities, were 5.9 ± 2.2 cm/s, 6.9 ± 2.5 cm/s, and 4.9 ± 1.7 cm/s in systole, early diastole, and late diastole, respectively. A breed effect was detected for several systolic and diastolic TDI variables. In all segments, systolic velocities were independent of fractional shortening. Conclusions and Clinical Relevance—LVFW myocardial velocities decreased from the endocardium to the epicardium and from base to apex, thus revealing intramyocardial radial and longitudinal velocity gradients. These indices could enhance conventional echocardiographic analysis of left ventricular function in dogs. Breed-specific reference intervals should be defined. (Am J Vet Res 2005;66:953–961)