Young D. Kim

Current Status of the Maze Procedure for the Treatment of Atrial Fibrillation

Since the first patient underwent the Maze procedure on September 25, 1987, 346 patients have undergone this operation for the treatment of atrial fibrillation. The procedure was designed as an open-heart operation performed through a median sternotomy. It underwent 2 major modifications relatively early in the series, evolving into the so-called Maze-III procedure, which has been used exclusively since April 16, 1992. Since that time, the Maze-III procedure has been adapted to allow it to be done by minimally invasive techniques. In addition, we recently performed the entire procedure in 2 patients without the use of cardiopulmonary bypass. The operative mortality rate has remained at 2% to 3%. This includes patients undergoing concomitant high-risk cardiac surgical procedures and all re-do cases. The overall success rate in curing atrial fibrillation has been 99%. The procedure itself has been shown to cause no permanent damage to the sinus node. The left atrium has been documented to function long-term postoperatively in 93% of patients and the right atrium functions in 99% of patients. The Maze-III procedure remains the surgical procedure of choice for the treatment of medically refractory atrial fibrillation.

17β-Estradiol Prevents Dysfunction of Canine Coronary Endothelium and Myocardium and Reperfusion Arrhythmias After Brief Ischemia/Reperfusion

BACKGROUND Brief myocardial ischemia is associated with myocardial and coronary endothelial dysfunction caused by oxygen free radicals released during reperfusion. Estrogen, known to have antioxidant activity, may prevent these complications. METHODS AND RESULTS We assessed the effect of 2 weeks of treatment with 17 beta-estradiol (E, 100 micrograms.kg-1.d-1, n = 12) or placebo (P, n = 15) on myocardial and coronary endothelial function during the first 2 hours of reperfusion in dogs subjected to 15 minutes of ischemia induced by occlusion of the left anterior descending coronary artery (LAD). Our results show that the incidence of ventricular arrhythmias significantly decreased in E (3 of 12) compared with P (11 of 15). Systolic shortening, significantly depressed in P during early reperfusion, was maintained at preischemic levels in E. During reperfusion, the increase in LAD flow to acetylcholine, attenuated in P (60 +/- 6%), was preserved in E endothelium. (151 +/- 28%) and was associated with increased serum nitrite/nitrate concentration. n-Pentane in exhaled gas in vivo, an index of lipid peroxidation, increased significantly during early reperfusion in P (from 9.1 +/- 1.9 to 41.6 +/- 13.0 ppb, P < .05) but not in E (23.0 +/- 6.9 ppb). In vitro, arterial segments from E generated significantly less superoxide anion after hypoxia/reoxygenation than those from P. Ischemic/reperfused LAD segments from E also revealed a better preservation of endothelium-dependent relaxation in vitro (maximum relaxation, 42 +/- 4% versus 24 +/- 4% in P; P < .05). CONCLUSIONS Estrogen protects against endothelial and myocardial dysfunction resulting from brief ischemia/reperfusion. This protection may relate to an antioxidant effect of estrogen.

Estrogen and homocysteine

Cardiovascular diseases are the major causes of illness and death in women. Premenopausal women are relatively protected from coronary artery disease and atherosclerosis as compared to postmenopausal women, and this protection is attributed to the effects of the female sex hormone (estrogen). The vasculature, like the reproductive tissues, bone, liver, and brain, is now recognized as an important site of estrogens action. Although estrogens beneficial effects on the cardiovascular system are well described in many studies, the molecular basis of estrogen protective mechanisms are still quite vague. Both genomic mechanisms, mediated primarily through estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta), and non-genomic mechanisms, through nitric oxide (NO), of estrogen action are controversial and do not entirely explain the effects of estrogen on vascular preservation during conditions of oxidative stress. Until recently, the atheroprotective effects of estrogen were attributed principally to its effects on serum lipid concentrations and cholesterol levels. However, two recent reports that estrogen therapy has no effect on the progression of coronary atherosclerosis in women with established disease, despite the favorable changes in LDL and cholesterol levels, leads to questions about the lipid/cholesterol mechanism of estrogen-mediated effects on atherosclerosis. Alternatively, the high level of homocysteine, found to correlate with accelerated cardiovascular disease and identified as an independent risk factor for atherosclerosis, was recently described to be diminished by estrogen. Protection against disturbed sulfhydryl metabolism and higher homocysteine level could be the missing link in understanding how exactly estrogen affects vascular cells metabolism and responses to oxidative stress. This review focuses on estrogen/homocysteine interactions and their relevance to the cardiovascular system.

Brief ischemia-reperfusion induces stunning of endothelium in canine coronary artery.

Background Brief ischemic episodes that induce stunning of the myocardium may also induce stunning of the coronary endothelium. To test this hypothesis, we examined both in vivo and in vitro responses of canine coronary arteries exposed to brief ischemia. Methods and Results Functional recovery of the endothelium was examined in vivo during reperfusion after 15 minutes of ischemia. Vasodilatory responses to acetylcholine were severely impaired during the first hour of reperfusion but gradually improved over a 90-minute period after ischemia. The vasoconstrictive response to U46619 was enhanced for the first 30 minutes of reperfusion and returned to normal within 60 minutes. In vitro vasomotor responses to potassium chloride, acetylcholine, bradykinin, and sodium nitroprusside were examined in isolated segments of canine coronary arteries preexposed in vivo to brief ischemia (10–30 minutes) and 20 minutes of reperfusion. The results showed enhanced contractile responses and blunted endothelium-dependent but not endothelium-independent vasodilatory responses of arterial rings subjected to 10 minutes of ischemia. Twenty and 30 minutes of ischemia completely impaired endothelium-dependent vasodilation. When reperfusion was extended to 120 minutes after 15 minutes of ischemia, vasodilatory responses to acetylcholine had recovered by almost 90%. Examination of endothelial integrity by transmission electron microscopy after 10–15 minutes of ischemia revealed no evidence of structural damage. Twenty and 30 minutes of ischemia induced cytoplasmic vacuolation, partial detachment of endothelium, and swelling of cytoplasmic organelles. Conclusions These data support the hypothesis that brief ischemia-reperfusion induces stunning of endothelium in which endothelium-dependent vasodilatory function is impaired temporarily without morphological damage.

The Maze-III Procedure Combined With Valve Surgery

Previous studies have suggested that the Maze procedure is not as effective in controlling atrial fibrillation when the arrhythmia is associated with significant valvular heart disease. In this study, we evaluate our own results in 83 patients who underwent 96 valve procedures in combination with the Maze-III procedure. Our results indicate that the Maze-III procedure is just as safe and effective in controlling atrial fibrillation associated with valvular heart disease as it is in controlling atrial fibrillation not associated with valvular heart disease.

Estradiol prevents homocysteine-induced endothelial injury in male rats

OBJECTIVE We investigated whether estradiol may prevent accelerated atherosclerosis due to hyperhomocysteinemia by enhancing the antioxidant system. METHODS Male Wistar rats were treated with placebo (P) or 1 mg (1E2) and 2 mg (2E2) 17 beta estradiol. Half of the animals (n=6) from each group received homocysteine (Hcy, 100 mg/kg/day) administered in the drinking water for 60 days (P/Hcy, 1E2/Hcy and 2E2/Hcy). Glutathione (GSH) content and glucose-6-phosphate dehydrogenase (G6PDH) activity were determined in myocardial tissues, as well as the serum Hcy concentrations and blood levels of hydrogen peroxide (H(2)O(2)). The relaxation response of aortic ring segments to acetylcholine (ACh) was used for the assessment of endothelial function, and hematoxylin-eosin stained thin sections of rat aorta were used for detection of the histological changes (namely endothelial damage and wall thickening). RESULTS Depression of relaxation to ACh occurred in P/Hcy compared to P (15.7 +/- 4% vs. 96.3 +/- 7%, P<0.0001), but estrogen significantly restored endothelium dependent relaxation in hyperhomocysteinemic rats (86.8 +/- 9.3%, P<0.001). Histological examination revealed aortic endothelial denudation in P/Hcy while the endothelial structures of the aorta from the 1E2/Hcy and 2E2/Hcy appeared normal. Significant reductions in GSH and G6PDH levels were detected in P/Hcy (1.5 +/- 0.01 micromol/g and 3.21 +/- 1.2 U/mg, respectively) compared to 1E2/Hcy (2.5 +/- 0.3 micromol/g and 12.81 +/- 1.5 U/mg, P<0.001) and 2E2/Hcy (3.11 +/- 1.1 micromol/g and 15.66 +/- 4 U/mg, P<0.001). In addition, blood H(2)O(2) level in 1E2/Hcy and 2E2/Hcy remained low while it was raised significantly in P/Hcy compared to P (P<0.001). CONCLUSIONS These data suggest that the observed reduction of GSH levels and suppression of G6PDH activity induced by Hcy coupled, with endothelial ultrastructural changes and impaired function, all reversed by estradiol, may have relevance to the mechanisms of atherogenesis and the beneficial effects of estrogen replacement therapy.

Nonanticoagulant Heparin Prevents Coronary Endothelial Dysfunction After Brief Ischemia-Reperfusion Injury in the Dog

BACKGROUND Coronary endothelial dysfunction after brief ischemia-reperfusion (IR) remains a clinical problem. We investigated the role of heparin and N-acetylheparin, a nonanticoagulant heparin derivative, in modulating coronary endothelial function after IR injury, with an emphasis on defining the role of the nitric oxide (NO)-cGMP pathway in the heparin-mediated effect. METHODS AND RESULTS Male mongrel dogs were surgically instrumented, and the effects of both bovine heparin and N-acetylheparin on coronary endothelial vasomotor function, expressed as percent change from baseline flow after acetylcholine challenge, were studied after 15 minutes of regional ischemia of the left anterior descending artery (LAD) followed by 120 minutes of reperfusion. In dogs treated with placebo (saline), coronary vasomotor function was significantly (P</=0.03) decreased after 15 and 30 minutes of reperfusion (65+/-12% and 73+/-12%) compared with preischemia (103+/-6%). In contrast, the vasodilatory response to the endothelium-independent vasodilator sodium nitroprusside was maintained during reperfusion. Preischemic administration of both bovine heparin and N-acetylheparin (6.0 mg/kg IV) preserved coronary endothelial function throughout reperfusion. In a parallel group of dogs, nitrate/nitrite (NOx) and cGMP levels in the LAD were measured after treatment and during 15-minute reperfusion. Preischemic administration of N-acetylheparin caused a significant increase in basal NOx and cGMP levels compared with saline controls. Pretreatment with N-acetylheparin also caused a significant increase in NOx and cGMP levels in the LAD after 15 minutes of reperfusion compared with IR alone. CONCLUSIONS These results suggest that heparin preserves coronary endothelial function after brief IR injury by a mechanism independent of its anticoagulant activity and that the effect of heparin may be mediated in part by activation of the NO-cGMP pathway.

17-β estradiol regulation of myocardial glutathione and its role in protection against myocardial stunning in dogs

We studied the effect of 2-week treatment with estradiol 17beta on myocardial glutathione concentration in dogs and isolated perfused rat heart subjected to brief coronary ischemia and reperfusion. Estradiol protected against ischemia/reperfusion-induced myocardial systolic shortening and malonylaldehyde production and increased myocardial glutathione concentration and glucose-6-phosphate dehydrogenase enzyme activity. Reduction of myocardial glutathione with buthionine sulfoximine to levels seen in the absence of estrogen reversed the protective effect of estradiol against myocardial dysfunction and lipid peroxidation associated with ischemia/reperfusion. These results suggest that the antioxidant effect of estradiol in ischemia/reperfusion may be mediated by regulation of myocardial glutathione metabolism.

Heparin And Nonanticoagulant Heparin Preserve Regional Myocardial Contractility After Ischemia-Reperfusion Injury: Role Of Nitric Oxide

OBJECTIVES These studies were performed to determine the effect of heparin and nonanticoagulant heparin on myocardial function after ischemia-reperfusion and to further evaluate the role that the nitric oxide-cyclic guanosine monophosphate pathway plays in mediating the effect of heparin. METHODS Fifteen dogs were subjected to 15 minutes ischemia followed by 120 minutes reperfusion and pretreated with either saline solution, bovine heparin (6.0 mg/kg intravenously), or N-acetyl heparin (6.0 mg/kg intravenously), a heparin derivative without anticoagulant properties. The left anterior descending artery was occluded for 15 minutes and regional systolic shortening, a unitless measure of myocardial contractility, assessed during reperfusion. To evaluate the role of nitric oxide, the inhibitor N(omega)-nitro-L-arginine, 1.5 mg/kg intracoronary, was given before heparin administration. Myocardial levels of cyclic guanosine monophosphate, the second messenger of nitric oxide, were also measured in the N-acetyl heparin group using radioimmunoassay. RESULTS Regional systolic shortening was significantly decreased in the saline group during 60 and 120 minutes compared with before ischemia (9.2 +/- 1.0 and 9.0 +/- 0.9 vs 12.2 +/- 1.2, p < or = 0.0003). Heparin and N-acetyl heparin-treated dogs, however, showed preservation of systolic shortening throughout reperfusion. Administration of nitro-L-arginine significantly attenuated the protective effect of heparin (9.2 +/- 1.2 vs 12.7 +/- 1.1, p < or = 0.0001) and N-acetyl heparin (9.3 +/- 0.3 vs 12.8 +/- 0.4, p < or = 0.0001) during 120 minutes reperfusion. Myocardial levels of cyclic guanosine monophosphate were also significantly increased in the N-acetyl heparin group compared with saline (199.1 +/- 7.1 vs 103.5 +/- 4.5 pmol/mg, p < or = 0.0001). CONCLUSIONS Heparin preserves myocardial contractility after ischemia-reperfusion independent of its anticoagulant properties. Furthermore, the protective effects of heparin during ischemia-reperfusion are mediated, at least in part, through a nitric oxide-cyclic guanosine monophosphate pathway.

17-β Estradiol Preserves Endothelial Cell Viability in an In Vitro Model of Homocysteine-Induced Oxidative Stress

High levels of homocysteine (Hcy) accelerate endothelial cell damage by producing hydrogen peroxide (H(2)O(2)). We investigated whether 17-beta estradiol may prevent the accelerated rate of endothelial cell detachment and reduced cell viability in cultured endothelial cells challenged with Hcy. Cultured bovine aortic endothelial cells (BAEC) were incubated for 72-h with either vehicle (alcohol) or different concentrations of 17-beta estradiol (1 nM [1E2] and 10 nM [10E2]) before being challenged with 0.5 mM of Hcy. Cell viability and H(2)O(2) levels were evaluated at 30 min, 1-, 2-, 4-, 8-, and 24-h after adding Hcy. Cell suspensions were frozen in liquid nitrogen and used later for spectrophotometric measurement of intracellular glutathione (GSH) levels. Cell viability 24 h after Hcy administration was significantly lower in vehicle versus 1 nM and 10 nM 17-beta estradiol (44 +/- 5% vs. 70.66 +/- 4%, [p < 0.001] and 79 +/- 5% respectively, [p < 0.001]). H(2)O(2) levels were higher in vehicle (1 +/- 0.05 microM) compared with 1E2 and 10E2 (0.8 +/- 0.1 microM, p = 0.02 and 0.1 +/- 0.05 microM, respectively, p < 0.001), whereas GSH content was increased in 1E1 and 10E2 versus control (27.69 +/- 4.6 nM/10(6) cells and 43.49 +/- 5.5 nM/10(6) cells vs. 13.33 +/- 1.5 nM/10(6) cells, p < 0.001). Bovine aortic endothelial cells treatment with 17-beta estradiol (0, 1, and 10 nM) and 0.1 mmol buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthase, abolished the beneficial effects of estradiol alone on cell viability, GSH content, and H2O2 generation. Estradiol prevents Hcy-induced endothelial cell injury by increasing the intracellular content of GSH.