Effects of in vivo cyclosporine administration on endothelium-dependent responses in isolated vascular rings. Although in vitro studies suggest that cyclosporine (CSA) reduces endothelium-dependent relaxation (EDR), controversy still remains regarding the effects of in vivo CSA treatment. The lack of correlation between CSA dosages and therapeutic efficacy has led to an increased emphasis on the monitoring of CSA blood levels in clinical immunosuppression. We therefore studied the effects of in vivo administration to rats of a therapeutic level of CSA on endothelium-dependent vascular reactivity using isolated vascular rings obtained from these animals. Thoracic aorta vascular rings from adult Sprague-Dawley rats treated with subcutaneous injections of CSA (5 mg/kg/day) for 7 and 21 days were suspended in Krebs buffer containing indomethacin and tested for EDR to methacholine (1 x 10(-7) to 5 x 10(-5) M) and for endothelium-independent relaxation (EIR) to nitroprusside (5 x 10(-6) M). Mean whole blood CSA trough levels were 978 +/- 287 and 2,865 +/- 379 ng/ml for the 7- and 21-day groups, respectively. No differences were noted in both EDR and EIR between untreated control rats and the treated groups. Maximal EDR (mean +/- SEM) was 83 +/- 3%, 79 +/- 2%, and 81 +/- 3% for control rats and 7- and 21-day treatment groups, respectively. Relative developed tension (grams) to 5 x 10(-6) M phenylephrine was significantly (p < 0.05) increased in the CSA-treated groups (1.03 +/- 0.01 and 1.08 +/- 0.01 g at 7 and 21 days, respectively, versus 0.73 +/- 0.01 g (p = NS) for untreated controls). Minimal endothelial disruption was evident on scanning electron microscopy in the CSA-treated animals. We conclude that CSA-induced vascular dysfunction may be in part a result of an increased sensitivity to direct vasoconstriction rather than of an attenuation of endothelium-dependent relaxation.


Extracorporeal membrane oxygenator rescue in children during cardiac arrest after cardiac surgery. Conventional cardiopulmonary resuscitation (CPR) for cardiac arrest after open-heart surgery in children is often unsuccessful despite the ability to perform open-chest massage. The purpose of this study was to review our results with mechanical support as rescue therapy in children with sudden circulatory arrest after cardiac surgery. From 1981 through 1991, we have used mechanical support with an extracorporeal membrane oxygenator (ECMO) circuit for cardiac support in 33 children. Eleven of the 33 patients (age, 15 +/- 7 months) suffered cardiac arrest intractable to conventional open-chest massage 39 +/- 15 hours after an open-heart procedure. The mean duration of CPR was 65 +/- 9 minutes until ECMO flow was started. ECMO support was continued for 112 +/- 8 hours. One patient had ECMO discontinued due to bleeding (survived); three were discontinued from ECMO and died from neurological complications; and one died of cardiac dysfunction. Sepsis on ECMO was seen in one patient (survived). Overall early survival was seven of 11 (64%) with one patient requiring heart transplantation due to irreversible cardiac dysfunction. One child died late (1 month) after ECMO support. There were no long-term sequelae in the survivors. We conclude that ECMO rescue in children with postcardiotomy cardiac arrest is a feasible option in selected patients even after prolonged CPR (as long as 60 minutes).


Extracorporeal membrane oxygenation in children after cardiac surgery. From August 1982 to May 1991, 65 children (32 boys), 1 day to 14 years old, received extracorporeal membrane oxygenation (ECMO) 0-50 hours after cardiac surgery. Forty-four (67.7%) were weaned, with 23 (35.4%) survivors. Analysis of 29 pre-ECMO factors including diagnosis, age, sex, blood gas data, systemic pressures, atrial pressures, ventricular function, and renal function was performed. Preoperative systemic ventricular shortening fraction was statistically less in survivors. The need for dialysis and length of support were predictors of survival once ECMO was initiated. There were five late deaths 6 days to 5 years after discharge; none were related to ECMO. The remaining 18 patients have been followed for a mean of 37.5 months (range, 1-85 months). Seventeen are New York Heart Association functional class I, with one patient still hospitalized. ECMO allows for myocardial recovery in the majority of patients with refractory postcardiotomy failure and permits some patients to survive who would not have otherwise.


Survival prediction in staged heart transplantation using Jarvik-7 artificial heart. Because mechanical circulatory assist as a bridge to heart transplantation places a further strain on current donor shortage as well as on medical cost containment, safe and effective use of the device is essential. To predict survival before undertaking staged heart transplantation with the Jarvik-7 artificial heart, our 58 attempts were reviewed retrospectively. Scores of 1-4 were given for six preoperative factors based on results obtained by univariate and multivariate analyses between survivors and nonsurvivors of staged heart transplantation: transplant rejection (scored 4: S4) or postoperative heart failure (S3) as the indication, recipient height < 175 cm (S3), body surface area < 1.8 m2 (S3), hyperbilirubinemia > 24 microM/l (S2), weight < 60 kg (S2), and age > 40 years (S1). Of 14 survivors, 13 had a total score < 4 (sensitivity, 93%), with an average score of 1.6 in contrast to 5.5 for 44 nonsurvivors (p < 0.001). Among 26 patients scored < 4, 21 had heart transplantation, of whom 13 left the hospital. Of 32 patients scored > or = 4, only four could be discharged after transplantation (specificity, 70%). Multiple preoperative factors successfully predicted transplantability and survival in staged heart transplantation. The results underscore the importance of preoperative condition and patient selection to achieve successful and effective use of Jarvik-7 as a bridge to heart transplantation.


Right ventricular/arterial coupling in the patient with left ventricular assistance. Improvements are known to occur in right ventricular (RV) ejection fraction after the use of a left ventricular assist device (LVAD); less is known, however, about the mechanism of this improvement. The concept of ventricular/arterial coupling was applied to investigate whether systolic pump function or afterload reduction was the major contributing factor leading to the improvement in RV ejection fraction. Eight consecutive patients who underwent Novacor LVAD implantation as a bridge to transplantation were studied intraoperatively with transesophageal echocardiogram and a catheter-tip manometer to examine the RV end-systolic pressure-area relation (ESPAR) before and after LVAD implantation. Fractional area change (FAC) obtained by echocardiogram was used as an approximation of ejection fraction. End-systolic elastance (Ees), area axis intercept of ESPAR (A0), maximal area (Amax), and pulmonary effective arterial elastance (Ea) were obtained. RV FAC improved from 0.20 +/- 0.09 to 0.29 +/- 0.13 (p < 0.05). There was a decrease in Ea from 12.06 +/- 5.79 to 4.92 +/- 2.51 mm Hg/cm2 (p < 0.01), which indicated a reduction in RV afterload. A0 increased from -0.14 +/- 7.81 to 6.83 +/- 9.42 cm2 (p < 0.05), which implied impaired systolic pump function. There was no difference in Ees and Amax. The concept of ventricular/arterial coupling predicts that an increase of A0 (reduced RV systolic mechanics) decreases FAC, whereas a reduction in Ea improves FAC. The improvement in RV FAC (improved RV pump performance) may result from the effect of reduced Ea (afterload reduction) overwhelming the effect of increased A0. Afterload reduction is the most likely mechanism by which RV ejection fraction improves after LVAD implantation.


Compositional analysis of a modified University of Wisconsin solution for extended myocardial preservation. A study of the left ventricular pressure-volume relation. The University of Wisconsin solution (UW) has been shown to be superior to the use of traditional types of simple crystalloids in extended heart preservation. This study was designed to determine the necessity of four potentially redundant components in UW. Forty canine hearts (n = 8 in each group) were preserved for 6 hours under hypothermic (1-2 degrees C), nonperfused conditions in unmodified UW, UW with an extracellular or reversed composition of sodium and potassium (UW-E), UW with chloride instead of lactobionate (UW-L), UW without raffinose (UW-R), and UW without hydroxyethyl starch (UW-HS). The left ventricular functions were assessed in an isolated heart preparation equipped with a computerized servo-volume pump to measure the pressure-volume relation. The systolic function was expressed in elastance derived from the end-systolic pressure-volume relation, and total ventricular performance was expressed in preload recruitable stroke work area derived from the stroke work-end-diastolic volume relation. Diastolic compliance was derived from the end-diastolic pressure-volume pressure relation. The results were compared with a control group with no ischemia. There was no significant deterioration in left ventricular systolic contractile functions as demonstrated by the analysis of elastance and the preload recruitable stroke work area in any of the modifications of UW. However, significant deterioration in the diastolic compliance occurred in the UW-E and UW-HS groups. A similar trend was found in the UW-L group, although it was not statistically significant, whereas the diastolic compliance was preserved in the UW-R group. The intracellular electrolyte composition and the hydroxyethyl starch are important in the preservation of left ventricular diastolic function, whereas the omission of raffinose was inconsequential. The replacement of lactobionate by chloride had less untoward functional effects compared with studies of other solid organ preservation.


Assessment of function, perfusion, metabolism, and histology in hearts preserved with University of Wisconsin solution. University of Wisconsin solution has shown promise for prolonged cardiac preservation. This study compared the effects of 24-hour cold storage and perfusion preservation techniques by assessment of function, perfusion, metabolism, and histological changes. Three groups of rabbit hearts (n = 6 each) were evaluated: 1) control with immediate reperfusion, 2) continuous perfusion preservation, and 3) cold storage. Hearts were reperfused for 30 minutes, and left ventricular systolic pressure (LVSP) was measured by isovolumetric balloon (LVEDP, 20 mm Hg). We used 201Tl to assess perfusion and 14C-acetate to assess metabolism by macroautoradiography. LVSP was similar for controls and hearts preserved with continuous perfusion (134.8 +/- 2.1 versus 112.2 +/- 6.0 mm Hg, respectively). Hearts preserved with cold storage techniques were significantly worse (36.7 +/- 6.0 versus 134.4 +/- 8.2 mm Hg, p < 0.001). Controls showed homogeneous perfusion and metabolism, whereas hearts in the continuous perfusion group showed mild hypoperfusion and histological damage (26.4 +/- 2.7% of left ventricular cross section). Hearts in the cold storage group had 51.7 +/- 1.2% of the left ventricle hypoperfused and damaged. Histology in the control group was normal; in the perfused group, there were only mild changes; and in the cold storage group, there were extensive derangements of cellular architecture. Continuous perfusion of the heart with 4 degrees C modified University of Wisconsin solution provided function comparable to that of control. Conversely, cold storage showed extremely poor return of function. Autoradiography confirmed mild perfusion and metabolism abnormalities in control and continuous perfusion hearts, whereas there was marked derangement of cellular architecture, perfusion, and metabolism in the cold storage hearts.


Oxyhemoglobin dissociation during hypothermic blood cardioplegia arrest. Coronary sinus effluent contains desaturated blood during the first few seconds of hypothermic cardioplegia infusion in humans. This occurs despite the high affinity of hemoglobin for oxygen at a low temperature and alkaline pH. The present study quantitates oxyhemoglobin dissociation during hypothermic cardioplegic arrest. Three infusions of a 4 degrees C alkalotic blood cardioplegia solution were given into the cross-clamped aortic root during 1 hour of cardioplegic arrest. Paired aortic root and coronary sinus blood samples were obtained before and shortly after initiating cardiopulmonary bypass and at t = 5 seconds and 30 seconds during each cardioplegia infusion. Throughout the study, the hemoglobin saturation in the aortic root samples was 100%. The mean coronary sinus hemoglobin saturation at t = 5 seconds during hypothermic cardioplegia infusion ranged from 63.0% to 66.5% (p < 0.05 coronary sinus compared with aortic root samples). The coronary sinus hemoglobin saturation approximated the aortic root hemoglobin saturation at t = 30 seconds during hypothermic cardioplegia infusion. The mean PO2 of the aortic root samples ranged from 214 to 307 mm Hg during hypothermic cardioplegia infusion. The mean PO2 of the t = 5 seconds coronary sinus samples ranged from 31 to 39 mm Hg, whereas the mean PO2 of the t = 30 seconds coronary sinus samples ranged from 85 to 119 mm Hg during cardioplegia infusion (p < 0.05 coronary sinus compared with aortic root samples). Oxygen dissociates from hemoglobin contained in a hypothermic, alkalotic blood cardioplegia solution during the nonperfused phase of cardioplegic arrest. However, the only oxygen delivered to the myocardium during the infusion of a hypothermic alkalotic blood cardioplegia solution is oxygen physically dissolved in the solution.


Coronary endothelial injury by cold crystalloid cardioplegic solution in neonatal lambs. Hypothermic cardioplegia generally improves the recovery of the mechanical function of the heart after ischemia, but some components of cold cardioplegia may produce endothelial injury that can offset the protective effects of cardioplegia. This study was undertaken to evaluate the effect of extremely hypothermic cardioplegia on the recovery of coronary endothelial and cardiac mechanical function after ischemia in the immature heart. Three groups of eight isolated, blood-perfused, neonatal lamb hearts each had myocardial temperature maintained at 10 degrees C during 2 hours of global ischemia but received hourly doses of crystalloid cardioplegic solution at temperatures of 10 degrees C (group A), 4 degrees C (group B), and 2 degrees C (group C). The percent recovery of isovolumic left ventricular maximum developed pressure in groups A (86.6 +/- 7.7) and B (90.5 +/- 7.5) was higher than in group C (78.6 +/- 6.3), and maximum dP/dt in groups A (89.6 +/- 8.6) and B (89.5 +/- 5.7) was higher than in group C (79.4 +/- 9.0) at 30 minutes of reperfusion (p < 0.05). Groups A (136.8 +/- 20.9) and B (142.8 +/- 27.7) achieved higher recovery of coronary blood flow (as percentage of baseline) at 15-minute reperfusion than group C (108.5 +/- 26.2), and myocardial oxygen consumption was higher in groups A (68.3 +/- 14.6, 92.1 +/- 21.1) and B (68.8 +/- 19.9, 85.3 +/- 25.5) than in group C (46.3 +/- 14.7, 57.2 +/- 14.2) at 15 and 30 minutes of reperfusion, respectively (p < 0.05). Percent recovery of the coronary vascular resistance responses to 10(-7) M concentration of an endothelium-dependent vasodilator (acetylcholine) in groups A (71.9 +/- 9.0) and B (66.2 +/- 23.1) was higher than in group C (24.2 +/- 14.3) (p < 0.05), whereas responses to 3 x 10(-5) M concentration of endothelium-independent vasodilator (nitroglycerin) were the same. Excessively cold cardioplegic solution may cause endothelial dysfunction (reduced acetylcholine response) and reduced recovery of mechanical function in the neonatal heart.


Heat shock. A new approach for myocardial preservation in cardiac surgery. Recent studies have indicated that heat shock (HS) induces protective genes and HS protein (HSP) expression, which enhances cellular tolerance to ischemic injury. The present study sought to determine if 42 degrees C blood cardioplegia could be used to induce HSP expression and improved myocardial salvage after 2 hours of cardioplegic arrest. To study this, pig hearts (n = 6) on cardiopulmonary bypass were subjected to HS by continuous infusion to the globally arrested heart of warm blood cardioplegia (K+ = 30 meq/l) at 42 degrees C for 15 minutes followed by 2 hours of intermittent hypothermic (4-6 degrees C) hyperkalemic (30 meq/l) crystalloid cardioplegic arrest and 1 hour of reperfusion (heat shock group). The control group (n = 6) was subjected to only 2 hours of hypothermic crystalloid cardioplegic arrest followed by 1 hour of reperfusion without HS. Left ventricular performance, coronary blood flow, and creatine kinase release were determined before arrest and during reperfusion. Prearrest control biopsies were taken in a separate group of pigs (n = 6) for both HSP and superoxide dismutase activity. Additional biopsies were taken for the same measurements in both control and HS groups at the completion of reperfusion. In a single additional pig in both the control and HS groups, biopsies were taken during the study to estimate changes in HSP expression. The cytosolic protein of ventricular tissue was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the HSP70 family protein was examined by Western blot analysis using monoclonal antibodies. HSP was found to be increasingly expressed from control levels after 15 minutes of HS pretreatment, increasing progressively to a level significantly above the non-HS group. Associated with this increased expression of HSP was a significant increase in superoxide dismutase activity in the HS animals and significant improvement in both global and regional functions and reduced creatine kinase release. The results show that preconditioning the heart with HS improves postischemic ventricular performance and attenuates cellular injury. HS induces a change in cellular metabolism, prompting the expression of HSP and improving antioxidant activity, leading to improved function and reduced tissue injury during ischemia and reperfusion.


Effect of aging on intracellular Ca2+, pHi, and contractility during ischemia and reperfusion. To investigate the effect of aging on myocardial ischemic and reperfusion injury, cytosolic calcium (Ca2+), intracellular pH (pHi), and mechanical performance were measured in isolated perfused rabbit hearts. Hearts of mature (4-5-month-old) and aged (28-38-month-old) rabbits were loaded with 10 microM of fura-2 or 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and subjected to 30 minutes of normothermic ischemia and reperfusion. Cytosolic Ca2+ levels ([Ca2+]) during the nonbeating ischemic period and end-diastolic Ca2+ levels ([EDCa2+]) during reperfusion were determined from the fura-2 fluorescence ratio of emission at 510 nm during excitation at 340 and 380 nm. pHi was obtained from the ratio of emission at 530 nm during excitation at 450 and 490 nm. [Ca2+] of the mature group (n = 8) increased from 188 +/- 19 nM (mean +/- SEM) to 373 +/- 32 nM during ischemia, and that of the aged group (n = 7) increased from 242 +/- 17 to 465 +/- 20 nM. The rise of [Ca2+] of the aged group was significantly greater (p < 0.05) than that of the mature group. Immediately after reperfusion, [EDCa2+] in both groups returned to the preischemic level. pHi decreased to the same extent (from 7.2 to 6.7) during ischemia and returned to preischemic values during reperfusion. The mature group recovered 84 +/- 3% of left ventricular peak pressure after ischemia, whereas the aged group recovered only 55 +/- 3% (p < 0.005). Functional recovery was inversely correlated to the increase of [Ca2+] during ischemia (r = 0.66). Aged hearts exhibit greater accumulation of [Ca2+] during ischemia and less functional recovery after ischemia than mature hearts. The greater rise of [Ca2+] in aged hearts is not a result of the difference of buffering capacity for ischemia-induced acidosis.


Alternative techniques of cardioplegia.

Alternative techniques of cardioplegia. Although normothermic cardioplegia has been used with acceptable clinical results, no studies have previously been performed to determine the metabolic consequences of these various techniques of myocardial protection. Therefore, we have performed a randomized clinical trial to assess the effects of three cardioplegic techniques on myocardial metabolic recovery. Seventy-four patients undergoing coronary artery bypass graft surgery were randomized to receive normothermic antegrade blood cardioplegia (n = 25), normothermic retrograde blood cardioplegia (n = 23), or intermittent cold antegrade blood cardioplegia (n = 26). Myocardial oxygen consumption and lactate production, adenine nucleotides, and adenine nucleotide degradation products were measured during the operation, and cardiac creatine kinase isoenzyme (CK-MB) release was assessed after surgery. Warm antegrade cardioplegia maximized myocardial oxygen consumption during cardioplegic delivery. Postoperative CK-MB release was less after warm antegrade cardioplegia, but the difference was not statistically significant. Warm retrograde cardioplegia resulted in the greatest degree of anaerobic lactate production but did not increase morbidity and mortality. Perioperative myocardial infarctions and postoperative low-output syndrome were most common after cold cardioplegia, but this trend was not statistically significant. During warm antegrade cardioplegia, adenosine triphosphate (ATP) was metabolized to diffusible precursors, which were washed out during cardioplegic infusion. Warm retrograde cardioplegia produced a breakdown of ATP to inosine and hypoxanthine, small molecules that accumulated during the cross-clamp period and were not washed out, perhaps because of inadequate perfusion with retrograde delivery. During cold cardioplegia, ATP was dephosphorylated, and adenosine diphosphate, adenosine monophosphate, and adenosine accumulated. These compounds were not regenerated to ATP but were not washed out of myocytes because they are large anionic molecules. Intermittent cold cardioplegia inhibited mitochondrial function but prevented the degradation of adenine nucleotides. Warm antegrade cardioplegia had the greatest myocardial oxygen consumption, and warm retrograde cardioplegia had the greatest anaerobic lactate production. There were no differences in clinical outcomes between cardioplegic groups.


Effect of normothermic blood cardioplegia on postoperative conduction abnormalities and supraventricular arrhythmias. Conduction defects and supraventricular tachycardia (SVT) are common after myocardial revascularization using current methods of cold hyperkalemic blood or crystalloid cardioplegia. The current retrospective study was undertaken to assess the influence of normothermic blood cardioplegia on conduction defects and SVT. The initial 92 patients underwent cardiopulmonary bypass (CPB) at 28 degrees C and blood cardioplegia at 6-8 degrees C. The subsequent 120 patients underwent CPB and blood cardioplegia at 37 degrees C. In all patients, cardioplegia was initially given by a combined antegrade/retrograde technique. The incidence of new postoperative conduction disturbances was significantly less in the normothermic group (p < 0.001): 27.5% versus 57.6% immediately after surgery; 9.2% versus 41.3% 1 day after surgery; 4.2% versus 32.6% 2 days after surgery; 1.7% versus 19.6% on hospital discharge; and 1.7% versus 17.4% on late follow-up. The incidence of supraventricular arrhythmias was not statistically different: 40.0% warm versus 42.4% cold. The groups were identical except that mean cross-clamp times were significantly longer (73.8 versus 60.1 minutes), mean number of grafts were significantly higher (3.7 versus 3.4), and mean cardioplegia volume was significantly greater (5,627 versus 3,710 ml) in the warm group (p < 0.05). In addition, the warm group had a higher incidence of prior transmural anterior myocardial infarctions (35% versus 9.8%, p < 0.001) and emergency operation (16.7% versus 6.5%, p < 0.05). Creatine kinase (CK) MB release was significantly less in the warm group immediately after operation (24.9 versus 60.9 units/l) and on POD1 (19.2 versus 46.5 units/l) (p < 0.001). Normothermic cardioplegia is associated with a marked decrease in new and permanent conduction disturbances and postoperative CK-MB release. This suggests that a significant factor in the pathogenesis of conduction blocks is cold-related injury. Supraventricular arrhythmias were not affected by the type of cardioplegia given.


Global left ventricular performance and regional systolic function after suture annuloplasty for chronic mitral regurgitation. In surgery for chronic mitral regurgitation, the mitral subvalvular apparatus, including annulus, may play an important role in preserving left ventricular (LV) performance. The suture annuloplasty for mitral regurgitation allows annular contraction of the mitral valve. The potential effects of suture annuloplasty on the postoperative LV performance have not been fully defined. Global and regional LV function in 12 patients with suture annuloplasty were compared with 12 patients with conventional mitral valve replacement (MVR). Cineangiography and echocardiography were obtained before and 10.8 months after surgery. End-diastolic volume index and end-systolic volume index decreased significantly in both groups after surgery (p < 0.01). Ejection fraction remained unchanged in the suture annuloplasty group, whereas it decreased significantly in the MVR group after surgery (p < 0.01). There was a significant inverse relation between ejection fraction and end-systolic wall stress in the two groups after surgery (suture annuloplasty group, r = -0.69, p = 0.01; MVR group, r = -0.60, p = 0.04). The intercept on the y axis was significantly (p < 0.005) higher in the suture annuloplasty group than in the MVR group. In the suture annuloplasty group, cross-sectional area ejection fraction at the mitral valve level and at the papillary muscle level by LV two-dimensional echocardiography remained unchanged after surgery. In the MVR group, they decreased significantly after surgery (p < 0.01). There was a significant correlation between the cross-sectional area ejection fraction and the global ejection fraction at both levels after surgery. Therefore, the improvement of the regional wall motion can be attributed to the improvement of the global LV performance after suture annuloplasty. These data suggest that suture annuloplasty can provide more desirable postoperative LV systolic performance than conventional MVR by preserving both the contraction of the mitral annulus and the mitral valvular-ventricular interaction.


Retrograde is superior to antegrade continuous warm blood cardioplegia for acute cardiac ischemia. Theoretically, the efficacy of continuous warm blood cardioplegia may be improved when administered retrogradely (RCWBC) rather than antegradely (ACWBC) in the setting of acute regional ischemia because of enhanced oxygen and substrate delivery to myocardial tissue distal to an acute coronary artery occlusion. Eighteen Yorkshire swine were instrumented for quantification of global left ventricular systolic, diastolic, and regional left anterior descending coronary artery (LAD) zone mechanics before and after 10 minutes of mid-LAD occlusion, followed by 60 minutes of cardiac arrest using continuous warm blood cardioplegia. Initially, 20 ml/kg of 37 degrees C oxygenated blood cardioplegia (hematocrit, 22 +/- 0.6%) was infused antegradely, followed by maintenance of 75 ml/min ACWBC (n = 9) or 60-100 ml/min of RCWBC (n = 9). LAD occlusion was released 20 minutes after cardiac arrest (30 minutes total LAD ischemia), simulating surgical revascularization. Postischemic recovery of global preload recruitable stroke work was nearly complete with RCWBC but significantly depressed with ACWBC (84.9 +/- 9.5% versus 52.4 +/- 5.1%, respectively; p < 0.01). LAD regional stroke work was also well preserved postischemically with RCWBC but showed no functional recovery and systolic bulging after ACWBC (87.4 +/- 13.7% versus -11.36 +/- 7.46% of control values; p < 0.01). Global diastolic stiffness calculated using the beta-coefficient of an exponential end-diastolic pressure-versus-volume relation was unchanged with ACWBC but increased significantly after RCWBC (from 0.027 +/- 0.002 to 0.028 +/- 0.003 mm Hg/ml and from 0.028 +/- 0.003 to 0.036 +/- 0.004 mm Hg/ml, respectively). These data suggest that with acute regional ischemia, both global and ischemic zone regional systolic function are depressed by ACWBC, whereas RCWBC affords adequate protection of contractile performance. However, a loss of diastolic compliance may result as a consequence of warm retrograde delivery.


Protection of platelets during long-term extracorporeal membrane oxygenation in sheep with a single dose of a disintegrin. Both short- and long-term extracorporeal membrane oxygenation (ECMO) causes platelet loss and dysfunction. Bitistatin is a reversible inhibitor of the platelet glycoprotein IIb/IIIa receptor. This study tests the hypothesis that inhibition of platelets by bitistatin during initial contact with the perfusion circuit preserves platelet number and function during long-term ECMO in sheep. Bitistatin, purified from crude snake venom, was tested for its effect on platelet count, responsiveness to ADP, release of platelet factor 4, and prevention of surface-adsorbed glycoprotein IIIa in vitro and during 24 hours of ECMO in nine splenectomized sheep. During simulated extracorporeal circulation, 0.5-1.0 microgram/ml bitistatin significantly prevented platelet adhesion, attenuated release of sheep platelet factor 4, and preserved platelet responsiveness to ADP. During ECMO at 1.8 l/min for 24 hours, a single dose of bitistatin (200 micrograms/kg) (n = 4) produced higher platelet counts (p = 0.0002) and suppressed release of platelet factor 4 (p = 0.035) for 16 hours compared with five control animals. This dose of bitistatin caused an immediate inhibition of platelet aggregation; however, between 4 and 24 hours of perfusion, platelets of bitistatin-treated animals were more responsive to ADP (p < 0.0001) compared with platelets in control animals. The amount of glycoprotein IIIa antigen extracted by Triton X-100 from the perfusion circuits was reduced in bitistatin-treated sheep. A single dose of bitistatin given before blood contact with the ECMO circuit briefly inhibits platelet adhesion and aggregation but thereafter preserves platelet numbers and function and suppresses alpha-granule release for 12-16 hours of ECMO.


Effect of human recombinant erythropoietin on reduction of homologous blood transfusion in open-heart surgery. A Japanese Multicenter study. Recombinant human erythropoietin (EPOCH) has been shown to increase erythropoiesis; therefore, EPOCH has been used in conjunction with autologous blood predonation (ABP) before surgery. However, the administration methods of EPOCH to obtain an adequate volume of ABP before open-heart surgery have not been determined. The effects of EPOCH on harvesting ABP and decreasing homologous blood transfusion (HBT) in open-heart surgery were examined prospectively in 205 patients treated in a 29-institute multicenter study. Single dose of 3,000, 6,000, or 9,000 IU of EPOCH were administered for 2 weeks (two or three times per week) without ABP (group 1, n = 69) or for 3 weeks (two or three times per week) with ABP (group 2, n = 97) and compared with control subjects (n = 39). Preoperative blood hemoglobin increase (delta Hb[g/dl]) was < 1.0 g/dl in group 1. When EPOCH was given three times a week, the delta Hb in each subgroup of group 2 was 0.6 +/- 1.1 (control), 2.1 +/- 1.3 (3,000 IU), 2.4 +/- 1.4 (6,000 IU), and 2.8 +/- 1.5 (9,000 IU), which was significantly higher than the control (p < 0.05) and was dose dependent. The HBT rates in patients with a moderate perioperative blood loss of between 15 and 50 ml/kg were 75.0% (control), 35.7% (3,000 IU), 52.9% (6,000 IU), and 66.7% (9,000 IU) in group 1, and respective volumes in group 2 were 40.0% (control), 20.0% (3,000 IU), 26.9% (6,000 IU), and 12.5% (9,000 IU). The overall HBT rate of EPOCH-treated patients with a moderate blood loss was 50% (20 of 40) in group 1 and 21% (13 of 62) in group 2. The HBT rate was significantly reduced by combination of preoperative EPOCH treatment (three times per week) and ABP (p < 0.0001). Dose-dependent increase of blood hemoglobin level was observed by EPOCH treatment with ABP; combination of EPOCH treatment and ABP can reduce HBT during open-heart surgery.


Comparative efficacy of ring and suture annuloplasty for ischemic mitral regurgitation. Patients with ischemic mitral regurgitation (MR) represent a therapeutic challenge, and results after combined valve replacement and revascularization have been poor. Valve repair is a promising approach, but the optimal method of repair is not known. In 60 patients with coronary artery disease and 3+ or 4+ MR, we used intraoperative Doppler echocardiography to study the efficacy of Carpentier-Edwards ring (n = 27) and commissural suture (n = 33) annuloplasty. Patients with ruptured papillary muscles, torn chordae, and ballooning or scalloping of the leaflets were excluded. Ring and suture groups were similar in preoperative ejection fraction (35 +/- 14% and 34 +/- 17%), MR grade (3.5 +/- 0.5 and 3.4 +/- 0.6), and acuity of MR (41% and 33% acute) (p = NS). Postoperatively, the ring group achieved a lower residual MR grade than the suture group (0.5 +/- 0.5 versus 1.5 +/- 1.1; p < 0.001), and the mitral annular diameter was reduced to a greater extent in the ring group (by 1.5 +/- 0.5 cm versus 0.5 +/- 0.4 cm; p < 0.001). Success (> or = 2 grade MR reduction) was more frequent in the ring than in the suture group (96% versus 67%, p < 0.01). One-year survival was similar (74 +/- 9% ring, 71 +/- 8% suture). Follow-up Doppler studies showed a higher mean gradient (4.0 +/- 1.2 mm Hg) and smaller valve area (2.1 +/- 0.5 cm2) in the ring group, but the postoperative New York Heart Association class was similar in both groups (83% versus 74% class I-II). Ring annuloplasty provides a more effective reduction of ischemic MR and a higher success rate than the suture technique. This may be related to uniform rather than localized shortening of the annulus and a greater reduction in annulus diameter.


Mitral valve repair using Carpentier techniques in patients more than 70 years old. Early and late results. Mitral valve incompetence in elderly patients raises the problem of whether to replace or to repair the mitral valve. The purpose of this study is to review our experience with mitral valve repair in patients > 70 years old. Between 1986 and 1991, 79 consecutive patients > 70 years old underwent mitral valve repair by Carpentier techniques. The most frequent cause was degenerative valve disease (65 of 79). Preoperative echocardiography showed that 6% of the patients had type I, 88% type II, and 5% type III mitral valve dysfunction. Anatomic lesions encountered at surgery confirmed the preoperative echocardiographic findings, with 88% of the patients with a leaflet prolapse either of the posterior leaflet (56%) or of both the anterior and posterior leaflets (32%). Multiple surgical procedures were required in each patient. Posterior leaflet resection was the most common technique used (76%). Prosthetic ring annuloplasty was used in 96% of patients. Associated procedures were performed in 21.5% of cases. Three patients died, for an operative mortality of 3.8%. One patient (1.3%) required reoperation for residual mitral insufficiency. Nonfatal complications related to the patients' preoperative condition were noted in more than half of the patients. Echocardiography obtained before discharge revealed absent or minimal mitral insufficiency in 91% of patients and mild mitral insufficiency (2+/4+) in 9%. Follow-up was available for 74 of 76 patients (97.3%) and ranged from 3 months to 6 years (mean, 22 months). Two patients (2.6%) were lost to follow-up. Sixty patients (89%) were in New York Heart Association functional class I or II. Seven patients died and one required reoperation. Actuarial analysis of the results showed overall survival at 5 years 81 +/- 11%; freedom from thromboembolism, hemorrhage, and reoperation 97 +/- 5%, 97 +/- 5%, and 98 +/- 4%, respectively. Color-coded echo Doppler studies obtained in 67 patients at the time of follow-up showed absent or minimal MI (91%) (n = 61), and mild MI in 9% (n = 6). These data suggest that mitral valve repair using Carpentier techniques should now be considered as the procedure of choice in patients of any age referred for mitral insufficiency.


Initial results of combined anterior mitral leaflet plication and ventricular septal myotomy-myectomy for relief of left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Several operations (most commonly ventricular septal myotomy-myectomy and also mitral valve replacement) have been performed to relieve symptoms and obstruction to left ventricular outflow in patients with hypertrophic cardiomyopathy (HCM). In an effort to establish an alternative to mitral valve replacement, combined septal myotomy-myectomy and suture plication of the anterior mitral valve leaflet was performed in a subgroup of 36 severely symptomatic patients with obstructive HCM. These patients were selected primarily because the mitral leaflets were judged morphologically at the time of operation to be of sufficient size relative to that of the outflow tract to represent a risk for residual systolic septal contact and outflow obstruction. The effects of operation were assessed in 34 patients; of the 33 with preoperative symptoms, 28 (85%) reported substantial functional improvement after surgery over an average follow-up of 2.2 years. Of 29 patients with complete hemodynamic data, basal outflow gradient was obliterated or reduced substantially by surgery (to < or = 35 mm Hg) in 26 patients (90%) and for the group from 81 +/- 42 to 16 +/- 24 mm Hg (p < 0.001); provocable gradient with isoproterenol infusion also decreased considerably (from 109 +/- 50 to 47 +/- 25 mm Hg; p < 0.001). Echocardiographic studies showed that plication limited the systolic anterior motion of anterior mitral leaflet. There was no hemodynamic evidence of mitral stenosis, and in only one patient did mitral regurgitation increase after surgery. Mitral valve plication combined with myotomy-myectomy in obstructive HCM 1) can be performed safely and does not adversely alter mitral valve function, 2) relieves symptoms and outflow obstruction under basal and provocable conditions, and 3) may represent an alternative to mitral valve replacement in selected patients with elongated and enlarged mitral leaflets.


Acute bacterial endocarditis. Optimizing surgical results. Acute bacterial endocarditis continues to be a condition with high morbidity. Although the majority of patients are treated by high-dose antibiotics, a high-risk patient group requires surgical intervention, which is the subject of this article. From 1972 to 1991, 3,820 patients underwent heart valve replacement at the Brigham and Women's Hospital, Boston. Of this group, 158 patients underwent surgery for acute bacterial endocarditis: 109 had native valve endocarditis (NVE), and 49 had prosthetic valve endocarditis (PVE). There were 108 men and 50 women with a mean age of 49 years (range, 16-79 years); 64% were New York Heart Association functional class IV before surgery, and 12% of the group had a history of intravenous drug abuse. In both NVE and PVE groups, Streptococcus was the predominant infecting agent. Uncontrolled sepsis, progressive congestive failure, peripheral emboli, and echocardiographically demonstrated vegetations were the most common indications for surgery. Eighty-five percent of patients had a single-valve procedure, 15% had a multivalve procedure, and 34 patients had other associated major cardiac procedures. The operative mortality was 6% in NVE and 22% in PVE. Long-term survival at 10 years was 66% for NVE and 29% for PVE. Freedom from recurrent endocarditis at 10 years was 85% for NVE and 82% for PVE. The main factors associated with decreased survival overall were PVE and nonstreptococcal infection. The morbidity and mortality after surgical treatment of acute endocarditis depend on the site, the severity, and the subject infected. Early aggressive surgical intervention is indicated to optimize surgical results, especially in patients with nonstreptococcal infection or PVE.


Spontaneous host endothelial growth on bioprostheses. Influence of fixation. Neither homografts nor bioprostheses have previously been seen to acquire a host endothelium. We previously reported a direct relation between aldehyde tanning and bioprosthesis calcification and the absence of calcification in the absence of aldehyde. Bovine pericardium was 1) treated with 0.625% glutaraldehyde and stored in 4% formaldehyde, 2) treated with 99.5% glycerol, and 3) treated with 99.5% glycerol and stored in formaldehyde (0.25-4%). The treated pericardium was used to construct stentless mitral valve prostheses (of a single pattern) that were implanted in weanling sheep. After the animals were killed, a strip of anterior cusp from annulus to papillary muscle was processed and examined by scanning electron microscopy for the presence of host endothelial growth. Avoidance of aldehyde allowed host endothelial growth in all cases (six of six), and pure aldehyde treatment inhibited growth in five of six animals. Exposure to aldehyde after glycerol treatment interfered with endothelialization significantly; after longer periods of implantation, however, endothelial growth occurred almost invariably in this group (12 of 13 implanted longer than 200 days). For this group, there was a statistically significant difference for duration of implantation between the valves that grew endothelium and those that did not (218.4 +/- 61.9 versus 128.5 +/- 65.4 days). Aldehyde treatment inhibits endothelial growth. With glycerol treatment, growth is uniformly present. Limited exposure to aldehydes after glycerol treatment inhibits endothelial growth, but this effect was ameliorated by prolonged implantation. The possibility of host endothelium-covered, noncalcifying bioprostheses is now real.


Mechanical cardiac valve thrombosis. Is fibrinolysis justified? Thrombosis is a serious complication of heart valve replacement, and management is often difficult. In recent years, thrombolytic therapy has been used as the primary technique by some investigators. Sixty-four consecutive patients presenting with 75 instances of prosthetic heart valve thrombosis (41 mitral, 33 aortic, one tricuspid) were treated with fibrinolytic agents. Obstructed prosthetic valves comprised 39 tilting disc and 36 bileaflet valves. The time interval between valve replacement and obstruction ranged from 15 days to 192 months (mean, 38 months). Fibrinolytic agents used were streptokinase (42 patients), urokinase (27 patients), or recombinant tissue-type plasminogen activator (six patients). Immediate results of fibrinolytic treatment were 1) full success after one or several consecutive fibrinolytic regimens in 55 cases (73%), 2) incomplete improvement in two cases, and 3) failure in 18 cases, leading to an emergency surgery in nine cases. Nine patients died (four strokes, four cardiac arrests, one hemorrhage). Only one severe hemorrhagic complication was observed, but 11 cases of embolism occurred during fibrinolytic treatment (14.6%) (four major cerebral embolisms with death). The immediate efficacy was better for thrombosed aortic prosthesis than with the mitral prosthesis (85% versus 63%). Fibrinolytic treatment appears to be an attractive nonsurgical alternative for prosthetic heart valve thrombosis, but because of the risk of cerebral embolism, its use should be reserved for tricuspid valve thrombosis or critically ill patients with mitral or aortic valve thrombosis. The use of a fibrinolytic agent in cases of small, nonobstructive paravalvular thrombosis demonstrated with transesophageal echocardiography needs further studies.


From Glenn to Fontan. A continuing evolution. Aristotle's and Galen's erroneous understanding of the circulation eventually was rectified, mostly by Colombo and Harvey, who in the 16th and 17th centuries, respectively, provided the foundation to our present knowledge of the pulmonary and systemic circulation. The "indispensability" of the right ventricle was not questioned until the 20th century. Rodbard, in 1948, for the first time successfully bypassed the canine right ventricle by anastomosing the right atrial appendage to the proximally ligated main pulmonary artery. This important experiment triggered a number of other studies that eventually led to the clinical introduction of the Glenn operation in 1959 and the Fontan operation in 1968. Clinical experience with modifications of the original Fontan operation at The Children's Hospital in Boston included 1) direct atrial-to-pulmonary artery connection (without valves), 2) cavocaval baffle-to-pulmonary artery connection, 3) bidirectional cavopulmonary artery anastomosis, and 4) fenestrated Fontan approach. The original surgical mortality of 20% has been reduced in 1990-1991 to 4%, including patients with complex pathology other than tricuspid atresia. The incidence of prolonged pleural effusions has also decreased from an earlier 40% to < 5% after bidirectional cavopulmonary artery anastomosis and to 11% after the fenestrated Fontan operation. Much progress has been made since Dr. Glenn's and Dr. Fontan's epic contributions. Ideally, a more appropriate selection of patients and some of the modifications of the original Fontan operation will have a more favorable impact on early and long-term results.


Fenestrated Fontan with delayed catheter closure. Effects of volume loading and baffle fenestration on cardiac index and oxygen delivery. BACKGROUND. The fenestrated Fontan operation has been applied to high-risk patients with univentricular hearts, resulting in improved survival. The purpose of this study was to determine the hemodynamic factors responsible for these improved results. METHODS AND RESULTS. We performed the fenestrated Fontan operation in 17 high-risk patients with univentricular hearts (median age, 3 years; age range, 1.2-25 years). High-risk characteristics were depressed ventricular function and/or hypertrophy (n = 12), atrioventricular valve insufficiency (n = 5), pulmonary artery distortion (n = 6), elevated pulmonary vascular resistance (> 2 units/m2) (n = 4), previously failed Fontan operation (n = 2), or associated Wolff-Parkinson-White syndrome (n = 1). Intraoperative hemodynamic measurements (n = 8) included cardiac index (by aortic flow probe), peripheral arterial O2 saturations, and left and right atrial pressures during inflow occlusion, followed by volume loading with open versus closed fenestration. Mean baffle fenestration was 3.5 mm (range, 2.7-5.0 mm). Multiple regression analysis (cardiac index versus atrial pressure) revealed cardiac index was greater with open than with closed fenestration (p < 0.001) during volume loading. Oxygen delivery (cardiac index multiplied by oxygen content) was also greater with open than with closed fenestration (p < 0.001). Survival was 100% with a mean follow-up of 10.4 months; pleural drainage was high in two patients. Subsequent transcatheter fenestration closure resulted in increased O2 saturation (87 +/- 1% to 96 +/- 0.3%, p < 0.05). CONCLUSIONS. The fenestrated Fontan operation improves survival in high-risk patients by increasing cardiac index and maintaining oxygen delivery, despite mild arterial O2 desaturation. Subsequent transcatheter fenestration closure can be performed after hemodynamic assessment.


Abolishment of chronic volume overload. Implications for diastolic function of the systemic ventricle immediately after Fontan repair. In patients with a univentricular heart, the chronic ventricular volume overload is acutely abolished by the creation of a Fontan circuit. This results in an immediate reduction of the ventricular cavity size but also in an inappropriate degree of ventricular wall thickness, at least in the early postoperative period. The implications for the diastolic properties of the ventricle are poorly understood. A chronic volume overload through a modified Blalock-Taussig shunt was created in 10 mongrel dogs. Six weeks later, the shunt was occluded percutaneously with a detachable balloon. The left ventricular end-diastolic dimension and posterior wall thickness were measured with transcutaneous echocardiography. Digitized high-fidelity pressure tracings were used to determine the time constant of isovolumic pressure decay, tau. The isovolumic relaxation time (A2-MVO) and time to minimal left ventricular pressure (A2-LVPmin) were recorded. All variables were followed up to 1 month after occlusion of the shunt. One hour after occlusion, there was an incomplete return to baseline values of the echocardiographic left ventricular dimension (+12 +/- 8% of baseline value, p < 0.01). Despite a 31 +/- 14% (p < 0.001) increase of the posterior wall thickness after removal of the volume overload, tau or ventricular relaxation showed no change from control values. In contrast, the early filling wave was blunted, suggesting diminished ventricular suction. A2-MVO (p < 0.01) and A2-LVPmin (p < 0.05) lengthened well above baseline values for up to 1 week after occlusion of the shunt. Over the following month, the volume-induced hypertrophy regressed, and indexes of early ventricular filling resumed control values. We conclude that early after removal of a chronic volume overload, the resultant increase of wall thickness is not associated with impaired relaxation but that viscosity and inertia caused by the increased mass-to-volume ratio will impair early ventricular filling.


Clinical-pathological correlations of coronary disease progression and regression. The initiation of atherosclerosis may result from blood flow oscillatory shear stress in certain vascular sites (bending points, bifurcations, etc.) producing chronic minimal injury resulting in functional alteration of the arterial endothelium type I injury; experimentally, this is potentiated by atherogenic risk factors such as hypercholesterolemia, hypertension, immunocomplexes, viral infections, and tobacco smoke. Such minimal injury leads to accumulation of lipid and monocytes (macrophages), and subsequently, toxic products released by the macrophages produce damage of the intimal surface with denuding endothelium type II injury or damage, which attracts platelets; all of these cells release growth factors, prompting migration and proliferation of smooth muscle cells and producing a "fibro-intimal lesion" or the outside of the capsule of a predominant "lipid lesion." The lipid lesions surrounded by a thin capsule tend to be small and rupture easily, causing type III injury or damage; that is, they are soft and weak, contain large numbers of macrophages, which may release collagenase and elastase to form abscesses, and by their location, are under the effect of flow shear forces. After plaque disruption there is thrombus formation; when thrombi are small, they can become organized and contribute to the growth of the atherosclerotic plaque; when thrombi are large and occlusive, they lead to the acute coronary syndromes. New data suggest that, at the time of plaque disruption, certain "thrombogenic" risk factors modulate the degree of thrombogenicity and, thereby, the growth of the plaque versus the various acute coronary syndromes. Aside from the need for better understanding of the basic biology of atherogenesis, emphasis on identifying and modifying the primary atherogenic and thrombogenic risk factors should continue for primary prevention. Also, new approaches should focus on the identification, stabilization, and regression of the small "lipid plaques" prone to rupture (these are not necessarily angiographically apparent), as well as on the use of better and safer antithrombotic agents for prevention of progression.


Antithrombotic therapy and progression of coronary artery disease. Antiplatelet versus antithrombins. Coronary artery disease develops and progresses over decades with lipid incorporation and coalescence into the arterial wall, leading to recurrent plaque disruption, thrombosis, and organization into fibromuscular lesions. The role of thrombin in arterial thrombosis is documented by observations that specific thrombin inhibition can completely prevent intraluminal mural thrombus in vivo, even though other factors that activate platelets are not inhibited. Platelet-rich thrombi associated with deep injury have a high thrombin content and require blood levels of specific thrombin inhibition with hirudin that are eight to 10 times those required to prevent thrombi associated with lesser injury or stasis. Total prevention of mural thrombus in deeply injured arteries is impossible with aspirin or conventional antithrombotic therapy, which can reduce occlusive thrombus. Thus, conventional antithrombotic therapies can reduce clinical events but are not effective in reducing progression of coronary artery disease. Whether newer antithrombins that can totally prevent mural thrombus after deep injury can be developed and administered orally and chronically without high risk of bleeding and will be able to reduce progression of coronary artery disease is unknown. Lesion growth, vascular injury, acute coronary syndromes, and principles of thrombus formation on ruptured plaque are discussed elsewhere in this issue. This article extends these findings and discusses the prevention and treatment of mural thrombosis, the pivotal role of thrombin in arterial thrombosis, and antithrombotic therapy for the prevention and the progression of coronary artery disease.


Interventions that beneficially influence the evolution of coronary atherosclerosis. The case for calcium channel blockers. Calcium channel blockers have been shown to retard the development of atherosclerosis in rabbits fed cholesterol-rich diets. The mechanism accounting for this effect is controversial but may be by stimulation of cholesteryl ester hydrolase activity in smooth muscle cells, by amelioration of hypercholesterolemia-induced endothelial dysfunction, or by inhibition of smooth muscle cell proliferation and migration. The effect of calcium channel blockers on the evolution of coronary atherosclerosis in humans has been assessed in two clinical trials. In the Montreal Heart Institute trial, nicardipine did not influence the overall rate of progression and regression; however, nicardipine-treated patients experienced significantly less progression of minimal lesions, defined as stenoses of < or = 20% severity. In the International Nifedipine Trial on Antiatherosclerotic Therapy, nifedipine had no effect on overall progression and regression but reduced the rate of appearance of new coronary lesions. These studies constitute a potentially important new approach to the management of coronary atherosclerosis.


Atherosclerosis. Potential targets for stabilization and regression. Reviewed are various aspects of atherosclerotic plaque stabilization and regression in humans and experimental animals. Plaque regression is a function of the dynamic balance among initiation, progression, stabilization, and removal of plaque constituents. Pseudoregression, the result of the triad thrombolysis, age- or lesion-dependent arterial dilatation, and relaxation of vasospasm, may readily give rise to angiographic misinterpretation. Although lowering of plasma cholesterol and low density lipoprotein-cholesterol has demonstrated significant clinical benefits in a number of clinical trials, the magnitude of angiographic regressive changes is relatively small despite aggressive lipid-lowering regimens. The emerging need for alternative or complementary therapeutic interventions has been emphasized. In particular, they should be targeted to pivotal cellular or molecular mechanisms in initiation, progression, or stabilization. Potentially important therapeutic targets include the use of antioxidants or free radical scavengers such as Probucol or its analogues, butylated hydroxytoluene, tocopherols, and possibly the tocotrienols. Other therapeutic targets include intimal monocyte-macrophage recruitment, macrophage cholesterol acyltransferase inhibition, stimulation of the high density lipoprotein-mediated reverse cholesterol transport system, smooth muscle cell migration to and proliferation in the arterial intima, and intimal connective tissue synthesis. Whether the isoprenylated proteins associated with the cholesterol biosynthetic pathway will give rise to compounds regulating smooth muscle cell growth has yet to be determined. Because of the importance of thrombosis in the pathogenesis and progression of lesions, the need to develop interventional strategies targeted at endothelial cell thromboresistance and thromboregulation must assume a high priority in future research and development. Other areas of therapeutic promise include the calcium channel blockers and angiotensin converting enzyme inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)


Intact and altered endothelium in regulation of vasomotion. The endothelium possesses the ability to modulate vascular tone by the release of vasodilator and vasoconstrictor substances, among them endothelium-derived relaxing factor (EDRF) and endothelin. Abnormalities in EDRF generation were demonstrated in various cardiovascular pathophysiological states, specifically atherosclerotic vascular disease, congestive heart failure, and essential and pulmonary hypertension. Moreover, increases in plasma endothelin concentration have been reported as well in these disease states. When these observations are taken together, these states may be characterized by an attenuated release of EDRF, whereas the release of endothelin is augmented. An imbalance between EDRF and endothelin may contribute to the alteration in vascular tone characteristic of cardiovascular disease. The following review summarizes the present knowledge of the role of EDRF and endothelin in such disease processes.


Mechanisms in intimal monocyte-macrophage recruitment. A special role for monocyte chemotactic protein-1. This article briefly addresses the role of the monocyte-macrophage in atherogenesis and the potential mechanisms participating in intimal blood monocyte recruitment. The obligatory components of the recruitment process, i.e., contact with the vascular endothelium, attachment, and migration into the subendothelial space, are addressed with reference to the influence of blood flow, plasma proteins (particularly low density lipoprotein), and inflammatory mediators and cytokines. The potentially important role of monocyte chemotactic protein-1 in regulating monocyte recruitment in plaque pathogenesis is discussed.


von Willebrand factor as a target for antithrombotic intervention. The adhesive protein von Willebrand factor is essential for the formation of platelet thrombi under flow conditions characterized by high shear stress. This function requires the interaction with two distinct platelet receptors, the glycoprotein complexes Ib-IX-V and IIb-IIIa. Interaction with the former results in platelet activation, a necessary step for binding to the latter and supporting stable aggregation. The inhibition of von Willebrand factor binding to glycoprotein Ib can be achieved with small recombinant fragments containing the specific functional domain of the molecule that interacts with this platelet receptor. Such fragments may provide a new selective approach to antithrombotic therapy.


Why do plaques rupture?

Why do plaques rupture? Rupture of the plaque surface, often with thrombosis superimposed, occurs frequently during the evolution of coronary atherosclerotic lesions. It is probably the most important mechanism underlying the sudden, rapid plaque progression responsible for acute coronary syndromes. The risk of plaque rupture depends on plaque type (composition) rather than plaque size (volume), because only plaques rich in soft extracellular lipids are vulnerable (rupture-prone). Most ruptures are tiny, occurring at the periphery of the fibrous cap that covers the lipid-rich core--points where the cap is usually thinnest and most heavily infiltrated by macrophage foam cells. Compared with intact caps, ruptured ones usually have less tensile strength and are more extensible, containing less collagen and glycosaminoglycans, more extracellular lipid, fewer smooth muscle cells, and more macrophages. Progressive extracellular lipid accumulation (lipid core formation) and cap weakening (macrophage related?) predispose the plaque to rupture and determine the actual vulnerability, which may change with time. Luckily, the plaque components responsible for vulnerability (soft lipid and probably macrophages) are apparently most likely to regress with treatment. The dynamic interplay between the actual plaque vulnerability and external stresses ("triggers") probably determines the particular moment and point of rupture, if this occurs. Vulnerability probably plays a more important role in rupture than triggers, because exercise stress testing of patients with advanced coronary artery disease rarely triggers a rupture/thrombus-related acute heart attack. A prerequisite is the presence of a vulnerable plaque.


Factors controlling the development of arterial lesions after injury. This review discusses the role of growth factors on the proliferation of smooth muscle cells (SMCs) in injured arteries. We have used a variety of procedures to injure rat carotid arteries and noted that removal of endothelium followed by platelet adherence does not always initiate SMC replication. Furthermore, thrombocytopenia did not reduce the early SMC replication induced by balloon catheter injury. Platelet-derived growth factor (PDGF) has been found to exert little effect on SMC replication but markedly influences the ability of SMCs to migrate to the intima. Basic fibroblast growth factor (bFGF) is a potent mitogen for SMCs in denuded arteries while having no effect on cells in control uninjured arteries. We have hypothesized that arterial injury leads to release of bFGF from injured SMCs and so stimulates cell replication. Rats were treated with antibodies to bFGF immediately before balloon injury, and this significantly reduced the SMC replication. These findings suggest that in vivo bFGF is an important mitogen for initiating SMC replication and that PDGF is important as a chemotactic for SMCs.


A cascade model for restenosis. A special case of atherosclerosis progression. Restenosis presently limits the long-term success of percutaneous transluminal coronary angioplasty (PTCA) and allied treatments of atheroma. Current views of the pathophysiology of restenosis fail to explain certain important clinical features: Thrombosis, often invoked as a cause of smooth muscle proliferation, wanes before intimal thickening peaks. Prolonged antithrombotic therapy does not eliminate restenosis after PTCA. Furthermore, only a minority of angioplastied lesions develop clinically significant restenosis. We propose a cytokine-growth factor cascade mechanism of restenosis pathobiology that could explain these features of human restenosis. According to this model, PTCA would produce acute local thrombosis and/or mechanical injury that triggers cytokine/growth factor gene expression by resident macrophages and smooth muscle cells. This early acute generation of cytokines could evoke a secondary growth factor and cytokine response that might establish a positive, self-stimulatory autocrine and paracrine feedback loop that would serve to amplify and sustain the proliferative response. This multistage schema would account for the lag between injury and restenosis and the failure of chronic antithrombotic therapy to prevent this process. Human atheromata contain variable numbers of macrophages. The macrophage content of a particular lesion could determine in part propensity to develop restenosis after angioplasty, explaining why all lesions do not develop this process. Several experimental observations support this novel mechanistic model. Leukocytes and smooth muscle cells express genes for cytokines and growth factors, and products of coagulation and thrombosis can activate mononuclear phagocytes. Cytokines and growth factors often augment their own gene expression and induce one another, providing a potential intralesional amplification loop. Experimental atheroma and advanced human atherosclerotic lesions do not express high levels of growth-stimulatory cytokines such as interleukin-1 or tumor necrosis factor in the basal state but exhibit inducible expression in response to an injurious stimulus. Thus, cascades of autocrine or paracrine mediators whose expression is triggered by vascular injury might contribute to deranged smooth muscle behavior during restenosis.


Induction of PDGF-responsive genes in vascular smooth muscle. Implications for the early response to vessel injury. Arterial injury induces vascular smooth muscle cells (VSMC) to modulate from a quiescent to a proliferative state characterized by cell division, migration, and secretion of matrix. These changes have been implicated in the development of intimal hyperplasia after balloon angioplasty. The transition of VSMC to a proliferative state is preceded by the accumulation of platelets and leukocytes, which may release growth factors and cytokines at the site of injury. Platelet-derived growth factor (PDGF) is secreted by platelets and a variety of cellular elements associated with the vessel wall and, as a VSMC mitogen and chemoattractant, has been implicated in the pathogenesis of intimal hyperplasia. We have found that, in addition to its effects on VSMC growth and migration, PDGF induces the expression in VSMC of the JE and KC genes, which encode monocyte and neutrophil chemoattractants, respectively. The induction of JE and KC by PDGF in VSMC culture involves several distinct transmembrane signaling pathways. In addition to their induction in VSMC culture, JE and KC messenger RNA accumulates rapidly and transiently in adult rabbit aorta after balloon dilatation, suggesting a role for these chemoattractants in the early vascular response to injury in vivo. The VSMC may therefore play a dual role in vessel injury, both as a mediator of the inflammatory response through chemoattractant release and as an effector of the hyperplastic response through proliferation.


Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have simulated and studied these processes in an ex vivo perfusion chamber and in an in vivo swine model. Our results suggest that specific local factors at the time of plaque disruption influence the degree of thrombogenicity, the stability of the growing thrombus, and, therefore, possibly also the various clinical syndromes. These factors can be divided into two groups: local vessel wall-related factors and systemic factors with local action at the area of risk. These factors include the following. 1) Exposed substrate-related effects: Plaque rupture produces a rough surface and stimulates the development of occlusive thrombus in proportion to the degree of damage. 2) Fluid dynamics-related factors: The more severe the stenotic lesion after plaque rupture, the higher the local shear rate, resulting in enhanced platelet deposition and thrombus formation. 3) Vasoconstrictive effects: Vasospasm is an important contributor to the pathogenesis of ischemic heart disease. 4) Systemic factors: There is clinical and experimental evidence to suggest that various systemic factors at the time of plaque rupture may enhance thrombogenicity (i.e., levels of epinephrine, levels of serum cholesterol, impaired fibrinolysis). We have investigated the role of residual thrombus on the process of rethrombosis and found that a residual thrombus is a very thrombogenic surface that may significantly contribute to reocclusion even in heparinized blood. Using recombinant hirudin as a pharmacological tool in our flow studies, we observed that rethrombosis is partially caused by thrombin bound to fibrin in the original thrombus, because the effect is abolished by the specific thrombin inhibitor.


Role of high density lipoproteins in the regression of atherosclerosis. Atherosclerosis is a slowly progressive disease characterized by the accumulation of cholesterol within the vessel wall. Plasma lipoproteins are particles of complex lipid and protein composition that transport lipids in blood. Low density lipoproteins (LDL) and high density lipoproteins (HDL) are the major cholesterol-carrier lipoproteins. LDL seem to be responsible for the delivery of lipids (cholesterol) from the liver to the tissues. Compelling evidence supports the concept that the lipids deposited in the arteriosclerotic lesions are derived primarily from plasma LDL. The term "reverse cholesterol transport" describes the transport of cholesterol from extrahepatic tissues to the liver, where it may be metabolized. Reverse cholesterol transport seems to be the major route for removal of the exchangeable cholesterol deposited in the extrahepatic tissue. It has been postulated that a major role of the plasma HDL particle is to act as a scavenger of tissue cholesterol. The hypothesis that high levels of plasma HDL are protective against coronary artery disease (CAD) was initially proposed by Barr et al in the early 1950s, but it was overlooked until confirmed by the Tromso and Framingham studies in 1977, which showed an inverse relation between HDL plasma levels and incidence of CAD. Similar observations have been made in 15 major experimental studies including eight countries.(ABSTRACT TRUNCATED AT 250 WORDS)


The relation between atherosclerosis and thrombosis. The relation between atherosclerosis and thrombosis has been recognized for over a century. Until very recently, however, this pathophysiological association has been largely based on observation with little information available to dissect molecular and cellular mechanism. The known associations between the principal determinants of thrombosis (platelets, fibrin and its proteolytic degradation products, and fibrinolytic enzymes) and atherosclerosis; the regulation of thrombotic determinants by cytokines and growth factors important in atherogenesis; and the modulation of thrombotic determinants by atherogenic lipoproteins, especially lipoprotein(a), are discussed. Within this conceptual framework, clear molecular and cellular mechanisms emerge, and a better basic understanding of the thrombotic determinants of atherogenesis can be developed.


A retrospective study of disposable extended wear lenses in 100 patients: year 2. We present the results of the second year of follow-up of 100 patients wearing disposable contact lenses on an extended wear basis. Thirty-seven males and 63 females participated in the study (mean age: 41.1 years +/- 13.88 (mean +/- 1 standard deviation); and the mean patient follow-up time was 26 months +/- 4.9). A total of 13 patients were lost to follow-up. Seventeen patients discontinued extended wear yet continued to wear soft lenses on a daily wear basis--the reasons for this finding are discussed. A significant decrease in the number of events defined as complications (32 events) was noted when compared to the first year of follow-up (136 events). Seven corneal infiltrates occurred during the second year, compared to 6 such events during the first year of the study. Additional complications included: giant papillary conjunctivitis (6 cases), corneal staining (5 cases), and corneal abrasions (4 cases). Disposable extended wear soft contact lenses offer a reasonable means of vision correction in the properly selected patient. At the same time, caution should be exercised in the fitting and wear of these lenses.


A European fitting philosophy for aspheric, high-Dk RGP contact lenses. Microbial keratitis, the most serious complication of contact lens wear, is most frequently associated with soft contact lenses. Rigid gas permeable (RGP) lens wearers are less often affected. Increased use of high-Dk RGP lenses could reduce the number of cases of microbial keratitis. In Europe, aspheric high-Dk RGP lenses are very popular. This article presents practical guidelines for computer-aided fitting of aspheric RGP lenses. Base curve selection using the keratometer to determine the corneal topography is described. This method, which is inexpensive and time-saving, is suitable for fitting cosmetic contact lenses or lenses used in treating such corneal pathology as keratoconus.


A clinical evaluation of two multifocal soft contact lenses. We fit two multifocal soft contact lenses, Bausch & Lomb's Bi-Tech and the Unilens contact lens from Unilens Corporation, in two separate populations of presbyopes. Most patients (24/42, 57%) had no prior contact lens experience. Patients were evaluated at 6 and 12 months for comfort, visual acuity, lens fit, and corneal findings. Both distance and near vision were found to be slightly decreased with each contact lens when compared to best corrected visual acuity with spectacles. Seventy-seven percent (14/18) of the Unilens wearers and 67% (16/24) of the Bi-Tech wearers continued to wear their lenses for at least 1 year. Those who discontinued lens wear did so because they were dissatisfied with their vision. Presbyopes who seek correction with soft contact lenses appear to be more tolerant of a decrease in distance vision than a decrease in near vision. Both lenses were comfortable and no corneal pathology was induced. Our results suggest that the Unilens (simultaneous vision design) provides more predictable correction of presbyopic symptoms than the Bi-Tech (alternating vision design) because it is independent of lower lid position and translation. Both of these lenses are viable options for the correction of presbyopic symptoms.


Microbial contamination of hydrophilic contact lenses. Part II: Quantitation of microbes after patient handling and after aseptic removal from the eye. We cultured Soflens (polymacon) contact lenses to determine the number of microorganisms present after patient handling and the number present after patient handling and 5 hours of lens wear. Twenty adapted contact lens patients were each dispensed two pairs of new sterile Soflens contact lenses. Both pairs of lenses were handled by the patients during a single experimental session. Prior to handling lenses, patients were instructed to wash their hands with soap and water, rinse with tap water, and dry with a paper towel. One pair (handled-only) was cultured immediately after handling. The second pair (handled-and-worn) was placed on the eyes by the patient, removed aseptically following 5 hours of wear, and then cultured. All 40 handled-only lenses had viable microorganisms associated with them (mean: 653 colony forming units (CFU) per lens). Bacteria were isolated on all of these lenses and fungi were detected on six. The mean bacterial count for the handled-and-worn lenses was 30 CFU/lens; fewer than half exhibited handled-and-worn lenses was 30 CFU/lens; fewer than half exhibited bacteria and no fungi were isolated. These data suggest that patient handling is a highly significant source of microbial contamination of hydrophilic contact lenses. Also, the number of microorganisms on lenses is significantly reduced (P < 0.0001) after the lens has been worn on the eye.


Collagen shields containing tobramycin for sustained therapy (24 hours) of experimental Pseudomonas keratitis. We compared collagen shields hydrated in 1.36% tobramycin with topical 1.36% tobramycin for sustained treatment of experimental Pseudomonas keratitis in rabbits. Antibiotic therapy for a total of 24 hours was initiated 14 hours after an intrastromal injection of 10(3) logarithmic phase Pseudomonas aeruginosa. Seven groups were treated as follows: groups 1-3, collagen shields hydrated in tobramycin supplemented with topical 1.36% tobramycin drops at 4, 6, or 8 hour intervals; group 4, collagen shields hydrated in tobramycin without any further topical supplementation; group 5, topical tobramycin therapy, initially every half-hour for 4 hours, then hourly; group 6, collagen shields hydrated in balanced saline solution; and group 7, no treatment. Each group contained four eyes. The groups treated with collagen shields supplemented every 4 or 6 hours with topical tobramycin had significantly fewer colony forming units (CFU) than those receiving topical or collagen shield therapy alone (P < 0.001). The group treated with collagen shields hydrated in sterile saline had 10(7) CFU per cornea, which was not significantly different from the untreated group (P > 0.2). Collagen shields hydrated in tobramycin and supplemented with topical tobramycin were effective in sustained treatment of experimental Pseudomonas keratitis.


Practical aspects of a corneal topography system. We used the EyeSys Corneal Topography System to examine several issues relating to corneal topography systems and the interpretation of their results. Interferometry measurements of EyeSys calibration spheres indicated that they deviated from suggested values by 0.05 +/- 0.13 D (mean +/- 1 standard deviation). The EyeSys unit reliably determined the calibration spheres to be spherical with differences between the flat and steep axis of 0.10 +/- 0.09 D. The data for the 3 mm chord circle was the least reliable. The spherical equivalent values for the calibration spheres were constantly greater than the 0.25 D reproducibility suggested by the manufacturer. Furthermore, the precision of the outputted values (0.01 D) is beyond the capability of the instrument. This gives the impression that the topography unit cannot consistently reproduce measurements of the calibration objects or chrome plated steel spheres. Image centralization and focus were found to be critical in obtaining accurate results. A target off center by more than 0.25 mm resulted in unreliable data; increasing the focal distance by greater than 1 mm beyond the focal point resulted in a sharp decrease in accuracy (a decrease in the focal distance was even more critical). When measuring aspheric contact lenses, it was found that the keratometer and EyeSys unit provided a close approximation of the surface characteristics of the lenses. A realistic view of the limitations of the topography system being used is critical for proper interpretation of the data.


The effect of pregnancy on corneal curvature. Even though they had been successful contact lens wearers previously, many women develop contact lens intolerance while pregnant. We prospectively followed 24 women during pregnancy, postpartum, and after cessation of breastfeeding. Six women (25%) developed contact lens intolerance during the study period. There were no changes observed in refraction, corneal sensitivity, corneal thickness, or intraocular pressure. However, there was a statistically significant (P < 0.05) increase in corneal curvature during the second and third trimester which resolved postpartum or after the cessation of breastfeeding. We discuss the clinical importance of this finding.


A quantitative method for LDH, MDH and albumin levels in tears with ocular surface toxicity scored by Draize criteria in rabbit eyes. We have established a quantitative method for evaluation of ocular surface lesions on the basis of lactate dehydrogenase (LDH) activity, malate dehydrogenase (MDH) activity, and albumin levels in rabbit tears. Lesions were produced with solutions of 0.005-0.02% benzalkonium chloride (BAK), 0.01-0.03% chlorhexidine digluconate (CHX), and 0.01-0.03% polyhexamethylene biguanide hydrochloride (PHMB), all of which are widely used in topical ophthalmic preparations. Two drops of test solution were instilled 15 times into rabbit eyes at 5 minute intervals. Sixty minutes after 0.02% BAK instillation, tear LDH activity increased from 1,840 U/L (without instillation) to 26,100 U/L, and concomitantly tear albumin levels rose from 0.11 mg/mL (without instillation) to 9.48 mg/mL. Instillation of 0.03% CHX and 0.03% PHMB caused smaller increases in LDH and MDH activity and albumin tear levels. LDH activity and albumin levels in tears were significantly correlated with the degree of total ocular surface lesions in both cornea and conjunctiva as observed by slit lamp biomicroscopy quantified using a modified Draize score. Based on the results of this study, we believe that LDH activity and albumin level in tears can be used as objective indicators for the quantitative evaluation of ocular surface lesions on both cornea and conjunctiva following application of topical ophthalmic preparations containing cytotoxic preservatives in animals and man.


Risk factors for HIV infection in homosexual men: the Cleveland men's study of risks in a low-prevalence area. Detailed questionnaires concerning alcohol and drug use, sexual practices, and medical history were completed by 301 homosexual men living in the Cleveland metropolitan area. Their sera were subsequently tested for antibodies to the human immunodeficiency virus. Fifty-six (18.6%) were seropositive. In a univariate analysis, age, drug use, and four specific sexual practices were associated with seropositivity. In a multiple logistic regression analysis, intravenous drug use and receptive anal-genital sex remained independent predictors of seropositivity.


Ordering respiratory care services for hospitalized patients: practices of overuse and underuse. Because of recent concerns about misallocation of respiratory care services and analyses suggesting that limiting services to comply with established guidelines reduces unneeded therapies without compromising quality of care, the authors audited the records of 170 patients newly ordered to receive at least one of five respiratory therapies (oxygen therapy, incentive spirometry, bronchopulmonary hygiene, aerosolized bronchodilator therapy, or intermittent positive pressure breathing) at The Cleveland Clinic Foundation. In reviewing whether the therapies that were ordered complied with published guidelines for these services, we found that 25.2% were "not indicated." This over-ordering incurred unnecessary total charges of $11,937 ($206.16 per patient) and occupied therapist time that could have been better allocated to other services. These costs were offset by the finding that 10.5% of the patients were not ordered to receive indicated respiratory therapies. Our proposed strategy of initiating protocols for ordering and providing respiratory care services (ie, via a respiratory care consult service) is an appealing means to address this misallocation, but it requires further evaluation.


Adults with congenital complete heart block: 25-year follow-up. Complete congenital heart block has been recognized since 1846, yet the prognosis of the disease has not been determined by comprehensive long-term studies. We reviewed 14 cases of complete congenital heart block at The Cleveland Clinic Foundation. The patients were followed for a mean of 25 years (range, 20 to 32 years). Ten patients had structurally normal hearts, and 4 had varying degrees of congenital heart disease. The patients were evaluated with regard to symptoms, and indications for permanent pacemaker implantation were studied. Seven patients received permanent pacemakers. Ages at the time of pacemaker implantation ranged from 15 to 38 years (mean, 25 years). Overall, the patients in our study tended to lead normal productive lives. The main indications for pacemaker implantation were symptoms alone. Guidelines for prophylactic pacemaker implantation have yet to be determined, and the development of these guidelines is difficult due to small numbers of patients at isolated centers. A large international study is needed to set these guidelines.


Adjuvant therapy for colorectal cancer.

Adjuvant therapy for colorectal cancer. The search for effective adjuvant therapy for colorectal cancer has been long and, until recently, largely unrewarding. Surgery alone is inadequate therapy in as many as 50% of patients. But recent studies demonstrate significant improvement in disease-free survival and overall survival for patients with advanced colon and rectal cancer who receive adjuvant therapy. Postoperative chemotherapy with fluorouracil and levamisole is the standard of care for patients with stage III colon cancer, and postoperative high-dose pelvic radiation combined with fluorouracil is the standard regimen for patients with stage II and III rectal cancer.


Cytokines and the pathogenesis of insulin-dependent diabetes mellitus. Insulin-dependent diabetes mellitus is an autoimmune phenomenon in humans. At onset, the diabetic pancreas shows a well-characterized insulitis. The inflammatory cells are specifically directed toward beta cells of the pancreatic islets. Several hypotheses link genetic susceptibility for diabetes to immunologic mechanisms. The cytokines interferon gamma and interleukin-6 have essential roles in the progressive destruction of beta cells. Studies with experimental models may improve definition of the pathogenesis of insulin-dependent diabetes mellitus. Combining genetic studies that detect susceptibility to insulin-dependent diabetes mellitus with future therapies aimed at interrupting cytokine production or cytokine receptor expression may lead to prevention of insulin-dependent diabetes mellitus.


The effect of sleep position on the diagnosis of obstructive sleep apnea: a word of caution. Sleeping in the supine position exacerbates obstructive sleep apnea. Patients sleeping off their backs during a polysomnographic study might have a normal study in spite of having a history of severe obstructive sleep apnea. This might be shown by repeating the study with the patients spending most of the study time sleeping on their backs. We report three patients illustrating this point and discuss the importance of monitoring sleep position while performing polysomnography. The effect of position in interpreting different therapeutic modes for obstructive sleep apnea should be considered.


The effect of do-not-resuscitate orders on length of stay. In 1988, a new do-not-resuscitate policy aimed at assisting professional staff, nurses, patients, and families in end-of-life choices replaced the existing policy at The Cleveland Clinic Foundation. We conducted a retrospective chart review to examine the effects of the new policy on length of stay. Data were collected on demographics, clinical information, length of stay, and the frequency of do-not-resuscitate orders for expired Medicare patients in 1987 (n = 125) and 1989 (n = 135). Length of stay for patients who received a do-not-resuscitate order was significantly reduced in 1989 compared with 1987, partly because the orders were issued earlier in patients' stays in 1989. The number of days from writing the order until death did not change significantly from 1987 to 1989. We conclude that a well-defined do-not-resuscitate policy can reduce length of stay.


New strategies in nonantibiotic treatment of gram-negative sepsis. Gram-negative bacterial infections are difficult to control and often lead to septic shock or septic syndrome. Many physiologic changes in sepsis are due to bacterial triggering of host responses. Improved understanding of these mechanisms has led to new treatment modalities that aim to block the runaway inflammatory process of sepsis. New therapeutic agents are currently being evaluated in animal and human studies. By combining these advances with adequate antibiotic therapy, it may be possible to improve overall survival in patients with gram-negative sepsis.


Renal pseudoenlargement secondary to retroperitoneal liposarcoma. A case of renal pseudoenlargement caused by a large retroperitoneal mass is reported. An intravenous urogram showed apparent enlargement of the right kidney and a normal left kidney. Computed tomography showed a normal-sized right kidney. The discrepancy was due to magnification produced by marked anterior displacement of the right kidney by a retroperitoneal liposarcoma.


Immunoreactive vasotocin in the zebra finch brain (Taeniopygia guttata). The distribution of vasotocin (VT)-immunoreactive cells and fibers in the zebra finch brain was studied with immunocytochemical techniques. A large number of VT-immunoreactive cells was found in the nucleus preopticus anterior and nucleus paraventricularis. In the lateral parts of the hypothalamus diffusely organized VT-immunoreactive cells were present. Some of these cells were found close to and embedded in the optic tract. An extra-hypothalamic parvocellular cell group was found at the level of the anterior commissure in the dorsal diencephalon. VT-immunoreactive fibers and varicosities were present in a number of extrahypothalamic regions i.e. the septum, the area ventralis of Tsai, the lateral habenula, the optic tectum, the substantia grisea centralis, the nucleus tractus solitarii, the lateral medulla, the nucleus intercollicularis and in the archistriatum surrounding the nucleus robustus archistriatalis. The VT-immunostaining in the lateral septum and dorsal diencephalon showed no sex differences and can not be influenced by testosterone administration. the topography of the central VT-immunoreactive network is similar to that in another song bird i.e. the canary; but seasonal and testosterone-dependent changes in VT-immunostaining in the lateral septum and dorsal diencephalon are only observed in the canary.


Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication.


Squamous cell carcinoma of the bladder in a patient on intermittent self-catheterization. Squamous cell carcinoma of the bladder has been associated with exstrophy, defunctionalized bladders, chronic infection, cystolithiasis, and chronic indwelling catheters. We report a case of squamous cell carcinoma of the bladder in a woman performing intermittent self-catheterization for the previous 14 years.


Large serotonin-like immunoreactive amacrine cells in the retina of developing Xenopus laevis. The earliest appearance of serotonin-like immunoreactivity (SLI) in different cell types and the development of large SLI amacrine cells were studied in the retina of Xenopus laevis from stage 33/34 to adult. Intense SLI was first found in the somas of large amacrine cells at stage 39. The somas of small amacrine cells showed weak SLI at stage 41, followed by bipolar cells at stage 43. The number of large SLI amacrine cells in the inner nuclear layer of the retina increased from 57 at stage 40 to 774 in adult. Over the same period, retinal area increased from 0.19 mm2 to 24.57 mm2 with an accompanying decrease of cell density from 301/mm2 to 32/mm2. in adult animals large SLI amacrine cells were non-uniformly distributed. Peak cell density of 50-60/mm2 was located in the center of the ventrotemporal quadrant and a trough of 8-15/mm2 in the dorsal periphery of the retina. Peak cell density region of the adult retina corresponded to part of the retina formed at early developmental stages where the rate of cell generation of large SLI amacrine cells was higher. These observations indicate that (1) SLI is expressed first by large amacrine cells, followed by small amacrine and bipolar cells; (2) large SLI amacrine cells are generated continuously throughout life, (3) the non-uniform retinal distribution of large cells results from a spatio-temporally differential cell generation at the ciliary margin.


Brain grafts of migratory GnRH cells induce gonadal recovery in hypogonadal (hpg) mice. Gonadotropin-releasing hormone (GnRH) neurons are derived from the olfactory placode and migrate into the CNS during embryogenesis. During this migration the GnRH neuronal population follows a very specific pathway through the nasal septum and forebrain with individual neurons 'stopping' at various points along the way. Following migration GnRH neurons elaborate axonal projections, the major one to the median eminence. The function of this neurosecretory connection can then be assessed by activation of the pituitary-gonadal axis. In previous experiments we had demonstrated that grafted post-migratory GnRH neurons could send axons to the median eminence and initiate gonadal development in hypogonadal (hpg) mice that lack GnRH. In the present experiment, grafts derived from the embryonic nasal septum, which contains the migratory population of GnRH neurons, were used to determine if the transplanted GnRH neurons could (1) continue their migration in the adult host brain, (2) elaborate axons to their normal target in the host and (3) stimulate the host pituitary-gonadal axis to induce gonadal development. Nasal tissue from normal mouse embryos was implanted into the preoptic area (n = 8), anterior hypothalamus (n = 3) or third ventricle (n = 1) of adult hpg males. Following survival of 10 days to 10 weeks, the distribution of GnRH immunoreactive elements was assessed and testicular weight recorded. Surviving GnRH neurons were few in number and were found within the graft (n = 3), the host brain (n = 2) or both (n = 1). Four grafts resulted in specific outgrowth of GnRH axons through the host parenchyma to the median eminence.(ABSTRACT TRUNCATED AT 250 WORDS)


Alterations of nerve-muscle interaction during postnatal development influence motoneurone survival in rats. The effect of temporary paralysis of rat soleus muscles shortly after birth on motoneurone survival was studied using retrograde labelling with HRP. Following a single application of alpha-bungarotoxin (alpha-BTX) at birth the muscles were paralysed for 24-48 h. The number of HRP-labelled motoneurones in the treated ventral horn of the spinal cord in 10-week-old rats decreased to 63.7% (+/- 2.7 S.E.M.) of the control ventral horn. This motoneurone loss occurs relatively late after alpha-BTX application, for in animals examined at 3-4 weeks of age, the number of labelled motoneurones in the treated ventral horn was not reduced. When paralysis of the soleus muscles was extended to 6-8 days by application of an additional alpha-BTX implant, then by 10 weeks of age only 34.7% (+/- 1.5 S.E.M.) of soleus motoneurones were present. Thus, prolonging the duration of paralysis reduced the number of surviving motoneurones. Furthermore, the mean area of motoneurones that survived alpha-BTX treatment was smaller than that of controls. There was also a shift in the size distribution of the motoneurones in that there was a relative increase in the proportion of small motoneurones. This finding is similar to observations on motoneurone sizes after neonatal nerve injury. Thus, interruption of neuromuscular interaction during early postnatal development causes many motoneurones to die, and in addition alters the size distribution of the remaining cells.


A molecular recognizing system of serotonin in rat fetal axonal growth cones: uptake and high affinity binding. Axonal growth cone particles (AGCP) isolated from prenatal and postnatal rat brain had different high-affinity 5-HT uptake characteristics. In postnatal AGCP the uptake behaves as in the adult rat brain, while in the prenatal AGCP the uptake characteristics seem to be in a transitional stage. Also in prenatal AGCP we observed specific, high-affinity 5-HT binding sites. These results support the idea of an important role for 5-HT during axogenesis.


Hyperactivity and altered amphetamine sensitivity in premature juvenile rats. 'Premature' rats that were delivered by cesarean section on day 21 of gestation and 'normal' rats that were delivered spontaneously on day 22 of gestation were tested for basal locomotor activity and locomotor stimulation in response to D-amphetamine at 19-21 days of age. Compared to normal rats, premature rats had increased basal levels of locomotor activity and showed enhanced sensitivity to the locomotor stimulant effects of D-amphetamine. Cesarean-delivered premature rats may be a useful animal model for investigating mechanisms of neurobehavioral deficits associated with premature birth in humans.


Serotonin 1B receptors form a transient vibrissa-related pattern in the primary somatosensory cortex of the developing rat. Serotonin (5-HT)-immunoreactive axons have a patterned distribution in the primary sensory cortices of developing rodents. This distribution becomes apparent shortly after birth and disappears around the end of the second postnatal week. We employed binding of [125I]cyanopindolol in the presence of isoproterenol to determine whether 5-HT1B receptors have a similar transient spatiotemporal distribution. In rats killed on postnatal day (P-) 8, 5-HT1B receptors have a distribution closely matching that of 5-HT-immunoreactivity. The receptors are very dense in lamina IV of both the primary visual and somatosensory cortices and, like 5-HT immunoreactive axons within the somatosensory cortex, form patches matching the distribution of the mystacial vibrissae. In adult animals, the density of these receptors in lamina IV and the supragranular layers of the visual and somatosensory cortices is reduced relative to that in the surrounding cortex. Autoradiograms of the flattened cortices of adult rats yield a 'negative image' of the pattern observed in perinatal animals. Thus, one subclass of 5-HT receptors, the 5-HT1B receptor, has a spatial distribution in cortex which changes in development much like that for serotoninergic axons.