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BACKGROUND:: Because pulmonary endogenous surfactant is altered during acute respiratory distress syndrome, surfactant replacement may improve clinical outcomes. However, trials of surfactant use have had mixed results. We designed this animal model of unilateral (right) lung injury to explore the effect of exogenous surfactant administered to the injured lung on inflammation in the injured and noninjured lung. METHODS:: Mice underwent hydrochloric acid instillation (1.5 mL/kg) into the right bronchus and prolonged (7 hours) mechanical ventilation (25 mL/kg). After 3 hours, mice were treated with 1 mL/kg exogenous surfactant (Curosurf®) (surf group) or sterile saline (NaCl 0.9%) (vehicle group) in the injured (right) lung or did not receive any treatment (hydrochloric acid, ventilator-induced lung injury). Gas exchange, lung compliance, and bronchoalveolar inflammation (cells, albumin, and cytokines) were evaluated. After a significant analysis of variance (ANOVA) test, Tukey post hoc test was used for statistical analysis. RESULTS:: At least 8 to 10 mice in each group were analyzed for each evaluated variable. Surfactant treatment significantly increased both the arterial oxygen tension to fraction of inspired oxygen ratio and respiratory system static compliance (P = 0.027 and P = 0.007, respectively, for surf group versus vehicle). Surfactant therapy increased indices of inflammation in the acid-injured lung compared with vehicle: inflammatory cells (685 [602-773] and 216 [125-305] × 1000/mL, respectively; P < 0.001) and albumin in bronchoalveolar lavage (BAL) (1442 ± 588 and 743 ± 647 μg/mL, respectively; P = 0.027). These differences were not found (P = 0.96 and P = 0.54) in the contralateral (uninjured) lung (inflammatory cells 131 [78-195] and 119 [87-149] × 1000/mL and albumin 135 ± 100 and 173 ± 115 μg/mL). CONCLUSIONS:: Exogenous surfactant administration to an acid-injured right lung improved gas exchange and whole respiratory system compliance. However, markers of inflammation increased in the right (injured) lung, although this result was not found in the left (uninjured) lung. These data suggest that the mechanism by which surfactant improves lung function may involve both uninjured and injured alveoli.

Evidence of diastolic dysfunction in cirrhosis contributed to the definition of cirrhotic cardiomyopathy. In 109 patients with chronic HCV infection with or without cirrhosis E/A ratio, a Doppler marker of diastolic dysfunction, was decreased in cirrhotics (0.89 ± 0.03 vs controls 1.21 ± 0.07, p < 0.01) and to a lesser extent in patients with advanced liver fibrosis (1.17 ± 0.07, p < 0.01). Left ventricular parietal wall thickness was increased. The nature of this abnormality in human cirrhosis has not been clarified, animal studies reporting cardiac hypertrophy. To this aim we employed the echo- cardiographic integrated backscatter (IBS) technique to obtain an indirect estimate of tissue density (decreased when a higher percentage of muscle fibres is present and increased when fibrosis prevails) to provide myocardial tissue charac- terization in a subset of patients with compensated HCV cirrhosis. The average IBS signal was reduced in cirrhotics at the level of the posterior wall (21.72 ± 1.46 dB versus 30.85 ± 1.40 dB in controls, p < 0.01). Our results confirm diastolic dysfunction in postviral cirrhosis pointing to cardiac hypertrophy as the anatomopathological background in the compen- sated stage of disease.

Aims Mitral regurgitation (MR) confers independent risk in patients with acute myocardial infarction. We utilized data from the VALsartan In Acute myocardial iNfarcTion echo study to relate baseline MR to left ventricular (LV) size, shape, and function, and to assess the relationship between baseline MR and progression of MR and cardiovascular (CV) outcomes. Methods and results We studied 496 patients with heart failure (HF) and/or systolic dysfunction after MI who underwent echocardiography at a median of 5 days after MI. MR severity, quantified as the regurgitant jet area/left atrial area ratio, was assessed at baseline, one and 20 months post-MI and related to LV size, shape, function, and clinical outcomes. Increased MR at baseline was associated with larger LV end-diastolic and end-systolic volumes, increased sphericity index, and reduced ejection fraction ( P trend < 0.001). Moderate–severe MR was an independent predictor of total mortality [adjusted hazard ratio (HR) 2.4 (1.1–5.3)], CV mortality [adjusted HR 2.7 (1.2–6.1)], hospitalization for HF [adjusted HR 2.5 (1.1–5.5)], or death or HF hospitalization [adjusted HR 2.5 (1.4–4.6)]. Patients with progression of MR during the first post-MI month were substantially more likely to die or develop HF (adjusted HR per increased MR grade 3.0, 95% CI 1.8–4.9). Progression of MR over 20 months in survivors was associated with increased hospitalizations for HF ( P < 0.001). Conclusion Following high-risk myocardial infarction, baseline mitral regurgitant severity is associated with larger LV volumes and worse LV function. Both baseline MR severity and progression of MR are associated with an increased likelihood of adverse outcomes.

Aspiration pneumonitis can lead to alveolar surfactant dysfunction. We employed a murine model of unilateral aspiration to compare surfactant synthesis in the injured (I) and noninjured (NI) contralateral lung. Mice were instilled with hydrochloric acid in the right bronchus and, after 18 h, an intraperitoneal dose of deuterated water was administered as precursor of disaturated phosphatidylcholine (DSPC)-palmitate. Selected bronchoalveolar lavage fluid (BALF) was collected at scheduled time points and lungs were removed. We measured DSPC-palmitate synthesis in lung tissue and secretion in BALF by gas chromatography-isotope ratio mass spectrometry, together with total proteins and myeloperoxidase activity (MPO) by spectrophotometry. BALF total proteins and MPO were significantly increased in the I lungs compared with NI and naïve control lungs. The DSPC pool size was significantly lower in the BALF of the I lungs compared with naïve controls. DSPC synthesis was accelerated in the I and NI lungs. DSPC secretion of the I lungs was similar to their respective naïve controls, and it was markedly lower compared with their respective NI contralateral lungs. DSPC synthesis and secretion were faster, especially in the NI lungs, compared with naïve control lungs, as a possible compensatory mechanism due to a cross-talk between the lungs triggered by inflammation, hyperventilation, and/or undetermined type II cell reaction to the injury.

Background Mitral regurgitation (MR) has been associated with adverse outcomes after myocardial infarction (MI). Without structural valve disease, functional MR has been related to left ventricular (LV) remodeling and geometric deformation of the mitral apparatus. The aims of this study were to elucidate the mechanistic components of MR after high-risk MI and to identify predictors of MR progression during follow-up. Methods The Valsartan in Acute Myocardial Infarction Echo substudy prospectively enrolled 610 patients with LV dysfunction, heart failure, or both after MI. MR at baseline, 1 month, and 20 months was quantified by mapping jet expansion in the left atrium in 341 patients with good-quality echocardiograms. Indices of LV remodeling, left atrial size, and diastolic function and parameters of mitral valve deformation, including tenting area, coaptation depth, anterior leaflet concavity, annular diameters, and contractility, were assessed and related to baseline MR. The progression of MR was further analyzed, and predictors of worsening among the baseline characteristics were identified. Results Tenting area, coaptation depth, annular dilatation, and left atrial size were all associated with the degree of baseline MR. Tenting area was the only significant and independent predictor of worsening MR; a tenting area of 4 cm 2 was a useful cutoff to identify worsening of MR after MI and moderate to severe MR after 20 months. Conclusions Increased mitral tenting and larger mitral annular area are determinants of MR degree at baseline, and tenting area is an independent predictor of progression of MR after MI. Although LV remodeling itself contributes to ischemic MR, this influence is directly dependent on alterations in mitral geometry.

Aims To assess the relationship between left atrial (LA) size and outcome after high-risk myocardial infarction (MI) and to study dynamic changes in LA size during long-term follow-up. Methods and results The VALIANT Echocardiography study prospectively enrolled 610 patients with left ventricular (LV) dysfunction, heart failure (HF), or both following MI. We assessed LA volume indexed to body surface area (LAVi) at baseline, 1 month, and 20 months after MI. Baseline LAVi was an independent predictor of all-cause death or HF hospitalization ( P = 0.004). In patients who survived to 20 months, LAVi increased a mean of 3.00 ± 7.08 mL/m2 from baseline. Hypertension, lower estimated glomerular filtration rate, and LV mass were the only baseline independent predictors of LA remodelling. Changes in LA size were related to worsening in MR and increasing in LV volumes. LA enlargement during the first month was significantly greater in patients who subsequently died or were hospitalized for HF than in patients without events. Conclusion Baseline LA size is an independent predictor of death or HF hospitalization following high-risk MI. Moreover, LA remodelling during the first month after infarction is associated with adverse outcome.

Use of local arterial distensibility measurements by change in carotid artery diameter divided by pulse pressure has limitations because blood pressure is often taken in a vessel distant or at a time different from where and when change in diameter is taken. In 92 subjects (23 to 91 years of age), carotid artery diameter was continuously measured ecographically, whereas blood pressure was continuously measured simultaneously tonometrically on the contralateral artery, the 2 signals being synchronized via 2 EKGs. Within each cardiac cycle, there was a linear relationship between the changes in vessel diameter and the changes in blood pressure during either the protomesosystole or the diastole after the dicrotic notch. The diastolic slope was displaced upward and steeper than the systolic slope, the pressure-diameter loop showing a hysteresis. Both slopes showed a high reproducibility when data were averaged over a several-second period. There were small differences between consecutive cardiac cycles, suggesting that modulation of arterial mechanical response to continuous changes in intravascular pressure may undergo physiological variations. In the 92 subjects, systolic and diastolic slopes correlated significantly with distensibility values obtained by Reneman formula and exhibited a close inverse relationship with each subject's age and systolic blood pressure, thereby showing the ability to reflect age- and pressure-dependent large artery stiffening. This method may allow precise assessment of man's arterial mechanical properties within each cardiac cycle. This highly dynamic assessment may help to collect information on properties of normal and altered large elastic arteries and the mechanisms involved in disease. © 2008 American Heart Association, Inc.

Diabetes is associated with a reduction of arterial distensibility. Limited information exists regarding whether or how early this appears in the course of the disease. We studied 54 normoglycemic, normotensive, healthy offspring of 2 parents with type 2 diabetes mellitus and 55 age- and sex-matched healthy control subjects. Carotid diastolic diameter and systodiastolic change were measured by echo tracking (Wall Track System) and wall thickness by echocolor Doppler (Sonos 5500, Philips). Pulse pressure was measured by a semiautomatic device positioned on the brachial artery and arterial distensibility calculated by Reneman formula. Blood pressure, blood glucose, glycohemoglobin, and insulin sensitivity (homeostasis model assessment index) were normal or only slightly elevated and by and large similar in the 2 groups. Compared with control subjects, offspring of diabetic parents showed similar carotid diameters at diastole and a reduced increase in carotid diameter at systole (−16%), a reduced carotid artery distensibility (−30%), and an increased pulse pressure (+21.8%), all differences being statistically significant ( P 2 ). Carotid artery wall thickness was not different between the 2 groups. Thus, subjects with predisposition to diabetes show carotid artery stiffening even in the absence of blood pressure alterations, as well as substantial alterations of glucose metabolism, body mass index, and changes in carotid wall thickness. This suggests that, in diabetes, alterations in arterial mechanical properties represent an early phenomenon, which may occur in the absence of metabolic and blood pressure alterations.

Background Acid aspiration is a complication of general anesthesia. Most animal models developed to define its pathophysiology have focused on the acute (< or =24 h) phase of the injury. The authors describe a model of acid aspiration allowing the study of this type of lung injury over time. Methods The authors instilled hydrochloric acid (0.1 m, 1.5 ml/kg) or normal saline in the right bronchus of mice. Lung injury was evaluated at 6 h, 12 h, 24 h, and 2 weeks by assessing arterial blood gases, respiratory system compliance, lung wet weight normalized by body weight, lung myeloperoxidase activity, and histology. Twelve hours and 2 weeks after injury, a computed tomography scan was obtained. Results In the hydrochloric acid group, arterial oxygen tension decreased (P < 0.05) at 12 and 24 h, whereas it recovered at 2 weeks; respiratory system compliance was lower both at 24 h and 2 weeks (P < 0.05). Lung weight increased at 12 and 24 h (P < 0.05). Myeloperoxidase activity peaked between 6 and 12 h. Computed tomography at 12 h showed that almost 30% of the injured lung was abnormally aerated. Although reduced, the abnormalities were still present at 2 weeks as confirmed by a fibrotic scar well evident at histologic examination. Conclusion The authors characterized a murine model of regional acid aspiration allowing long-term survival. Despite a partial recovery, at 2 weeks the injury persisted, with evidence of fibrosis and lung compliance reduction. This long-term, low-mortality model seems suitable for assessment of the effects of different therapies on lung injury and repair.