Surgery for acute type a aortic dissection: comparison of techniques.

OBJECTIVE: In order to determine the optimal surgical strategy for acute ascending aortic dissection, the graft inclusion technique was compared with the open resection technique. METHODS: Between 1985 and 1995 a consecutive series of 193 patients (77% male, mean age 58 years) had emergency surgery during a mean interval of 13.2 h after onset of symptoms. Graft replacement of the ascending aorta was performed in all patients (supracoronary graft 143/193=74%, aortic root replacement 50/193=26%, aortic valve replacement 73/193=38%, arch replacement 44/193=20%) The open resection technique was applied in 93 patients and the inclusion technique in 100 patients with a Cabrol-shunt in 26%. Preoperative risk factors were equally distributed between groups (inclusion technique vs. open technique): left ventricular ejection fraction<45% (13 vs. 2%, not significant (n.s.)), neurological deficit (31 vs. 25%; n.s.), systolic blood pressure<90 mm Hg (20 vs. 15%, n.s.) pericardial tamponade (25 vs. 9%, n.s.), renal failure (6 vs. 4%; n.s.). RESULTS: The overall early mortality was 24%. Following graft inclusion it was 31% compared with 16% in the open technique group (P=0.0154). Postoperative complications (graft inclusion vs. open technique): myocardial infarction (9 vs. 12%, n.s.), low cardiac output (40 vs. 32%, n.s.), reexploration for hemorrhage (23 vs. 25%, n.s.). Survival at 8 years was significantly increased in the open technique group (P=0.0300). Pseudoaneurysm formation occurred in 3% of patients and only after graft inclusion. Freedom from reoperation was 80% at 8 years and did not differ between groups. Graft inclusion was an independent significant predictor of early (P=0.0069; relative risk=2.3673) and late mortality (P=0.0119; relative risk=2.0981). CONCLUSIONS: Surgery of acute ascending aortic dissection still carries a considerable early mortality whereas the late outcome is satisfactory. The open resection technique is the method of choice showing superior early and late results and avoiding pseudoaneurysm formation. The inclusion technique may be indicated in situations with increased risk of bleeding. A consequent decompression of the perigraft-space could reduce the rate of pseudoaneurysms.

[R-hirudin (lepirudin, refludan) as an alternative anticoagulant in heparin-induced thrombocytopenia during cardiopulmonary bypass connection]. / R-Hirudin (Lepirudin, Refludan) als alternatives Antikoagulans bei Heparin-induzierter Thrombozytopenie während des Anschlusses an den extrakorporellen Kreislauf.

A 72-year-old patient with heparin-induced thrombocytopenia (HIT) and global cardiac decompensation underwent cardiac surgery using an extracorporeal circuit (ECC). For systemic anticoagulation r-Hirudin (lepirudin, Refludan) was administered as a heparin substitute during extracorporeal circuit. During cardiopulmonary bypass (100 min) the concentration of r-Hirudin was between 2.9 and 4.6 mcg/ml under continuous infusion of r-Hirudin at between 1.5 and 4.5 mcg/kg/min. The operation was successful and during its course no abnormal bleeding or fibrin formation in the extracorporeal circuit was observed. One hour after operation haemorrhage occurred and rethoracotomy was performed without discovering the cause of the surgical bleeding. After substitution with fresh frozen plasma, thrombocytes and Prothromblex the bleeding stopped on the operation day. The further postoperative course was uncomplicated. After 3 days the patient came to nursing station and was discharged from hospital to a rehabilitation centre after 13 days. After a further 3 weeks he went home in a good general condition.

Myocardial infarction caused by a large coronary artery aneurysm.

A large coronary aneurysm, originating from a side branch of the right coronary artery, caused recurrent ischemia resulting in myocardial infarction. Successful surgical excision, without concomitant coronary artery bypass grafting, is described.

Paravalvular leakage after mitral valve replacement: improved long-term survival with aggressive surgery?

BACKGROUND: Following mitral valve replacement, surgical closure of paravalvular leaks is usually advised in severely symptomatic patients and in those requiring blood transfusions for persisting haemolysis. However, the long-term prognosis of less symptomatic patients or those not needing blood transfusions is unknown. METHODS: Between 1987 and 1997, we observed 96 patients with mitral paravalvular leakage. A paraprosthetic leak was diagnosed after a median time of 119 days (range: 1 day-23 years) after primary mitral valve replacement. During an average follow-up of 5 years (range: 1-23 years), 50/96 patients were referred for surgical closure. RESULTS: Compared with patients who received conservative treatment, those referred for surgery had a significantly lower mean preoperative haematocrit (P = 0.002) with a higher proportion of patients being in the NYHA class III/IV (P = 0.03). Age, gender, left ventricular function and number and size of leaks did not differ between the groups. The 30-day postoperative mortality for valve reoperation was 6% (3/50); during follow-up three further patients died, resulting in an overall mortality rate of 12%. In the group treated conservatively there was a mortality rate of 26% (12/46). Thus, the actuarial survival for patients referred for surgery was 98, 90 and 88% after 1, 5 and 10 years, compared with 90, 75 and 68% for patients treated conservatively (long-rank P = 0.03). In addition, there was a significant increase in mean haematocrit levels (P = 0.0001) and an improvement in NYHA class III/IV symptoms (P = 0.002), vertigo (P = 0.001) and fatigue (P = 0.001) after surgery. CONCLUSIONS: Following mitral valve replacement, a more aggressive surgical treatment is recommended for patients with paraprosthetic leaks. Surgery should be offered to less symptomatic patients, as well as those not requiring blood transfusion.

Composite graft replacement of the aortic root: long-term results, incidence of reoperations.

BACKGROUND: Long-term results after composite graft replacement of the aortic root may depend on the insertion technique. METHODS: 181 consecutive patients (mean age 53 years; 153 men) operated on between 1983 and 1993 were studied. Indications for surgery were annuloaortic ectasia (n=98), acute aortic dissection (n = 46), other indications (n = 12), and various indications after previous aortic valve replacement (n = 25). Mean follow-up was 28 months. The open-button technique was performed in 74 patients (41 %) and the Bentall inclusion technique in 107 patients (59%), with a Cabrol shunt to the right atrium in 16 patients. RESULTS: Overall survival was 75% after 7 years, significantly decreased in acute aortic dissection (p = 0.0019) and without difference between the two surgical techniques (p = 0.3166). Reoperation-free survival was 69% at 7 years and significantly decreased after acute dissection (p = 0.0421 ). Pseudoaneurysm formation only occurred in 3 patients operated with the Bentall technique not including a Cabrol shunt. CONCLUSIONS: Long-term results are satisfactory. In acute aortic dissection survival is decreased and late reoperations more frequent. The open technique is safe in non-dissection and in acute dissection and avoids pseudoaneurysm formation. The Bentall technique combined with Cabrol shunt is indicated if there is a high risk of hemorrhage. Long-term monitoring of the aorta is mandatory in patients with acute dissection and/or Marfan disease.

Dual chamber pacing with a single-lead DDD pacing system.

The successful application of single-lead VDD pacing during the last few years has generated the idea of single-lead DDD pacing. Preliminary data from several single-lead VDD studies attempting to pace the atrium by a floating atrial dipole are unsatisfactory, causing an unacceptably high current drain of the device. We studied the feasibility as well as the short- and long-term stability of atrioventricular sequential pacing, using a new single-pass, tined DDD lead. In eight consecutive patients (age 73+/-16 years) with symptomatic higher degree AV block and intact sinus node function, this new single-pass DDD lead was implanted in combination with a DDDR pacemaker. Correct VDD and DDD function was studied at implantation; at discharge; and at 1, 3, and 6 months of follow-up. At implant, the atrial stimulation threshold was 0.6+/-0.1 V/0.5 ms. During follow-up, the atrial pacing thresholds in different every day positions averaged 2.1+/-0.5 V at discharge, 2.9+/-0.5 V at 1 month, 3.8+/-0.4 V at 3 months, and 3.4+/-0.4 V at 6 months (pulse width always 0.5 ms). The measured P wave amplitude at implantation was 4.5+/-2.2 mV; during follow-up the telemetered atrial sensitivity thresholds averaged 2.1+/-0.3 mV. Phrenic nerve stimulation at high output pacing (5.0 V/0.5 ms) was observed in three (38%) patients at discharge and in one (13%) patient during follow-up; an intermittent unmeasurable atrial lead impedance at 3 and 6 months follow-up was documented in one (13%) patient. This study confirms the possibility of short- and long-term DDD pacing using a single-pass DDD lead. Since atrial stimulation thresholds are still relatively high compared to conventional dual-lead DDD pacing, further improvements of the atrial electrodes are desirable, enabling lower pacing thresholds and optimizing energy requirements as well as minimizing the potential disadvantage of phrenic nerve stimulation.

Conservative treatment of the aortic root in acute type A dissection.

OBJECTIVE: In acute type A dissection long-term results of conservative aortic root surgery were compared with the outcome of primary valve and/or root replacement. METHODS: Between 1985 and 1995, 199 patients (mean age 59 years, 154 men) were operated on. The aortic root was involved in the dissection process and valve incompetence of varying degree was present without exception. Replacement of a proximal aortic segment was standard procedure in all patients. The aortic valve was preserved in 126 patients: commissural suture resuspension (12 patients), root reconstruction with GRF-glue (gelatine-resorcin-formaldehyde/glutaraldehyde-glue) (114 patients). Valve replacement was performed in 73 patients (50 composite grafts, 23 valve prostheses with separate supracoronary grafts). Preoperative risk factors (valve replacement vs. preservation): coronary artery disease (11 vs. 8%, NS), tamponade (18 vs. 17%, NS), unstable hemodynamics (22 vs. 15%, NS), renal failure (4 vs. 6%, NS), neurologic disorder (19 vs. 32%, NS). RESULTS: The overall early mortality was 23.6% (47/199 patients) and increased after commissural suture resuspension compared with GRF-glue reconstruction (P = NS). Parameters of the early postoperative period did not differ between conservative treatment and root/valve replacement: low cardiac output, 34 versus 38% (P = NS); myocardial infarction, 10 versus 11% (P = NS); hemorrhage, 25 versus 23% (P = NS); duration of intensive care (P = NS). Survival was 61% after 8 years without difference between the two principal treatment groups (P = NS) and between the two conservative subgroups (P = NS). At 2 years, GRF-glue reconstruction had an increased freedom from reoperation on the aortic root (92 vs. 70%, P = 0.0253) and event free survival (77 vs. 41%, P = 0.0224) compared with suture resuspension. Commissural suture resuspension was an independent, significant predictor for reoperation (P = 0.0221, relative risk = 4.7130). CONCLUSION: Surgery for acute type A dissection still carries a considerable early risk. Preservation of the aortic root is safe in the absence of Marfan or annuloaortic ectasia, but a certain incidence of reoperations on the aortic valve and the aortic root has to be accepted. Root reconstruction using GRF-glue is the method of choice and is superior to suture resuspension, with a significantly better reoperation-free and event-free survival.

Explanted cryopreserved allografts: a morphological and immunohistochemical comparison between arterial allografts and allograft heart valves from infants and adults.

OBJECTIVE: Life expectancy of cryopreserved allografts implanted in infants is different from those implanted in adults. A morphological study of explanted allograft heart valves was performed to determine the mechanism of deterioration and to compare cryopreserved arterial and heart valve allografts from adult patients with those explanted from infants. METHOD: Between 1987 and 1996, 209 cryopreserved allografts were implanted: 125 valved conduits or monocusps to reconstruct the right ventricular outflow tract in congenital heart disease, 50 allograft heart valves to treat native aortic and prosthetic aortic valve endocarditis and 34 cryopreserved arterial allografts to replace mycotic aortic aneurysms or infected aortic prosthetic grafts. Two months to 8 years after implantation, 23 heart valve allografts, 11 right-sided and 12 left-sided, and four arterial allografts had to be explanted for reasons such as degeneration, recurrent infection, aneurysm formation or rupture. Besides conventional staining, immunohistochemical detection of cell populations was performed as follows: CD45RO, CD3 and CD43 for T lymphocytes, CD20 for B lymphocytes, CD68 for macrophages, protein S100 for Langerhans-cells, vimentin for fibroblasts, alpha-actin for smooth muscle cells and factor VIII for endothelial cells. RESULTS: Explanted cryopreserved allografts were all fibrotic, acellular, non-vital and without endothelial cells. The fibrous tissue was preserved. T lymphocytes, indicating rejection, were found in all right-sided allografts from the paediatric population, but only in 9% of left-sided valves explanted from adults and in one of the four of arterial allografts. Macrophages and Langerhans-cells were found only in right-sided allografts from paediatric patients. CONCLUSION: Right-sided cryopreserved allografts from a paediatric population showed ongoing cellular rejection. By contrast, there was only a weak T-cell mediated rejection to adult heart valve and arterial allografts. Therefore, similar long-term results can be expected in adult arterial and heart valve allografts, whereas longevity of right-sided heart valve allograft in the paediatric age group seems endangered by cellular rejection.

Epicardial, biatrial synchronous pacing for prevention of atrial fibrillation after cardiac surgery.

About 30% of patients develop AF after open heart surgery. Biatrial synchronous pacing (BSP) has been shown to promote sinus rhythm in patients with paroxysmal AF refractory to drug therapy. We conducted a prospective, randomized study to test the effect of BSP via epicardial electrodes on the incidence of AF after heart surgery, as compared to conventional therapy. To apply BSP, we attached two epicardial electrodes to the right and one to the left atrium. Immediately following surgery, BSP was initiated in the AAI-Mode at a rate of 10 beats/min above the underlying rhythm (maximum 110 beats/min) and continued for 3 days, during which the rhythm was continually monitored. After 21 (age 63 +/- 9 years) of the planned 200 patients, the study was prematurely aborted because of the proarrhythmic effect of BSP: 6 of the 12 patients treated with BSP developed sensing failure (P amplitude < 1 mV), which provoked AF in 5 of these 6 patients. BSP was discontinued due to diaphragmal stimulation in two patients and due to ventricular stimulation by a dislocated left atrial electrode in one patient. Two patients in the control group (n = 9) developed AF. Using the available standard technology, BSP via epicardial electrodes is not suitable to suppress AF after heart surgery, primarily due to postoperative deterioration of atrial sensing and its profibrillatory effect. In patients requiring atrial pacing after heart surgery, sensing thresholds must be closely monitored to prevent induction of AF.

[How to do: initial experiences with a new device in minimally invasive heart surgery]. / How to do: Erste Erfahrungen mit einem neuen Instrument in der minimal-invasiven Herzchirugie.

A special surgical technique is required for minimal-invasive cardiac surgery. The view for the coronary artery anastomosis under beating heart conditions is important and coronary artery blood might prevent a clear view of the opened coronary artery vessel. A new system called VisoFlo promises to improve visualisation at the surgical site. VisoFlo delivers a column of air to help provide a clear view of anastomosis site and in addition has a controllable mist to help prevent desiccation of the graft and surrounding tissue. This system was tested on 45 patients with coronary-artery-bypass graft surgery under beating heart conditions and at 65 patients with standard coronary-artery-bypass graft surgery. Our conclusions are, that the VisoFlo system is easy to use, guarantees a clear view of the anastomosis site and the surgical work will not be impaired.

Preoperative predictors of recurrent atrial fibrillation late after successful mitral valve reconstruction.

OBJECTIVE: Late outcome after mitral valve repair was examined to define preoperative predictors of recurrent atrial fibrillation late after successful mitral valve reconstruction. METHODS: One hundred and eighty-nine patients, 112 with preoperative sinus rhythm and 72 with preoperative chronic or intermittent atrial fibrillation, were followed for 12.2 +/- 10 years after valve repair. Clinic, hemodynamic end echocardiographic data were entered into Cox-regression and Kaplan-Meyer analysis to assess predictors for recurrent atrial fibrillation late after successful mitral valve repair. RESULTS: Univariate and multivariate predictors for recurrent atrial fibrillation late after successful mitral valve reconstruction were preoperative atrial fibrillation (P = 0.0001), preoperative antiarrhythmic drug treatment (P = 0.005), heart rate (P = 0.01), left ventricular ejection fraction (P = 0.01) and increased left ventricular posterior wall thickness (P = 0.05). Patients > 57.5 years with a mean pulmonary artery pressure > or =23 mm Hg and a history of preoperative antiarrhythmic drug treatment had an odds ratio of 53.33 (95% confidence limits 6.12-464.54) for atrial fibrillation late after successful mitral valve repair. CONCLUSION: Older patients with a history of atrial fibrillation, antiarrhythmic treatment or an elevated pulmonary artery pressure may present atrial fibrillation late after successful mitral valve repair. They could be considered for combined mitral valve reconstruction and surgery for atrial fibrillation even though sinus rhythm is present preoperatively.

Endothelial cell injury in cardiac surgery: salicylate may be protective by reducing expression of endothelial adhesion molecules.

OBJECTIVE: Cardiac surgery with cardiopulmonary bypass induces ischemia to the heart, hypoxemia to various tissues and release of endotoxins. The endothelial cell may suffer from hypoxia and trigger cascades of adverse reactions by activation of neutrophils through adhesion molecules. The authors measured expression of intercellular adhesion molecule-1 (ICAM-1), during hypoxia and normoxia and hypothesized that salicylate, which inhibits the nuclear factor-kappaB (NFkappaB), an hypoxia-dependent transmission factor, could reduce this expression. METHODS: Human umbilical vein endothelial cells were cultured and exposed to normoxia and hypoxia in the presence of lipopolysaccharide (LPS). The endothelial cells were thereafter treated with salicylate or indomethacin under the same conditions. The surface expression of ICAM-1 was measured by whole cell enzyme-linked immunosorbent assay (ELISA) and the NFkappaB expression by Western blotting. RESULTS: In the presence of LPS and under hypoxic conditions, the endothelial cells produced a 300 +/- 41% increased expression of ICAM-1 compared with normoxia. The addition of salicylate (0.02-20 mM) completely inhibited the enhanced expression of ICAM-1, the addition of indomethacin at equivalent concentrations did not reduce ICAM-1 expression under either condition. CONCLUSION: ICAM-1 expression is greatly enhanced by the hypoxic endothelial cell in the presence of circulating endotoxin. Pre-treatment with salicylate completely abolishes the enhanced expression. The study suggests that salicylate administered before cardiopulmonary bypass might protect the heart against ischemic/reperfusion injuries and reduce the load of the overall inflammatory reaction.

Composite graft replacement of the aortic root in acute dissection.

OBJECTIVE: In acute type A dissection the indication for composite graft replacement of the aortic root and the optimal implantation technique are a matter of debate. In this study early and late results of root replacement in acute dissection are determined and compared with supracoronary graft replacement. Two implantation techniques (open vs. inclusion) are evaluated. METHODS: Between 1985 and 1995, 207 consecutive patients (mean age 58 +/- 12 years, 78% men) were operated for acute type A dissection of the aorta. Root replacement in 50 patients (inclusion technique in 34/50 patients with Cabrol shunt in 15/34 patients, open technique in 16/50 patients) was compared with more conservative procedures in 157 patients: supracoronary graft replacement in 143 patients (with aortic valve replacement in 23 patients) and local repair without graft interposition in 14 patients. Preoperative risk factors, like hemodynamic instability, renal failure, neurologic disorder and coronary artery disease did not differ in the two treatment groups. RESULTS: Early results, survival and reoperation-free survival after 5 years were insignificantly better after root replacement: mortality 10/50 (20%) vs. 38/157 (24%) P = n.s.; hemorrhage 10/50 (20%) vs. 39/157 (25%) P = n.s.; stroke 5/50 (10%) vs. 27/157 (17%) P = n.s.; survival 70 +/- 7% vs. 63 +/- 4%, reoperation free survival 92 +/- 6% vs. 78 +/- 5% P = 0.0815). For the open technique, early mortality was 18.8 vs. 20.6%, P = n.s. and reoperation free survival at 5 years was 80.7 vs. 65.2%, P = n.s. Perioperative complications did not differ in the two technical groups and a single pseudoaneurysm occurred in the Bentall group. CONCLUSION: In acute dissection composite graft replacement of the aortic root can be carried out with good early and late results not inferior to more conservative procedures. The open technique is the implantation method of choice and the modified Bentall technique is indicated in situations with increased risk of bleeding.

Recurrent myocardial infarction caused by a giant coronary aneurysm.

We report on a patient with a giant aneurysm arising from the right coronary artery leading to infarction due to a steal phenomenon. Emergency coronary angiography was performed. The orifice of the aneurysm was occluded by balloon catheter restoring blood flow and resolving ischemia. Aneurysmectomie was done subsequently. The patient recovered very soon, and the following course was uneventful. This case illustrates that occasionally causes other than usual coronary atherosclerosis may lead to acute coronary syndromes.

Late outcome of coronary artery bypass grafting in young versus older patients.

BACKGROUND: We compared long-term results of coronary artery bypass grafting between 1976 and 1988 in 176 patients 40 years old or younger with a matched control group of 176 patients 25 to 30 years older. METHODS: Mean age was 37.4 +/- 2.7 years (+/- standard deviation) in the study group and 64.2 +/- 2.9 years in the control group. Matching criteria were age, sex, left ventricular ejection fraction, number of bypass grafts, and year of operation. RESULTS: The study group had more smokers (p = 0.000) and more patients with hypercholesterolemia (p = 0.026), unstable angina (p = 0.003), and preoperative myocardial infarction (p = 0.009); fewer patients had hypertension (p = 0.000) and diabetes (p = 0.005) in this group than in the control group. The internal mammary artery was used in 31% of the study patients and in 30% of the controls. The actuarial survival rates after 5, 10, and 15 years were 92%, 86%, and 72% in the study group and 92%, 86%, and 66% in the control group (p = 0.202). Young age was a predictor of cardiac reoperation. CONCLUSIONS: Late survival is similar for young and older patients, but the reintervention rate is higher in the younger group. The absence of unstable angina, a left ventricular ejection fraction greater than 0.45, and the use of internal mammary artery grafts increase survival in all patients.

Disadvantages of local repair in acute type A aortic dissection.

BACKGROUND: In acute type A dissection of the aorta, local repair with glue-aortoplasty was compared with aortic replacement. METHODS: Between 1992 and 1996, 106 consecutive patients (mean age, 59 years; 84 men) were operated on average 14.5 hours after onset of dissection. A local repair (gelatin-resorcine-formaldehyde/glutaraldehyde glue, Trigon AG, Monchengladbach, Germany) without graft replacement was performed in 21 patients. Graft replacement and reinforcement of aortic stumps with gelatin-resorcine-formaldehyde/glutaraldehyde glue was performed in 85 patients (supracoronary graft, 68; aortic root replacement, 17). RESULTS: Survival was 79% after 30 days and 69% after 2 years. There was no difference in early mortality (p = 0.2240) and survival (p = 0.07649). Risk factors for early mortality were preoperative shock, neurologic disorder, duration of crossclamp, and extracorporeal circulation. The rate of reoperation on the proximal aorta was 31.6% (6 of 19) after local repair and 9% (6 of 64) after aortic replacement (p = 0.0157). Local repair was a significant predictor for reoperation (p = 0.0087), with decreased reoperation-free survival (p = 0.01164). In all reinterventions (four supracoronary grafts, including two valve replacements; two composite grafts; two arch replacements) breakdown of the aortoplasty was confirmed. CONCLUSION: Local repair has satisfactory early results but an increased incidence of reoperations due to a breakdown of the glue-aortoplasty. Indications for local repair should be restricted to high-risk patients requiring a minimal emergency surgical procedure.

Improved exposure of the pulmonary arteries for thromboendarterectomy.

Pulmonary thromboendarterectomy is a surgical technique for treating pulmonary hypertension caused by unresolved pulmonary embolism. It has been recommended to perform this procedure under deep hypothermic circulatory arrest. Here we describe two technical modifications: (1) improved exposure to the right pulmonary artery by division of the superior caval vein and (2) thromboendarterectomy in normothermic cardiopulmonary bypass, with beating heart or electrically induced ventricular fibrillation. These modifications allow complete endarterectomy of both pulmonary arteries under normothermic conditions, thus avoiding hypothermic circulatory arrest, which results in short cardiopulmonary bypass times and reduces the morbidity and mortality of this procedure.

Synthesis and SAR of a novel, potent and structurally simple LTD4 antagonist of the quinoline class.

The two geminal ethyl groups in the succinic acid moiety of CGP57698 (4-[3-(7-fluoro-2-quinolinyl-methoxy)phenyl-amino]-2,2-diethyl-4-oxo- butanoic acid) are responsible for the high in vitro and in vivo potency of this peptidoleukotriene antagonist of the quinoline type. The synthesis and structure activity relationships of CGP57698 and its analogs are described.

A new approach for DDD(R) pacing using a single-pass DDD lead.

Short- and long-term results for DDD pacing using a single-pass DDD lead are presented for 3 patients. Single-lead DDD pacing is feasible and may provide major advantages by eliminating the necessity of a second lead.