Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury.

Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia-reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage-produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE(-/-) mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti-HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE(-/-) mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in Jα18(-/-) mice reconstituted with RAGE(-/-) iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia-reoxygenation, alveolar macrophage-derived HMGB1 augmented IL-17 production from iNKT cells in a RAGE-dependent manner. These results suggest that HMGB1-mediated RAGE activation on iNKT cells is critical for initiation of lung IR injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung IR injury.

Sustained ventricular tachyarrhythmias within 2 months of acute myocardial infarction: results of medical and surgical therapy in patients resuscitated from the initial episode.

Sustained ventricular tachycardia or fibrillation that develops during the early recovery period after acute myocardial infarction is a common clinical problem whose management remains controversial. Fifty-three patients who survived an initial episode of sustained ventricular tachycardia or fibrillation occurring between 3 and 60 days (mean +/- SD 21 +/- 16) after myocardial infarction were evaluated. Most of these patients had had a large (peak creatine kinase = 1,729 +/- 882 IU) complicated infarction. Forty-two (79%) of the 53 patients had had repetitive sustained ventricular arrhythmias and the condition of 19 of these could not be stabilized with drug therapy. Twenty-eight patients received medical therapy only. Twenty-four survived and were discharged from the hospital. Twenty-five patients underwent infarctectomy or aneurysmectomy either on an emergency basis (16 patients) or electively because of coexistent heart failure or angina (9 patients). Intraoperative mapping was attempted in these patients but was completely successful in only 13 (52%). Operative mortality was 16% with all deaths occurring in patients who were in shock before surgery. Five of 21 surgically treated survivors required long-term antiarrhythmic therapy. Twenty-one of 24 patients medically treated remain alive and well after 15 +/- 10 months of follow-up. Nineteen of 21 surgically treated patients remain alive and well after 17.9 +/- 11 months. One of these patients required reoperation for severe mitral regurgitation. These results confirm the poor medical prognosis of sustained ventricular tachyarrhythmias that present during the first 2 months after myocardial infarction but demonstrate that an acceptable rate of survival can be achieved with a combined medical and surgical approach to therapy.

Use of a regional wall motion score to enhance risk stratification of patients receiving an implantable cardioverter-defibrillator.

OBJECTIVES: We postulated that preoperative assessment of both regional wall motion and left ventricular ejection fraction would serve as an accurate prognostic indicator of long-term cardiac mortality and functional outcome in patients treated with an implantable cardioverter-defibrillator. BACKGROUND: Long-term cardiac mortality has remained high in patients receiving an implantable cardioverter-defibrillator. The ability to risk stratify patients before defibrillator implantation is becoming increasingly important from a medical and economic standpoint. METHODS: The hypothesis was retrospectively tested in 74 patients who had received an implantable cardioverter-defibrillator. Left ventricular ejection fraction and regional wall motion score, derived from centerline chord motion analysis, were calculated for each patient from the preoperative right anterior oblique contrast ventriculogram. Wall motion score was the only significant independent predictor of long-term cardiac mortality and functional status by multivariate analysis because of its enhanced prognostic capability in patients with an ejection fraction in the critical range of 30% to 40%. RESULTS: Patients with an ejection fraction > 40% had a 3-year cardiac mortality rate of 0% compared with 25% for those with an ejection fraction of 30% to 40% and 48% for those with an ejection fraction < 30% (p < 0.05). Similarly, 75% of patients with an ejection fraction > 40% were in New York Heart Association functional class I or II during long-term follow-up compared with 59% of those with an ejection fraction 30% to 40% and 29% of those with an ejection fraction < 30%. Among patients with an ejection fraction of 30% to 40%, those with a wall motion score > 16% had a 3-year cardiac mortality rate of 0% compared with 71% of those with a wall motion score < or = 16% (p = 0.002). In addition, 86% of patients with a wall motion score > 16% were in functional class I or II during long-term follow-up compared with 13% of those with a wall motion score < or = 16% (p = 0.001). CONCLUSIONS: Long-term cardiac mortality and functional outcome in patients receiving an implantable cardioverter-defibrillator can be predicted if the left ventricular ejection fraction and regional wall motion score are measured preoperatively.

Surgical treatment of the failing heart.

Heart failure is one of the leading causes of hospitalization worldwide. Currently, most therapeutic strategies are aimed at resolving the acute exacerbation of failure, resulting in a high readmission rate. Despite significant advances in the medical treatment of heart failure, the results are far from perfect. Mortality remains high and hospitalization costly. Surgical management is still required for patients with end-stage heart failure. Unfortunately, its evolution has occurred in a less structured fashion. In addition to transplantation, strategies for the treatment of heart failure currently under investigation include implantation of pacemakers, left ventricular reconstruction, mitral valve repair, coronary revascularization, cardiomyoplasty and mechanical circulatory support. In the end however, the surgical management of patients with heart failure rests on the type of underlying cardiomyopathy. Hence, care must be taken to accurately diagnose these patients as either having dilated or ischemic cardiomyopathy.

Atypical carcinoid tumor of the lung. A clinicopathologic study of 17 cases.

We describe 17 atypical carcinoid tumors of the lung that are histologically intermediate between small-cell undifferentiated carcinoma and typical carcinoid tumor. Atypical carcinoid tumors have a distinctive microscopic pattern of nests, trabeculae, and ribbons of intermediate-sized, moderately pleomorphic cells that lack the nuclear molding and dense hyperchromasia of small-cell undifferentiated carcinoma. Mucin was present in 15 cases and nine contained argyrophilic granules. The three primary tumors and one metastasis studied ultrastructurally contained dense-core granules and variable degrees of squamous and glandular differentiation. Eleven patients were men; six were women. Their mean age was 58 years. Sixteen patients were known smokers. Twelve tumors involved the upper lobes and three were located in the right middle lobe. Mean tumor size was 4.9 cm (median 4; range 2.5--20). Four of 13 patients having potentially curative resection died of tumor. The other nine patients were disease free with a mean follow-up of 20 months. Four additional patients treated palliatively died.

Comparison of the usefulness of the implantable cardioverter-defibrillator and subendocardial resection in patients with sustained ventricular arrhythmias and poor regional wall motion associated with coronary artery disease.

The implantable cardioverter-defibrillator (ICD) and subendocardial resection are effective forms of therapy for sustained ventricular arrhythmias associated with coronary artery disease in selected patients. The relative efficacy of these 2 treatments in equivalently matched patients is not known. A regional wall motion score has been shown to be a powerful predictor of long-term outcome after both ICD implantation and subendocardial resection. This study retrospectively analyzed the long-term outcome of patients with coronary artery disease and ventricular arrhythmias treated during the same period with an ICD (n = 53) or by subendocardial resection (n = 65). Treatment outcomes were compared in subgroups determined by preoperative regional wall motion scores of either < or = 16 or > 16%. The 3-year cardiac mortality of the 2 therapies was not significantly different among patients with a wall motion score of > 16% (0% ICD vs 11% endocardial resection) or of < or = 16% (41% ICD vs 35% endocardial resection). Similarly, the 3-year sudden cardiac death mortality was similar among patients with a score of > 16% (0% for both ICD and endocardial resection) or of < or = 16% (9% ICD vs 14% endocardial resection, p = NS). At 24 months after hospital discharge, the percentage of patients who were in New York Heart Association functional class I or II was similar among patients with a wall motion score of > 16% (75% ICD vs 86% endocardial resection, p = NS) or with a wall motion score of < or = 16% (26% ICD vs 45% endocardial resection, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of magnesium ion on human ventricular defibrillation after aortocoronary bypass surgery.

The administration of magnesium ion (Mg++) has been reported to defibrillate the ventricles and to decrease the incidence of arrhythmias after cardiopulmonary bypass. In a prospective study of 76 randomly selected patients undergoing coronary artery bypass grafting, patients received either no Mg++, 0.25 mEq/kg of Mg++ during cardiopulmonary bypass with the aorta clamped, or 0.375 mEq/kg of Mg++ before cardiopulmonary bypass. Spontaneous resumption of a cardiac rhythm or spontaneous defibrillation during reperfusion was not significantly affected by Mg++ administration. However, the number of shocks to initial and to sustained defibrillation and the energy required for the last direct-current shock was greatest in patients who received Mg++ before bypass and in those whose plasma Mg++ was greater than 2.26 mg/dl. Thus, the administration of Mg++ may have adverse effects on the heart if intraoperative plasma Mg++ exceeds 2.26 mg/dl.

Getting funded.

Getting funded is still possible for cardiothoracic surgeons. You must have a clear hypothesis, have an organized approach, and develop excellent preliminary data. Most important, you need to apply to get funded.

Getting promoted.

Promotion is an active process. At the beginning of his or her academic career, the surgeon should begin planning for this process. Surgeons need to understand the promotion documents at their institutions and to have a timetable for achieving tenure at the appropriate time.

Extended subendocardial resection. A surgical approach to ventricular tachyarrhythmias that cannot be mapped intraoperatively.

The optimal surgical management of patients with sustained, uniform-morphology ventricular tachycardia is endocardial activation sequence mapping during ventricular tachycardia and directed resection and/or cryoablation of the involved endocardium. The results of these procedures are superior to those obtained with nondirected aneurysmectomy. The optimal operative procedure when stable uniform ventricular tachycardia cannot be induced intraoperatively is uncertain. Between April, 1982, and April, 1984, intraoperative endocardial mapping was attempted on 33 patients with prior ventricular tachycardia. There were six perioperative deaths. Completely satisfactory intraoperative electrophysiologic maps were obtained in only 17 of the remaining 27 patients (63%). In 10 of these 27 patients, stable ventricular tachycardia could not be induced in the operating room, and satisfactory mapping thus could not be performed. In the first three of these 10 patients, limited subendocardial resection was performed either in regions with fractionated activity during sinus rhythm (two patients) or in regions suggested by preoperative catheter mapping (one patient). Ventricular tachycardia recurred postoperatively in two of these three patients. In the next seven patients, all visible endocardial scar around the border of the aneurysm was resected. Clinical ventricular tachycardia could not be induced at postoperative electrophysiologic study and has not recurred in these seven patients. These results suggest that complete endocardial resection provides an acceptable operative approach when intraoperative electrophysiologic mapping is not satisfactory.

Probing of the canine mammary artery damages endothelium and impairs vasodilation resulting from prostacyclin and endothelium-derived relaxing factor.

It is routine practice for many cardiac surgeons to probe internal mammary arteries to dilate them before their use. The effects of such probing on endothelium integrity, prostacyclin production, and vasodilation resulting from endothelium-derived relaxing factor and from prostacyclin were investigated in vessels isolated from mongrel dogs. Dose-dependent relaxation responses of isolated segments of probed and unprobed mammary arteries to the endothelium-dependent vasodilators methacholine, calcium ionophore (A23187), and melittin were determined in both the presence and absence of indomethacin. Prostacyclin production by probed versus unprobed vascular segments was determined under basal and A23187-stimulated conditions by radioimmunoassay for 6-keto-prostaglandin F1 alpha, and endothelial integrity was determined by scanning electron microscopy. Scanning electron micrographs of segments revealed marked endothelial cell disruption in probed versus unprobed vessels. The dose-dependent relaxation responses to all drugs studied were significantly impaired (p less than 0.05) in probed versus unprobed vessels in both the presence and absence of indomethacin. In addition, prostacyclin release as measured by production of 6-keto-prostaglandin F1 alpha was significantly (p less than 0.05) impaired in probed versus unprobed vessels under both basal and A23187-stimulated conditions. These results imply that routine probing of the internal mammary artery may damage endothelium, impair prostacyclin production, and impair endothelium-dependent vasodilation resulting from both prostacyclin and endothelium-derived relaxing factor.

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.

Evaluation of postoperative flow reserve in internal mammary artery bypass grafts.

The internal mammary artery has been advocated for use in bypass grafting owing to its superior long-term patency when compared to saphenous vein grafts. Concern exists that the flow through the internal mammary artery may be inadequate during periods of peak myocardial demand. This flow was investigated in 24 consecutive patients with a mean proximal left anterior descending artery stenosis of 87.5% who were selected for coronary bypass using the internal mammary artery. Within 8 weeks of operation, all were evaluated by exercise thallium 201 scintigraphy. Thallium activity, expressed as a ratio of anteroseptal activity to posterolateral wall activity (or inferior wall activity if the posterolateral wall was deemed abnormal), was 0.97 +/- 0.15. A second group of 25 patients, with normal coronary arteries, was similarly evaluated. The mean septal to posterolateral wall thallium activity ratio for these control patients was 1.0 +/- 0.15. A third group of 26 patients who underwent single-vessel percutaneous transluminal coronary angioplasty of the left anterior descending artery and a fourth group of 28 saphenous vein graft recipients were compared by stress thallium scintigraphy. Thallium 201 activity for the vein graft group (0.96 +/- 0.19) was not significantly different from that for the mammary artery group, whereas the flows obtained with a single attempt at angioplasty were significantly inferior (p less than 0.05). The internal mammary artery provides excellent coronary flow at peak myocardial demand and compares favorably to angioplasty and saphenous vein grafting.

The effect of renin-angiotensin system blockade on visceral blood flow during and after thoracic aortic cross-clamping.

Surgical procedures necessitating clamping of the thoracic aorta are associated with a high incidence of postoperative renal dysfunction. Plasma renin activity is elevated during and after thoracic aortic occlusion in animals. The pathophysiology of the renal dysfunction may involve the renin-angiotensin system. Blockade of the renin-angiotensin system was studied in a canine model during occlusion of the thoracic aorta. Saralasin, a competitive blocker of angiotensin II, and the converting enzyme inhibitor MK422 were studied. Sixteen animals were separated into three treatment groups: control (five animals), saralasin (five), and MK422 (six). All dogs underwent clamping of the thoracic aorta for 60 minutes. In control animals, plasma renin activity increased from 0.16 +/- 0.04 to 6.41 +/- 1.57 ng/ml/hr at 30 minutes after thoracic aortic occlusion (p less than 0.05). Thirty minutes after cross-clamp release, plasma renin activity remained 10 times greater than baseline, 1.47 +/- 0.20 ng/ml/hr (p less than 0.05). Renal blood flow was measured with 15 micron microspheres before, during, and after thoracic clamping. In control animals, renal cortical blood flow decreased during cross-clamping and remained below baseline after clamp release: baseline, 7.05 +/- 0.98 ml/gm/min (standard error of the mean); 30 min after clamp release, 3.77 +/- 0.43 ml/gm/min (standard error of the mean) (p less than 0.05). In the MK422 group, renal cortical blood flows returned to baseline after cross-clamp release: baseline, 6.38 +/- 0.49 ml/gm/min; 30 minutes after clamp release, 7.30 +/- 1.6 ml/gm/min. Infusion of MK422 after placement of the thoracic aortic cross-clamp resulted in normal renal blood flow after clamp release. This protective effect was not seen with saralasin. The resumption of normal renal cortical blood flow after the administration of the converting enzyme inhibitor MK422 suggests that elevated plasma renin activity may contribute to renal dysfunction after thoracic aortic occlusion.

Fibrin glue application through the flexible fiberoptic bronchoscope: closure of bronchopleural fistulas.

Closure of bronchopleural fistulas can be accomplished by applying fibrin glue through a flexible fiberoptic bronchoscope. The advantages of this method include the avoidance of general anesthesia and thoracotomy and the excellent extended access to the bronchial tree provided by the flexible bronchoscope.

Complete prevention of postischemic spinal cord injury by means of regional infusion with hypothermic saline and adenosine.

Spinal cord injury after operations on the descending thoracic and thoracoabdominal aorta remains a persistent clinical problem. Previous attempts to decrease the risk of this devastating complication by lowering the rate of metabolism of the spinal cord have met with varying success. We hypothesized that the tolerance of the spinal cord to an ischemic insult could be improved by means of adenosine. Twenty New Zealand white rabbits underwent 40 minutes of isolated infrarenal aortic occlusion after heparin anticoagulation. Clamps were placed both below the left renal vein and above the aortic bifurcation. In 10 rabbits (group A), a bolus of adenosine (100 mg) was infused into the isolated aortic segment immediately after crossclamping and this bolus was followed by a flush of hypothermic saline (8 degrees C, 30 ml/kg) over the first 10 minutes of ischemia. In one control group of five animals (group B), the descending infrarenal aorta was crossclamped without infusion of adenosine or saline. In another control group of five animals (group C), the aortic segment was flushed with normothermic saline (37 degrees C) in a fashion identical to that of the study group. The aortic clamps were removed after 40 minutes, the abdomen was closed, and the animals were allowed to recover from anesthesia. Spinal cord function was assessed 12, 24, 48, 72, and 96 hours after operation by the Tarlov scale. All animals were put to death at 96 hours after operation and spinal cords were harvested for histologic analysis. The spinal cord function of all group A animals was fully intact with Tarlov scores of 5; group B and group C animals were all paraplegic with Tarlov scores of 0 (p < 0.001, general linear models analysis of variance). Histologic examination of spinal cords from group A rabbits revealed no evidence of cord injury, whereas spinal cords from groups B and C had evidence of extensive cord injury with central gray necrosis, axonal swelling, dissolution of Nissl substance, and astrocyte and macrophage infiltration. Regional infusion of the crossclamped infrarenal rabbit aorta with hypothermic saline and adenosine completely prevented paraplegia in our model despite a 40-minute ischemic insult.

Safe ex vivo coronary angiography with isosmotic contrast agent.

Plain-film coronary angiography of the cardiac explant on the operating table should be considered when conventional cardiac catheterization is desired but unavailable. We compared the effects of three contrast solutions on cold-preserved, isolated guinea pig hearts. Hearts were excised, perfused for 30 minutes, and arrested with Plegisol solution at 7 degree C. Twenty minutes after arrest, experimental hearts were perfused with one of three solutions: hyperosmolar Hexabrix solution (n = 6), hyperosmolar Renografin-76 solution (n = 6), or diluted, isosmotic Omnipaque solution (n = 8). The hearts were flushed with cold Plegisol solution 5 minutes later. Control hearts received no contrast during arrest (n = 9). The hearts were reperfused after 1 hour of arrest, and coronary blood flow (in millimeters per minute), left ventricular developed pressure (in millimeters of mercury), and rate of developed pressure (in millimeters of mercury per second) were measured. Endothelium-dependent smooth muscle relaxation to bradykinin administration and endothelium-independent relaxation to sodium nitroprusside administration were also assessed. No significant difference in myocardial or endothelial function was noted between control hearts and hearts perfused with Omnipaque solution. Hearts perfused with Renografin solution or Hexabrix solution, however, were found to have significantly impaired endothelial and myocardial function. We conclude that an isosmotic contrast solution should be used for ex vivo coronary angiography in cold-preserved hearts to avoid impairment of endothelial and myocardial function.

Interrupted aortic arch. A conservative approach for the sick neonate.

Interrupted aortic arch with associated ventricular septal defect is a congenital cardiovascular defect which, untreated, is lethal in nearly 100% of the cases. We have treated nine patients by reconstructing the aorta with endogenous arch vessels; in five of them, concomitant pulmonary artery banding was also done. If two infants with preoperative complete renal failure are excluded, the mortality with this approach is only 29%. Long-term follow-up of these patients demonstrates excellent hemodynamic results with marked reduction of the anastomotic gradient in the older survivors. Growth of the anastomosis has been noted in the older survivors.

Chylothorax: an assessment of current surgical management.

The development of chylothorax is a serious and often life-threatening clinical entity. Optimal management of this problem has not been well defined to date. We reviewed our experience with chylothorax in patients of all ages during the past 10 years. Ages ranged from 2 days to 69 years. The etiologies were traumatic in 17 and congenital or idiopathic in three. Six patients (five infants) were treated nonoperatively with either repeated thoracenteses or chest tube drainage. Fourteen patients (11 infants) underwent operative treatment: transthoracic thoracic duct ligation (five patients), pleuroperitoneal shunting (seven), pleuroperitoneal shunting combined with reoperation on a patient with congenital heart disease (one), and reoperation alone on a patient with congenital heart disease (one). Duration of preoperative therapy ranged from 9 days to 2 months (average 3.3 weeks). Five of six (83.3%) patients treated nonoperatively died. Of the surgically treated group, only two of 14 (14.3%) died, and 11 of the 12 survivors had resolution of the chylothorax and immediate clinical improvement. Our experience suggests that both pediatric and adult patients respond poorly to nonoperative treatment of chylothorax and that this treatment has a high mortality rate. Post-traumatic and congenital chylothorax should be treated operatively after a limited trial (1 to 2 weeks) of nonoperative therapy. Pleuroperitoneal shunting may offer a reasonable and effective alternative to thoracotomy and thoracic duct ligation.

A reappraisal of limited-stage undifferentiated carcinoma of the lung. Does stage I small cell undifferentiated carcinoma exist?

Patients with small cell undifferentiated carcinoma of the lung (SCUC) have a poor prognosis. Surgical excision is avoided if the diagnosis can be made with small biopsy specimens or cytologic preparations. We reviewed 323 consecutive patients with pulmonary neoplasms diagnosed as SCUC, oat cel carcinoma, and undifferentiated or poorly differentiated carcinoma. At the time of diagnosis, only 18 patients had neoplasms classified as clinical Stage I, and only one of these had SCUC after histologic review. Fifteen patients had atypical carcinoid, a tumor with features intermediate between ordinary bronchial carcinoid and SCUC. In two instances, there was insufficient tissue for definitive diagnosis. Cumulative survival of the 15 patients with Stage I atypical carcinoid tumor was 80% at 1 year and 60% at most recent follow-up (mean follow-up 20 months). Mean survival for the 305 remaining patients was 7.9 months. Atypical carcinoid may be misdiagnosed as SCUC or poorly differentiated carcinoma, particularly with limited tissue samples or cytologic preparations. Stage I SCUC exists but is exceedingly rare. Many examples of purported Stage I SCUC probably represent atypical carcinoid. Because atypical carcinoid has a far better prognosis than SCUC, precise diagnosis is important and surgical resection should be considered.