Effects of nitroglycerin-induced hypotension on myocardial blood flow in a two vessel occlusion-stenosis anesthetized canine model.

The effects of acute occlusion of the left anterior descending coronary artery on regional blood flow (microspheres) to the remote bed supplied by either an unstenosed or a stenosed circumflex coronary artery were assessed during the infusion of intravenous nitroglycerin in 11 open chest barbiturate-anesthetized mongrel dogs. Left anterior descending coronary artery occlusion in the presence of an unstenosed left circumflex artery during nitroglycerin infusion caused systolic aortic and distal circumflex pressure to decrease significantly from 98 +/- 4 to 91 +/- 3 and from 99 +/- 4 to 92 +/- 3 mm Hg, respectively. Remote circumflex bed flow was unchanged. The infusion of intravenous nitroglycerin in the presence of a left circumflex stenosis (gradient 31 +/- 3 mm Hg) reduced systolic aortic and distal circumflex pressure to 98 +/- 2 (p = 0.001) and 71 +/- 4 mm Hg (p = 0.001), respectively, and lowered remote circumflex bed endocardial flow from 1.00 +/- 0.08 to 0.79 +/- 0.07 ml/min per g (p = 0.001). When the left anterior descending coronary artery was occluded under these conditions, systolic aortic and distal left circumflex pressure decreased to 89 +/- 3 (p = 0.005) and 62 +/- 4 mm Hg (p = 0.08), respectively. Remote circumflex artery bed endocardial and transmural flow were significantly reduced to 0.58 +/- 0.07 (p = 0.01) and 0.65 +/- 0.07 ml/min per g (p = 0.03), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial thallium-201 kinetics and regional flow alterations with 3 hours of coronary occlusion and either rapid reperfusion through a totally patent vessel or slow reperfusion through a critical stenosis.

Myocardial thallium-201 kinetics and regional blood flow alterations were examined in a canine model using 3 hours of coronary occlusion and different methods of reperfusion. Group I comprised 10 dogs undergoing a 3 hour left anterior descending artery occlusion and no reperfusion. Group II comprised seven dogs undergoing 3 hours of left anterior descending artery occlusion and rapid reperfusion through a totally patent vessel. Group III comprised 10 dogs undergoing 3 hours of left anterior descending artery occlusion and slow reperfusion through a residual stenosis. All dogs received 1.5 mCi of thallium-201 after 40 minutes of coronary occlusion. During occlusion and 2 hours of reperfusion, serial hemodynamic, blood flow and myocardial thallium-201 activity measurements were made. The relative thallium-201 gradient (normal zone minus ischemic zone activity when initial normal activity is expressed as 100%) during left anterior descending coronary occlusion was similar in all groups. Group I, 87 +/- 3%; Group II, 78 +/- 6%; Group III, 83 +/- 6% (p = NS). After 2 hours of either method of reperfusion, the final relative gradient had decreased to a similar level (Group II, 51 +/- 9%; Group III, 42 +/- 6%). These values were not significantly different from the final relative thallium-201 gradient seen in dogs undergoing a sustained 3 hour occlusion (Group I, 55 +/- 5%). After 2 hours of reperfusion, both methods of reflow were associated with similar degrees of "no reflow." Transmural flows in the central ischemic zone were 89 +/- 10% of normal in Group II and 71 +/- 6% of normal in Group III after reperfusion, with both flows substantially higher than the relative thallium-201 activities in these dogs. Infarct size (percent of left ventricle) determined with triphenyltetrazolium chloride was similar in all groups (Group I, 24 +/- 4%; Group II, 29 +/- 4%; Group III, 25 +/- 4%). Thus, in this experimental canine model, 3 hours of coronary occlusion followed by either rapid reperfusion through a totally patent vessel or slow reperfusion through a critical stenosis resulted in little delayed thallium-201 redistribution or myocardial salvage as assessed histologically, despite significant recovery of regional flow.

Mechanism of remote myocardial ischaemia after coronary occlusion in open chest dogs.

To determine whether or not the fall in coronary perfusion pressure after coronary occlusion is the cause of remote myocardial ischaemia, regional myocardial blood flow was measured using radiolabelled microspheres before and after left anterior descending (LAD) occlusion in the presence of a left circumflex artery stenosis in 22 anaesthetised dogs. Aortic pressure was maintained constant at the time of left anterior descending artery occlusion in 13 dogs (group 1) and proximal left circumflex artery pressure was held constant by a servocontrolled pump in nine dogs with a carotid artery-left circumflex artery shunt (group 2). Despite the maintenance of constant mean aortic pressure in group 1, remote posterior bed mean(SEM) endocardial flow fell from 0.69(0.05) to 0.43(0.07) ml.min-1.g-1 (p less than 0.05). In the dogs in which left atrial pressure rose to less than or equal to 9 mmHg after left anterior descending artery occlusion, remote bed endocardial flow did not fall significantly (0.66(0.07) to 0.56(0.11) ml.min-1.g-1; NS). In contrast, remote bed endocardial flow fell from 0.73(0.07) to 0.28(0.06) ml.min-1.g-1 (p less than 0.0001) after left anterior descending artery occlusion in the dogs in which left atrial pressure rose to greater than 9 mmHg. The fall in remote bed endocardial flow was prevented in group 2 dogs by maintaining proximal left circumflex artery pressure constant (0.95(0.08) to 0.86(0.09) ml.min-1.g-1; NS). An important mechanism for the development of remote myocardial ischaemia appears to be the fall in proximal coronary perfusion pressure at the time of coronary occlusion.

Biologic actions and pharmacokinetic studies of auranofin.

The preclinical profiles of auranofin (Ridaura), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate, gold thioglucose, and their respective ligands were compared. Auranofin was more effective than gold sodium thiomalate in suppressing inflammation and stimulating cell-mediated immunity. In contrast to gold sodium thiomalate and gold thioglucose, auranofin inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. The respective ligands were without significant biologic activity. In rats, a higher fraction of gold was associated with blood cells after auranofin administration than after gold sodium thiomalate. The absorption, distribution, metabolism, and excretion of auranofin are uniquely different from other gold compounds.

Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators.

The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension.

The influence of preoperative shock on outcome in sequential endocardial resection for ventricular tachycardia.

Sequential endocardial resection was used in 92 consecutive patients to treat ventricular tachycardia. All patients had coronary artery disease with previous myocardial infarction. All patients had repeated cycles of mapping and resection of arrhythmogenic foci in the normothermic beating heart until ventricular tachycardia was no longer inducible. Eighty-six patients (93%) survived to hospital discharge. The survival rate in patients normotensive at the time of operation was 98% and in patients in shock at the time of operation, 43%. By Cox regression analysis, preoperative shock was the significant predictor (p less than 0.001) of operative mortality. Seventy-four of the 86 operative survivors (86%) had no sustained ventricular tachycardia at initial postoperative electrophysiologic study when receiving no antiarrhythmic drugs. Eighty-three of the 86 operative survivors (97%) had no sustained ventricular tachycardia at final postoperative electrophysiologic study when using antiarrhythmic drugs as needed. After a median follow-up of 21 months (range 1 to 79 months) there were 4 sudden cardiac deaths, 12 other cardiac deaths, and 3 noncardiac deaths. There were no documented nonfatal episodes of sustained monomorphic ventricular tachycardia after hospital discharge. Use of the sequential endocardial resection technique is effective in curing ventricular tachycardia with low operative morbidity and mortality.

Sequential endocardial resection for the surgical treatment of refractory ventricular tachycardia.

The optimal surgical therapy for refractory ventricular tachycardia is controversial. The usual operation involves induction of tachycardia and endocardial mapping during normothermic cardiopulmonary bypass, followed by systemic hypothermia, aortic cross-clamping, and resection of the identified site of origin of the tachycardia. Our initial experience with this technique in 20 patients (mean age 60 years, mean ejection fraction 29%, mean number of failed antiarrhythmic drugs three) resulted in five (25%) surgical deaths, three caused by ventricular tachycardia and two by respiratory or heart failure. Electrophysiologic study showed that 11 of 15 survivors were free from ventricular tachycardia after operation, for a success rate in the survivors of 73%. Most failures occurred in patients with multiple tachycardia morphologies that were not eradicated by initial resection. Thereafter, the technique of sequential endocardial resection was used. After completion of endocardial mapping, directed normothermic endocardial resection is performed; more attempts to induce ventricular tachycardia are made and followed by further mapping and resection until tachycardia can no longer be induced. Fifty patients (mean age 59 years, mean ejection fraction 33%, mean number of failed antiarrhythmic drugs three) were treated by this method, with a mean of two resections per patient (range one to six). Mean perfusion time in the sequential resection group (101 +/- 28 minutes) was not significantly different from that of the earlier patients (101 +/- 40 minutes). There were four (8%) surgical deaths, one caused by persistent arrhythmia and three caused by respiratory or heart failure. Electrophysiologic study after operation showed that 40 of 46 survivors (87%) were free of ventricular tachycardia. Symptoms in the six with inducible tachycardia on postoperative electrophysiologic study were well controlled with medication. These data suggest that sequential endocardial resection guided by intraoperative mapping is a highly effective operative approach for patients with ventricular tachycardia.

Growth potential of porcine reduced-size mature pulmonary lobar transplants.

The use of mature pulmonary lobes for pediatric lung transplantation has recently been described. Successful application of this technique could help alleviate the pediatric donor lung shortage. Whether an already mature lobe can grow by forming new alveolar units after transplantation into a developing recipient is not known. We therefore measured functional residual capacity, fixed lung volume and weight, alveolar size and air space volume percent, and total number of alveoli in mature left lower lobe porcine lung transplants 12 weeks after transplantation into growing piglets. Comparisons were made with nontransplanted mature left lower lobes to determine if functional or morphologic growth had occurred after transplantation. The transplanted and control lobes were all taken from 6-month-old animals (mean body weight 105 +/- 4 kg). Recipients of the transplanted lobes were 9 weeks old and weighed 22 +/- 2 kg. By the end of the 12-week holding period, the recipient animals increased their body weight approximately fourfold (85 +/- 4 kg). No significant differences were seen in functional residual capacity or morphologic analysis of total alveolar number and alveolar size between the transplanted and nontransplanted lobes (p = not significant). Although the reduced-size mature porcine lobar transplants did not display a significant increase in either functional residual capacity or total alveolar number, there was significant growth of the transplanted mature lobes as determined by fixed volume and total lobar weight (p < or = 0.05 versus control animals).

Airway obstruction after autologous reimplantation of the porcine lobe.

Bronchiolitis obliterans (irreversible small airway obstruction) is a late complication of heart-lung transplantation. Chronic immune rejection is believed to be the major cause of this complication. Our hypothesis was that denervation might contribute to airway obstruction. To test this hypothesis in the absence of immune rejection, we performed a lobectomy of the upper lobe of the left lung and autologous reimplantation of the lower lobe of the left lung in 13 growing pigs. To serve as age-matched controls, six other pigs had sham left thoracotomy and nine others had a lobectomy of the upper lobe of the left lung alone. Nine to 10 weeks after operation, the animals were anesthetized and the lungs mechanically ventilated. The lobes were then isolated in vivo to measure differential transrespiratory mechanics and volumes. Dynamic compliance was significantly lower in the reimplanted lobe than it was in the contralateral right lung. This was the case after lobectomy of the upper lobe of the left lung or sham thoracotomy. Dynamic resistance was significantly higher in the reimplanted lobe than it was in the contralateral right lung and in the left lung after sham thoracotomy. Measurements of extravascular lung water, dry lobe weight, alveolar cross-sectional area, and volumetric proportions of lung parenchyma and alveolar spaces did not demonstrate abnormal structural growth after reimplantation. We conclude that lobectomy of the upper lobe of the left lung and autologous reimplantation of the left lower lobe leads to adverse changes in flow-dependent measurements of airway patency. Changes in bronchomotor regulation imposed by denervation may contribute to airway obstruction after heart-lung transplantation.

Denervation of the immature porcine lung impairs normal airway development.

Reimplantation or allotransplantation of the immature porcine left lower lobe results in long-term functional dynamic airway obstruction that is associated with abnormally small distal airways. We have attributed this small airway size to bronchoconstriction resulting from chronic denervation rather than to impaired airway growth. To further investigate these findings, we transplanted mature left lower lobes from adult pigs into young piglets after left pneumonectomy. After approximately 12 weeks of somatic growth, the lobes were harvested and fixed through the airways with formalin. Cross-sectional areas of terminal, noncartilaginous airways from the lung periphery were traced on a video monitor. Five groups were examined: control innervated mature left lower lobes, innervated left lower lobes subjected to compensatory growth after left upper lobectomy at approximately 9 weeks of age, mature left lower lobe transplants, reimplanted immature left lower lobe autografts, and transplanted immature left lower lobe allografts. Unlike the immature porcine lobe, transplantation of the mature porcine lobe does not result in abnormally small airways. The small airways seen after transplantation or reimplantation of the immature porcine lobe are likely, therefore, to be due to impaired airway development and not to bronchoconstriction caused by denervation.

Assessing clamp-related vascular injuries by measurement of associated vascular dysfunction.

The development of vascular clamps requires a reliable method to quantitate clamp-related vascular injuries. The degree of vessel damage usually is estimated subjectively from photomicrographs made with scanning electron microscopy. In order to test whether the use of vascular rings to assess residual vascular function may be a better method, rabbit thoracic aortas were occluded by five types of clamps: a Fogarty softjaw bulldog, a Fogarty Hydragrip, a 6-inch Satinsky clamp, an Edslab bulldog, and a silicone vessel band. Each area of clamp injury was sectioned into a vascular ring and suspended in a tissue bath. Residual vascular function was determined by contraction in response to phenylephrine and by relaxation in response to methacholine chloride and sodium nitroprusside. Morphologic studies with use of Evans blue dye and scanning electron microscopy complemented the vascular-function studies. The Fogarty bulldog clamp was the best at preserving vascular contraction and relaxation; the more crushing Satinsky clamp was the worst. The testing of vascular rings for residual function appears to be a useful technique for objectively quantitating vascular clamp-related vascular damage.

Vena caval involvement with renal tumors: surgical considerations.

We reviewed the experience at the University of Virginia over the past 10 years with renal tumors involving the inferior vena cava. There were 107 patients with renal tumors, 41 with invasion of the renal vein and 18 with involvement of the inferior vena cava. The groups with and without vena caval tumors were compared, and the operative approach is described. Although the rate of complications was higher in operations on the vena cava, none were fatal and no patient required chronic dialysis. Life-table analysis revealed that patients with involvement of the inferior vena cava survived longer than those with incomplete resection. Because extraction of these tumors can be accomplished with acceptable morbidity and mortality, because complete resection confers a survival advantage, and because chemotherapy and radiation are ineffective, we recommend aggressive workup and resection of renal tumors involving the inferior vena cava.

Coronary artery bypass grafting in patients with ventricular fibrillation.

The role of coronary artery revascularization in the management of survivors of cardiac arrest remains controversial. Patients with sustained monomorphic ventricular tachycardia rarely respond to revascularization, but the response of patients with ventricular fibrillation as their basic arrhythmia has not been characterized. Coronary artery bypass grafting was performed in 8 patients with a history of cardiac arrest known to be caused by ventricular fibrillation without preceding sustained monomorphic ventricular tachycardia. All patients had critical double-vessel or triple-vessel coronary artery disease, and 7 of 8 had wall motion abnormalities from a prior myocardial infarction. After successful operation, 5 patients had no spontaneous arrhythmias and no inducible arrhythmias at a postoperative electrophysiological study. Three patients, however, had spontaneous, recurrent episodes of ventricular fibrillation unassociated with recurrent ischemia. Clinical factors were not useful predictors of response. The effect of coronary artery revascularization in patients with ventricular fibrillation is unpredictable, and full postoperative electrophysiological evaluation is necessary to judge the success of the procedure.

Reduced-size porcine lung transplantation: long-term studies of pulmonary vascular resistance.

The use of isolated adult lobes for pediatric lung transplantation has recently been reported and could potentially help alleviate the profound pediatric donor lung shortage. However, the effect of chronic denervation on pulmonary vasculature of isolated mature lobar transplants is not well understood. Previously, we reported that chronic denervation of the immature porcine lobe results in abnormal pulmonary vascular compliance. We now present studies of long-term pulmonary hemodynamics in young pigs 12 weeks after transplantation of a reduced-size mature left lower lobe. Resting pulmonary vascular resistance of the transplanted mature lobes was similar to that of innervated lobes of age-matched controls. In addition, pulmonary vascular resistance of the transplanted mature lobes did not rise abnormally in response to increased flow caused by clamping the contralateral pulmonary artery. We conclude that denervation of the mature porcine lobe does not result in abnormal pulmonary vascular resistance. In addition, vascular compliance of reduced-size mature porcine lobar transplants is superior to that of denervated reimplanted immature lobes. These findings suggest a deleterious effect of denervation on pulmonary vascular development of the growing porcine lung.

Transhiatal esophagectomy: a safe alternative for selected patients.

One hundred one consecutive patients underwent an esophagectomy with gastric interposition for benign and malignant processes from January 1982 through July 1990. Seventy-seven underwent transhiatal esophagectomy and 24, transthoracic esophagectomy. Multivariate analysis was performed comparing the hospitalization experience of the two groups. There was no significant difference found between the mean intraoperative blood loss for transhiatal esophagectomy (770 +/- 105 mL) and that of transthoracic esophagectomy (700 +/- 175 mL). There was a significant difference between operative time, with transhiatal esophagectomy averaging 5.4 hours and transthoracic esophagectomy averaging 7.3 hours. Postoperative stay was not significantly different although there was a wide range of values for the transthoracic esophagectomy group. An 8% operative mortality was experienced by both groups. There were a significant number of minor anastomotic leaks at the cervical anastomotic level for the transhiatal esophagectomy group, but all responded to nonoperative management. The highest morbidity and mortality were seen in the subgroup of transhiatal esophagectomies done for laryngocervical malignancies. The lowest morbidity and mortality were seen in the subgroup of 12 patients who underwent transhiatal esophagectomy for nonmalignant esophageal conditions. Transhiatal esophagectomy appears to be a safe alternative for early intrathoracic esophageal malignancies at any level, for bulky distal esophageal lesions, and for benign conditions requiring total esophagectomy.

Decreased vascular compliance after reimplantation of the left lower lobe in young pigs.

The effects of chronic denervation on pulmonary vasculature are not well understood. Three groups of young pigs were prepared: (1) those receiving sham thoracotomy, (2) those having left upper lobectomy alone (innervated left lower lobe), and (3) those receiving left pneumonectomy followed by reimplantation of the left lower lobe (denervated left lower lobe). At 10 weeks after operation, animals were anesthetized and instrumented for study. No changes in baseline pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, or pulmonary vascular resistance were observed. With diversion of the entire cardiac output to the left lung or lobe, however, the group with reimplanted lobes had a significantly higher pulmonary artery pressure and pulmonary vascular resistance than the other groups. This may result from chronic denervation of the pulmonary vasculature and receptor upregulation.

Incidence and risk of reintervention after coarctation repair.

We examined the need for intervention after coarctation repair in a retrospective study of 197 procedures performed between 1967 and 1989. Reintervention was required in 23 patients. No technique of coarctation repair was free from complications. Although there were only two stenoses in the group receiving Dacron patch angioplasty, only seven of these procedures were performed in children under the age of 1 year. The risk of stenosis was inversely correlated to the age at primary repair, with children less than 1 year old being at greater risk than those more than 1 year of age (p less than 0.05). Subclavian flap angioplasty had a lower risk of reoperation than end-to-end anastomosis (p less than 0.02). Formation of true aneurysms was confined to the Dacron patch angioplasty group. The morbidity and mortality for reintervention was low in all groups, with only one procedure-related death and no incidence of paraplegia. Although no technique is free from risk, subclavian flap angioplasty leads to fewer reinterventions in younger patients.

Does a posterior aneurysm increase the risk of endocardial resection?

The bias has been that the ideal anatomic circumstance for endocardial resection is the anterior left ventricular location. Posterior left ventricular aneurysms have been thought to be problematic to map and more difficult to close, and possibly to have a different substrate for ventricular tachycardia. To address this problem, we retrospectively reviewed the cases of 110 consecutive patients who underwent sequential endocardial resection for ventricular tachycardia between 1983 and 1991. Ninety-six patients had an anterior aneurysm, and 14 patients had a posterior aneurysm or infarct. Operative survival and 5-year survival were very similar between the two groups (p = not significant). A positive postoperative electrophysiological study was present in 11% of the anterior group versus 14% of the posterior group (p = not significant). There was a significantly greater incidence of mitral valve replacement in the posterior group, and we believe this was most likely due to frequent localization of the arrhythmia to the papillary muscle. Otherwise, patients with a posterior aneurysm or infarct had surgical results equivalent to those in patients with an anterior location. As long as there is a discrete aneurysm or infarct, endocardial resection is a safe and effective therapeutic procedure for ventricular tachycardia.

Successful treatment of postoperative chylothorax using an external pleuroperitoneal shunt.

We report 3 patients with chylothorax who were successfully managed as outpatients using external pleuroperitoneal shunts. This external shunt has the advantage over subcutaneously placed shunts of pumping large volumes of fluid with each compression of the pumping chamber, of not causing the discomfort associated with pumping a subcutaneous chamber, of not becoming difficult to find in the subcutaneous space, and of being constructed of larger components which do not kink or become easily clogged with fibrinous debris.

Denervation of transplanted porcine lung causes airway obstruction.

Lung transplantation can be complicated by a form of small airway obstruction known as bronchiolitis obliterans. We tested the hypothesis that lung denervation causes small airway obstruction in young pigs (10 +/- 1 weeks). Control pigs had an innervated native lobe, and study pigs had either a denervated native lobe or a denervated transplant lobe. Transplanted pigs received standard immunosuppression. At 10 weeks we measured isolated left lobe pulmonary mechanics. Dynamic resistance in both study groups was significantly higher than in the lobectomy group, whereas dynamic compliance in both study groups was significantly lower than in the lobectomy group. No significant difference in resistance or compliance was noted between the transplant and reimplant groups. Histologic changes consistent with rejection were noted in the transplant lobes. We conclude that the small airway obstruction noted in this model is due to operative denervation rather than to immunosuppression or rejection.