In patients with severe aortic regurgitation and reduced left ventricular ejection fraction (LVEF), uncertainty remains whether to recommend aortic valve replacement (AVR) over heart transplantation, ...especially when mitral regurgitation and/or coronary heart disease coexist.
We assessed outcomes in 26 consecutive AVR patients aged </=70 years with severe aortic regurgitation and reduced LVEF, comparing the group undergoing isolated AVR with the group requiring combined surgery.
The difference in mortality and morbidity between the groups was 10% vs 6%, which was not significant (p = 0.6 in both cases). Also observed was a significant improvement in functional class and a reduction in LV end-diastolic diameter from a median value of 69 to 64 mm in the isolated AVR group and to 66 mm in the combined group (p < 0.05).
AVR in patients with symptomatic severe aortic regurgitation and reduced LVEF is feasible, even in the presence of concomitant mitral regurgitation and/or coronary heart disease requiring a combined surgical procedure.
Wiskott-Aldrich syndrome is a primary immunodeficiency characterized by infections, thrombocytopenia, and eczema. We present a 33-year-old man with this syndrome who underwent a one-stage ascending ...aorta, aortic arch and descending aortic aneurysm repair under moderate hypothermia and continuous visceral and cerebral perfusion. Histologic examination showed the presence of an aortitis with granulomatous inflammatory response and multinucleated cells.
Regional myocardial acidosis, as measured with tissue pH electrodes during cardiac surgery, has been shown to be reflective of regional myocardial ischemia. This study examined the relationship ...between intraoperative regional myocardial acidosis and long-term survival of patients undergoing cardiac surgery with cardiopulmonary bypass.
A total of 496 adult patients who underwent valve replacement, coronary artery revascularization, or both with intraoperative myocardial pH monitoring in the anterior and posterior left ventricular walls were followed up for 3 to 17 years (average 10.2 ± 4.9 years) for all cause mortality. Regional myocardial acidosis in each patient was defined by the lower of the anterior and posterior wall pH values.
A bivariate automatic interaction detection analysis identified three significant regional myocardial acidosis thresholds that affected long-term mortality: pH
37C less than 6.63 before aortic crossclamping, integrated mean pH
37C less than 6.34 during the period of aortic crossclamping, and pH
37C less than 6.73 at discontinuation of cardiopulmonary bypass. Cox proportional hazard regression analysis identified each of these thresholds to be independently determinant of survival, with pH
37C during aortic crossclamping having the highest risk ratio (risk ratio 2.15, 95% confidence interval 1.37-3.37). Raising pH
37C from lower than threshold before aortic crossclamping to higher than threshold during clamping increased the median survival by 40.2%.
In adult patients undergoing cardiac surgery with cardiopulmonary bypass, regional myocardial ischemic acidosis before aortic crossclamping, during aortic crossclamping, and at discontinuation of cardiopulmonary bypass are independently associated with reduced long-term postoperative survival. Reversing or avoiding myocardial acidosis during cardiac surgery improves long-term patient survival.
Intraoperative regional myocardial acidosis (RMA) during cardiac surgery has been shown to be reflective of regional myocardial ischemia and an independent predictor of adverse postoperative ...outcomes. This study identifies the determinants of intraoperative RMA.
Intramyocardial tissue pH37C in the anterior and posterior LV walls was measured in 641 adult patients during cardiac surgery. RMA at two intraoperative periods was quantified as integrated mean pH37C < 6.35 during aortic clamping (AC) and pH37C < 6.73 at the end of cardiopulmonary bypass (CPB). These pH thresholds were chosen because of their demonstrated relationship to long-term patient survival. Multivariate logistic regression models were constructed. An acidosis prediction score was constructed based on the factors determining RMA at the end of CPB.
Independent determinants of RMA during AC were preoperative New York Heart Association class III/IV (P=.007), current smoker (P=.0088), pH37C < 6.63 prior to AC (P < .0001), and intraoperative myocardial management technique (P=.0001). Independent determinants of RMA at end of CPB were ASA class IV/V (P=.0042), pH37C < 6.63 prior to AC (P=.035), pH37C < 6.35 during AC (P=.001), and total duration of CPB ≥ 212 minutes (P=.001).
RMA during cardiac surgery is determined by patient risk factors, the magnitude of preceding regional myocardial acidosis, and the duration of CPB.
Integrin LFA-1 is a receptor that is able to transmit multiple intracellular signals in leukocytes. Herein we show that LFA-1 induces a potent and transient increase in the activity of the small ...GTPase Rac-1 in T cells. Maximal Rac-1 activity peaked 10–15 min after LFA-1 stimulation and rapidly declined to basal levels at longer times. We have identified Vav, a guanine nucleotide exchange factor for Rac-1, and PI3K/Akt, as regulators of the activation and inactivation phases of the activity of Rac-1, respectively, in the context of LFA-1 signaling based on the following experimental evidence: (i) LFA-1 induced activation of Vav and PI3K/Akt with kinetics consistent with a regulatory role for these molecules on Rac-1, (ii) overexpression of a constitutively active Vav mutant induces activation of Rac independently of LFA-1 stimulation whereas overexpression of a dominant-negative Vav mutant blocks LFA-1-mediated Rac activation, (iii) pharmacological inhibition of PI3K/Akt prevented the fall in the activity of Rac-1 after its initial activation but had no effect on Vav activity, and (iv) overexpression of a dominant-negative or a constitutively active Akt-1 induced or inhibited, respectively, Rac-1 activity. Finally, we show that T cells with a sustained Rac activity have impaired capacity to elongate onto ICAM-1. These results demonstrate that down-regulation of the activity of this GTPase is a requirement for the regulation of T cell morphology and motility and highlight the importance of temporal regulation of the signaling triggered from this integrin.
The MAL proteolipid, an integral protein present in glycolipid- and cholesterol-enriched membrane (GEM) rafts, is an element of the machinery necessary for apical sorting in polarized epithelial ...Madin-Darby canine kidney cells. MAL was the first member identified of an extended family of proteins that have significant overall sequence identity. In this study we have used a newly generated monoclonal antibody to investigate an unedited member of this family, named BENE, which was found to be expressed in endothelial-like ECV304 cells and normal human endothelium. Human BENE was characterized as a proteolipid protein predominantly present in GEM rafts in ECV304 cells. Coimmunoprecipitation experiments revealed that BENE interacted with caveolin-1. Confocal immunofluorescence and electron microscopic analyses indicated that BENE mainly accumulated into intracellular vesicular/tubular structures that partially colocalize with internal caveolin-1. In response to cell surface cholesterol oxidation, BENE redistributed to the dilated vesicular structures that concentrate most of the caveolin-1 originally on the cell surface. After cessation of cholesterol oxidation, a detectable fraction of the BENE molecules migrated to the plasmalemma accompanying caveolin-1 and then returned progressively to its steady state distribution. Together, these features highlight the BENE proteolipid as being an element of the machinery for raft-mediated trafficking in endothelial cells.
To characterize the ultrastructural and metabolic changes occurring in the hypertrophied ventricle during cardiac operations in man, we studied 36 patients with valvular heart disease undergoing ...valve replacement, during which multiple doses of cold potassium cardioplegic solution were administered (Group I). Each patient had substantial ventricular hypertrophy according to measurements made of left ventricular mass, with a mean of 232.1 +/- 19.8 gm/m2 (normal: 92 +/- 16 gm/m2). Serial biopsy specimens were obtained from the left ventricular apex at the initiation of bypass, during the cross-clamp interval, and during reperfusion. Each specimen was scored from 0 to 4 according to ischemic changes in nuclear chromatin, mitochondrial swelling, myofibrillar edema, glycogen depletion, and overall cell morphology. Myocardial pH and temperature were measured continuously in the left ventricular free wall. During the cross-clamp period, ischemic injury was evidenced by changes in nuclear chromatin (0.38 +/- 0.10 to 1.25 +/- 0.21, p less than 0.0001), intracellular edema (0.43 +/- 0.06 to 0.97 +/- 0.14, p less than 0.002), overall cell morphology (0.37 +/- 0.06 to 0.97 +/- 0.14, p less than 0.001), and mitochondria (0.10 +/- 0.05 to 0.19 +/- 0.07, p less than 0.0001). During reperfusion, mitochondrial swelling increased further (0.19 +/- 0.07 to 0.35 +/- 0.08, p less than 0.0001) and glycogen stores were depleted (0.63 +/- 0.13 to 0.96 +/- 0.17, p less than 0.02), while the other structures remained unchanged. Myocardial pH declined during ischemic arrest from 6.89 +/- 0.04 to 6.40 +/- 0.04 (p less than 0.001). The changes in myocardial pH in Group I were compared to changes in myocardial pH in 10 patients (Group II) with no left ventricular hypertrophy undergoing isolated coronary bypass graft operations with the same protective techniques. In contrast to Group I, myocardial pH did not fall in Group II during ischemic arrest (6.98 +/- 0.06 to 6.94 +/- 0.05, p = not significant). Thus, with the use of current myocardial protective techniques, ultrastructural and metabolic changes indicative of ischemia are produced in the hypertrophied myocardium. The structural alterations consist of changes in nuclear chromatin and intracellular edema during the ischemic phase and by mitochondrial swelling during reperfusion.
Regional differences in myocardial acid production have not been characterized during administration of either asanguineous or sanguineous cardioplegia. To investigate this, miniature glass pH ...electrodes were placed in the right ventricular (RV) myocardium, the left ventricular subendocardial (LV endo) region, and the subepicardial (LV epi) region in a canine model. Multiple doses of either blood cardioplegia (Group 1; N = 11) or crystalloid cardioplegia (Group 2; N = 11) were administered during 4 hours of aortic cross-clamping. The accumulation of hydrogen ions during the cross-clamp period was greater in Group 2 than Group 1 in the LV endo region (629 ± 79 nm/L versus 66 ± 31 nm/L;
p < 0.001), the LV epi region (623 ± 66 nm/L versus 72 ± 32 nm/L;
p < 0.001), and the RV myocardium (814 ± 296 nm/L versus 150 ± 54 nm/L;
p < 0.05). Within each group, the time course of myocardial pH and the accumulation of hydrogen ions did not differ among the LV endo region, LV epi region, and the RV myocardium (
p = not significant). These data indicate that transmural and interventricular differences in myocardial pH and hydrogen ion accumulation are not produced in the vented, arrested canine heart. In addition, when compared with asanguineous cardioplegia, blood cardioplegia globally and transmurally reduces acid accumulation during ischemic arrest.
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