Oz M. Shapira

Ascending Aortic Dilatation Associated With Bicuspid Aortic Valve Pathophysiology, Molecular Biology, and Clinical Implications

Ascending aortic dilatation occurs more frequently and at a younger age in patients with bicuspid aortic valves (BAV) than it does in patients with normal trileaflet aortic valves (TAV). The clinical significance of the correlation between BAV and dilatation of the ascending aorta is based on 2 factors. First, BAV is the most common congenital cardiac abnormality, occurring in 0.46% to 1.37% of the population.1–4 Second, aortic dilatation has a propensity for dissection and rupture, making it a potentially lethal disease. Ascending aortic dilatation with BAV warrants frequent monitoring, with possible early prophylactic surgical intervention to prevent dissection or rupture. The purpose of this article is to review the etiology and natural history and to make suggestions regarding management of the disease on the basis of the limited data available. ### Differential for Etiology of Ascending Aortic Aneurysms Most ascending aortic aneurysms have unknown etiology and are classified as idiopathic.5 In contrast to aneurysms of the descending aorta, ascending aortic aneurysms are not commonly a result of atherosclerosis.6,7 Among heritable connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome, ascending aortic aneurysms are a clinical component of the syndrome. BAV disease, also a heritable disorder, is known to have an increased risk of ascending aortic aneurysm as well. Marfan syndrome and BAV aortic disease share common histopathological findings, including medial degeneration, increased matrix metalloproteinase (MMP) activity, and decreased fibrillin-1 in the aortic wall.8 ### Anatomic Boundaries of BAV Disease Development of a BAV is part of a larger spectrum of structural developmental abnormalities involving the great vessels. The aortic valve and ascending aorta share a common embryonic origin: they both develop from neural crest cells.9–12 The vascular smooth muscle cells (VSMCs) that undergo apoptosis in the media of the ascending aorta are of neural crest origin.13 The pulmonary trunk demonstrates histopathological changes similar to those of the …

Effect of gender on postoperative outcomes and hospital stays after coronary artery bypass grafting.

BACKGROUND Compared to men, women undergoing coronary artery bypass grafting appear to have a higher morbidity and mortality, particularly in the perioperative period. This study was designed to answer the questions of whether such differences in clinical outcomes between men and women still exist with improvements in surgical techniques and determine whether it is gender or associated comorbid conditions in women that lead to higher morbidity. METHODS An analysis of a single centers contemporary experience (1994 to 1997) of 1,743 consecutive patients undergoing primary coronary artery bypass grafting was performed. Only reoperations were excluded. Data were collected prospectively and presented as mean +/- standard deviation (p<0.05). RESULTS Women represented 30.0% of patients. Compared with men, women were older (68.4 versus 63.8 years; p<0.05), and had more urgent surgical interventions (70.0% versus 56.7%; p<0.05), a higher incidence of diabetes (42.1% versus 26.7%; p<0.05), hypertension (82.0% versus 73.9%; p<0.05), lower body surface area (1.73+/-0.18 m2 versus 2.03+/-0.19 m2; p<0.05), and hematocrit (31.7%+/-3.9% versus 36.2%+/-3.9%; p<0.05). Ejection fraction, incidence of previous myocardial infarction, chronic obstructive pulmonary disease, left main (LM) disease, renal insufficiency, extent of coronary disease, and preoperative intraaortic balloon pump were similar. Women received fewer arterial grafts (91.0% versus 95.5%; p<0.05) and distal anastomoses (3.31+/-0.88 versus 3.49+/-0.94 p<0.05). Despite these differences, there were no statistical differences in the incidence of postoperative death (1.5% versus 1.0%), myocardial infarction (0.6% versus 0.6%), or cerebrovascular accident/transient ischemic attack (1.1% versus 0.4%) between men and women. Women had a higher inotropic support (10.2% versus 4.4%; p<0.05) and longer hospital stays (7.3+/-5.7 days versus 6.3+/-4.2 days; p<0.05). Using multivariate analysis, female gender was not an independent predictor of death or postoperative complications but was a predictor of length of hospital stay, use of arterial grafts, and extent of coronary revascularization. CONCLUSIONS After accounting for differences in their risk variables, the incidences of death, perioperative myocardial infarction and cerebrovascular accident/ transient ischemic attack after coronary artery bypass grafting in women and men were not statistically significant. Perioperative complications are related to comorbid risk factors but not to female gender itself. Further studies are warranted.

Papillary fibroelastoma: increasing recognition of a surgical disease

Papillary fibroelastomas are uncommon benign tumors usually involving the heart valves, which historically have been diagnosed at autopsy. With the advent of echocardiography, however, the number of patients diagnosed in life has increased. Papillary fibroelastomas represent a surgically treatable cause of cerebrovascular and cardiovascular ischemia and infarction making their identification clinically important. We report three unusual cases of papillary fibroelastoma; two patients presenting with symptoms of cerebrovascular ischemia and one presenting with myocardial infarction. We also present a comprehensive review of the literature and provide a compilation of all case reports to date.

Effect of Anticoagulation Protocol on Outcome in Patients Undergoing CABG With Heparin-Bonded Cardiopulmonary Bypass Circuits

BACKGROUND We have demonstrated that the use of heparin-bonded cardiopulmonary bypass circuits (HBCs) combined with a lower anticoagulation protocol as an adjunct to an integrated blood conservation strategy decreases the incidence and magnitude of homologous transfusion and improves clinical outcome in patients undergoing primary coronary artery bypass grafting. It is not known whether it is the lower anticoagulation protocol that influences outcome in patients treated with HBCs. Furthermore, the thrombogenic risk of using lower anticoagulation with HBCs still is debated. METHODS To answer these questions, a prospective randomized study was conducted in which 244 patients undergoing primary coronary artery bypass grafting were treated with HBCs and randomized to undergo either a full (activated clotting time, > 450 seconds) or a lower (activated clotting time, > 250 seconds) anticoagulation protocol. In addition to clinical outcome, levels of thrombin generation markers during and after cardiopulmonary bypass were assessed in a consecutive subset of 58 patients (full anticoagulation profile = 28, lower anticoagulation profile = 30) by measuring thrombin-antithrombin complexes and prothrombin fragment 1.2. Levels of these markers also were correlated with the activated clotting time during cardiopulmonary bypass. RESULTS Preoperative and intraoperative risk profiles and other characteristics were similar in both groups, with more than 60% of patients undergoing nonelective operation. Compared with the full anticoagulation protocol group, patients in the lower anticoagulation protocol group were less likely to require blood products (24.2% versus 35.8%, respectively; p = 0.047) and received substantially fewer homologous donor units (0.50 +/- 0.92 versus 1.08 +/- 2.10 U, respectively; p = 0.005). Clinical outcomes were uniformly outstanding (but similar) in both treatment groups, with a modest reduction in the length of the hospital stay in the lower anticoagulation protocol group (5.26 +/- 1.23 versus 5.63 +/- 1.73 days, respectively; p = 0.05). The use of HBCs with a lower anticoagulation protocol was not associated with any adverse clinical events. Thrombin generation increased during cardiopulmonary bypass in both treatment groups, but was unrelated to the anticoagulation protocol or the activated clotting time (r2 = 0.03). No differences between the full and lower anticoagulation protocol groups were noted in the number of microemboli detected by transcranial Doppler analyses during cardiopulmonary bypass (n = 40) or in the postoperative neurologic and neuropsychologic outcomes (n = 30). CONCLUSIONS This study definitively demonstrates that, when used appropriately, patients who are treated with HBCs and a lower anticoagulation protocol have a lower incidence and magnitude of homologous transfusion and are not at any added risk for clinical, hematologic (thrombin-antithrombin complex and fragment 1.2 measurements), or microscopic (transcranial Doppler analyses) thromboembolic complications or for neurologic or neuropsychologic deficits.

Reduction of Allogeneic Blood Transfusions After Open Heart Operations by Lowering Cardiopulmonary Bypass Prime Volume

BACKGROUND Despite recent advances in blood conservation techniques, up to 30% to 80% of patients undergoing open heart operations require allogeneic blood transfusions. A prospective, randomized study was performed to test the effect of lowering cardiopulmonary bypass prime volume (as an additional component of an integrated blood conservation strategy) on clinical outcome and allogeneic blood transfusion. METHODS One hundred fourteen patients undergoing open heart operations were randomized to either full prime (FP) volume (1,400 mL of Plasmalyte solution) or reduced prime (RP) volume (600 to 800 mL). The reduction of prime volume was achieved by slowly draining the cardiopulmonary bypass circuit into a cell-saving device before the initiation of bypass. Firm transfusion thresholds were observed. RESULTS There were no significant differences between the groups with respect to baseline characteristics, body surface area, type and urgency of the procedures, perfusion technique, and hematologic profile. Mortality (FP, 1.7%; RP, 0%; p approximately 1.0) and overall morbidity (FP, 28.1%; RP, 22.8%; p = 0.53) were similar. However, transfusion requirements were significantly lower in the RP group: total donor exposure, 3.8 +/- 10.1 versus 1.0 +/- 2.4 units (p = 0.044); percentage of patients transfused, 54% (n = 31) versus 35% (n = 20) (p = 0.036). Twenty-four-hour chest tube drainage was similar: 455 +/- 223 mL for FP versus 472 +/- 173 mL for RP (p = 0.66). The lowest hematocrit on bypass was significantly higher in the RP group: 29.3% +/- 4% versus 26.3% +/- 5.3% (p = 0.009). CONCLUSIONS Lowering cardiopulmonary bypass prime volume resulted in a significant decrease in allogeneic blood product use. Because postoperative 24-hour chest tube drainage was similar in both groups, and hematocrit during bypass was higher in the RP group, the reduction in allogeneic blood transfusions appears to be related to a decrease in prime-induced hemodilution. This technique is effective, simple, and safe. It therefore should be strongly considered for patients undergoing operations using normothermic or near-normothermic cardiopulmonary bypass who are at high risk for allogeneic blood transfusion.

p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor α-Dependent Pathway in Response to Black Tea Polyphenols

Black tea has been shown to improve endothelial function in patients with coronary artery disease and recent data indicate the polyphenol fraction of black tea enhances endothelial nitric oxide synthase (eNOS) activity through p38 MAP kinase (p38 MAPK) activation. Because the mechanisms for this phenomenon are not yet clear, we sought to elucidate the signaling events in response to black tea polyphenols. Bovine aortic endothelial cells (BAECs) exposed to black tea polyphenols demonstrated eNOS activation that was inhibited by the estrogen receptor (ER) antagonist ICI 182,780, and siRNA-mediated silencing of ER expression. Consistent with this observation, black tea polyphenols induced time-dependent phosphorylation of ERα on Ser-118 that was inhibited by ICI 182,780. Phosphorylation of ERα on Ser-118 was due to p38 MAP kinase (p38 MAPK) as, it was inhibited by SB203580 and overexpression of dominant-negative p38α MAPK. Conversely, constitutively active MKK6 induced p38 MAPK activation that recapitulated the effects of polyphenols by inducing ERα phosphorylation and downstream activation of Akt, and eNOS. The key role of ERα Ser-118 phosphorylation was confirmed in eNOS-transfected COS-7 cells, as polyphenol-induced eNOS activation required cotransfection with ERα subject to phosphorylation at Ser-118. This residue appeared critical for functional association of ERα with p38 MAPK as ERα with Ser-118 mutated to alanine could not form a complex with p38 MAPK. These findings suggest p38 MAP kinase-mediated eNOS activation requires ERα and these data uncover a new mechanism of ERα activation that has broad implications for NO bioactivity and endothelial cell phenotype.

Nitroglycerin is superior to diltiazem as a coronary bypass conduit vasodilator

BACKGROUND Recent reports of improved radial artery patency have been attributed, in part, to routine use of diltiazem to prevent vasospasm. However, diltiazem is costly, and its use may be associated with negative inotropic and chronotropic side effects. This study compares the vasodilatory properties of diltiazem to those of nitroglycerin. METHODS In vitro, with the use of organ chambers, the vasodilatory properties of diltiazem and nitroglycerin were compared in matched segments of radial artery, internal thoracic artery, and saphenous vein that were harvested from the same patients (n = 11). The vasodilatory response of the radial artery to intravenous diltiazem or nitroglycerin was compared in vivo (n = 10) with the use of ultrasonographic measurements of radial artery diameter. RESULTS The maximum relaxation of radial artery (100% +/- 4%), internal thoracic artery (96% +/- 4%), and saphenous vein (100% +/- 3%) to nitroglycerin were significantly greater than the response to diltiazem (33% +/- 6%, 22% +/- 7%, and 34% +/- 5%, respectively; P <.001). The thromboxane mimetic, U46619, induced radial artery spasm with a median effective concentration of 3.7 +/- 0.8 nmol/L. Physiologic concentrations of nitroglycerin (0.1+/- micromol/L) significantly inhibited the radial artery response to U46619 (median effective concentration, 6.2 +/- 1.1 nmol/L; P =.046), whereas diltiazem (1 micromol/L) did not (median effective concentration, 3.7 +/- 0.8 nmol/L; P =.64). In vivo, nitroglycerin increased radial artery diameter 22% +/- 3%, which was significantly greater than diltiazem (3% +/- 0.5%; P =.001). CONCLUSION Nitroglycerin is a superior conduit vasodilator and is more effective in preventing graft spasm than diltiazem. Nitroglycerin should be strongly considered as the drug of choice to prevent conduit spasm after coronary bypass grafting.

ECG changes and cardiac arrhythmias in chronic renal failure patients on hemodialysis

Serial 12-lead electrocardiogram (ECG) recordings and 24-hour Holter monitoring were carried out in 39 patients with chronic renal failure, starting just before a routine dialysis session. In an attempt to identify risk factors for cardiac arrhythmias, the results obtained from each patient were correlated with a variety of clinical, hematological, and biochemical data. All patients exhibited ECG changes, which were most pronounced during the first 2 hours of dialysis. The most frequent of these changes were a decrease in T wave amplitude and increase in Tmax time (all patients), an increase of QRS amplitude (61% of patients), shortened or prolonged QTc interval (61%) and ischemic-like ST-T changes (22% and 39%, respectively). Potentially clinically significant arrhythmias occurred in 12 patients (31%) of which 8 were supraventricular, 3 were combined ventricular and supraventricular, and 1 was pure ventricular. The only clinically identified risk factor for complex ventricular and supraventricular arrhythmia was advanced age. The arrhythmia and nonarrhythmia groups differed significantly in their predialysis hematocrit, O2 content, serum urea, and osmolarity, and in their postdialysis serum phosphorus and osmolarity. The results indicate that patients with chronic renal failure frequently exhibit ECG changes and a high incidence of ventricular and supraventricular arrhythmias, which may be prognostically significant, during and after hemodialysis.

Anterior ischemic optic neuropathy after open heart operations

BACKGROUND The overall incidence of anterior ischemic optic neuropathy after open heart operations at the Lahey Clinic is less than 0.5%. However, during the 2-year period, March 1, 1990, to March 1, 1992, an increased incidence (8 of 602 patients or 1.3%) of this complication was observed. METHODS A rigorous analysis was conducted of all 602 patients who underwent operation during this period. RESULTS No preoperative risk factors were identified. The development of anterior ischemic optic neuropathy was associated with prolonged cardiopulmonary bypass time, low hematocrit levels, excessive perioperative body weight gain, and the use of epinephrine and amrinone. Other hypothetical risk factors include systemic hypothermia, anemia, increased intraocular pressure, and microembolization. Treatment options include the use of corticosteroid medications, reduction of intraocular pressure, and optic nerve fenestration, although recent evidence and our experience indicate that the fenestration procedure is of no benefit. CONCLUSIONS Because all methods of treatment have had limited success, efforts to prevent this complication are of paramount importance.

CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential

Lung cancer is the second most common malignancy and the leading cause of cancer-related death in the western world. Moreover, despite advances in surgery, chemotherapy and radiotherapy, the death rate from lung cancer remains high and the reported overall five-year survival rate is only 15%. Thus, novel treatments for this devastating disease are urgently needed. Chemokines, a family of 48 chemotactic cytokines interacts with their 7 transmembrane G-protein-coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells, which express a relatively restricted repertoire of chemokine and chemokine receptors, utilize and manipulate the chemokine system in a manner that benefits both local tumor growth and distant dissemination. Among the 19 chemokine receptors, CXCR4 is the receptor most widely expressed by malignant tumors and whose role in tumor biology is most thoroughly studied. The chemokine CXCL12, which is the sole ligand of CXCR4, is highly expressed in primary lung cancer as well as in the bone marrow, liver, adrenal glands and brain, which are all sites for lung cancer metastasis. This review focuses on the pathologic role of the CXCR4/CXCL12 axis in NSCLC and on the potential therapeutic implication of targeting this axis for the treatment of NSCLC.