Monocyte migration into the subendothelial space of a coculture of adult human aortic endothelial and smooth muscle cells.

Human aortic endothelial cells (EC) and smooth muscle cells (SMC) were isolated and used to form a multilayer of EC-SMC separated by a layer of collagen. SMC and/or collagen layers exerted minimal effects on Na+ transport but impeded the transport of LDL. The presence of an endothelial monolayer markedly reduced the transport of Na+ and LDL. When monocytes were presented to the complete coculture, in the absence of added chemoattractant, one monocyte entered the subendothelial space for every one to three EC present. In contrast, neither collagen nor SMC plus collagen nor EC plus collagen induced comparable monocyte migration. Despite massive migration of monocytes into the coculture, no significant alteration in Na+ transport was observed. LDL transport into the preparation during massive monocyte migration increased modestly, but this was far less than the amount of LDL transported in the absence of an endothelial monolayer. We conclude that (a) the endothelial monolayer was the principal permeability barrier, (b) a substantial migration of monocytes occurred in the absence of added chemoattractant when both EC and SMC were present in the coculture, (c) endothelial barrier function was largely maintained after monocyte migration; and (d) these experiments indicate the need to study all three cell types (monocytes, EC, and SMC) together to understand the complex interactions that occur between these cells.

A new antiinflammatory compound, leumedin, inhibits modification of low density lipoprotein and the resulting monocyte transmigration into the subendothelial space of cocultures of human aortic wall cells.

Addition of leumedin, N-[9H-(2,7-dimethylfluorenyl-9-methoxy) carbon]-L-leucine at 30-60 microM together with LDL almost completely prevented the induction of monocyte chemotactic protein mRNA, reduced monocyte chemotactic protein 1 levels by 84%, and inhibited monocyte migration into the subendothelial space of cocultures of human aortic wall cells by < or = 98%. LDL incubated with leumedin formed a stable complex that remained intact even after refloating in an ultracentrifuge. Leumedin at 50 microM did not change conjugated diene formation during coculture modification of LDL or Cu++ catalyzed oxidation of LDL. Unlike LDL from control rabbits, LDL isolated from rabbits that were injected with 20 mg/kg leumedin was remarkably resistant to modification by the coculture and did not induce monocyte migration to a significant degree. Moreover, HDL isolated from rabbits injected with leumedin was far more effective in protecting against LDL modification by the artery wall cocultures than HDL from control rabbits. We conclude that leumedins can associate with lipoproteins in vivo, rendering LDL resistant to biological modification and markedly amplifying the protective capacity of HDL against in vitro LDL oxidation by artery wall cells.

Recipient mononuclear cell recognition and adhesion to graft endothelium after human cardiac transplantation. Lymphocyte recognition leads to monocyte adhesion.

Transendothelial migration of mononuclear cells is crucial in the development of allograft rejection and transplant coronary disease. Adhesion of circulating cells to endothelium is the initial step in transendothelial migration. Human aortic endothelial cell cultures were established from aortic tissue harvested at the time of organ donation for cardiac transplantation which allowed specific recipient mononuclear cell-graft endothelial interactions to be studied. Confluent untreated endothelial cells were incubated with recipient mononuclear cells for 15 min to assess adhesion. Adhesion of recipient mononuclear cells to endothelium derived from their graft was threefold higher than adhesion to nonspecific endothelium (93 +/- 20 vs. 30 +/- 11 cells/high power field, P < 0.005). Graft-specific adhesion was inhibited by preincubation of the endothelium with antibodies to class I HLA (34 +/- 16 cells/high power field, P < 0.005). Immunofluorescence performed after adhesion showed that 73 +/- 6% of both specific and nonspecific adherent cells were monocytes. The use of purified lymphocyte and monocyte preparations showed that graft-specific lymphocytes induce unrelated monocytes to become adherent. These results suggest that lymphocytes are primed in vivo to recognize endothelium derived from their graft which leads to a rapid increase in lymphocyte and monocyte adhesion. Such allo-recognition may involve endothelial class I HLA molecules.

Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.

Incubation of cocultures of human aortic endothelial (HAEC) and smooth muscle cells (HASMC) with LDL in the presence of 5-10% human serum resulted in a 7.2-fold induction of mRNA for monocyte chemotactic protein 1 (MCP-1), a 2.5-fold increase in the levels of MCP-1 protein in the coculture supernatants, and a 7.1-fold increase in the transmigration of monocytes into the subendothelial space of the cocultures. Monocyte migration was inhibited by 91% by antibody to MCP-1. Media collected from the cocultures that had been incubated with LDL induced target endothelial cells (EC) to bind monocyte but not neutrophil-like cells. Media collected from cocultures that had been incubated with LDL-induced monocyte migration into the subendothelial space of other cocultures that had not been exposed to LDL. In contrast, media from separate cultures of EC or smooth muscle cells (SMC) containing equal number of EC or SMC compared to coculture and incubated with the same LDL did not induce monocyte migration when incubated with the target cocultures. High density lipoprotein HDL, when presented to cocultures together with LDL, reduced the increased monocyte transmigration by 91%. Virtually all of the HDL-mediated inhibition was accounted for by the HDL2 subfraction. HDL3 was essentially without effect. Apolipoprotein AI was also ineffective in preventing monocyte transmigration while phosphatidylcholine liposomes were as effective as HDL2 suggesting that lipid components of HDL2 may have been responsible for its action. Preincubating LDL with beta-carotene or with alpha-tocopherol did not reduce monocyte migration. However, pretreatment of LDL with probucol or pretreatment of the cocultures with probucol, beta-carotene, or alpha-tocopherol before the addition of LDL prevented the LDL-induced monocyte transmigration. Addition of HDL or probucol to LDL after the exposure to cocultures did not prevent the modified LDL from inducing monocyte transmigration in fresh cocultures. We conclude that cocultures of human aortic cells can modify LDL even in the presence of serum, resulting in the induction of MCP-1, and that HDL and antioxidants prevent the LDL induced monocyte transmigration.

Interaction of monocytes with cocultures of human aortic wall cells involves interleukins 1 and 6 with marked increases in connexin43 message.

Medium from cocultures of human aortic endothelial cells (HAEC) and smooth muscle cells (HASMC) taken from the same donor contained approximately two- to fourfold more macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and up to 5.1-fold more transforming growth factor beta than could be accounted for by the sum of the activities of media from equivalent numbers of HAEC and HASMC cultured separately. After pulse labeling, immunoprecipitated [35S]fibronectin and [14C]collagen were also found to be substantially increased in the coculture compared to the sum of HAEC and HASMC cultured separately. The cocultivation of HAEC and HASMC resulted in a 2.7-fold increase in connexin43 messenger RNA. When direct physical contact between HAEC and HASMC was prevented by a membrane that was permeable to medium, the levels of [35S]fibronectin and [14C]collagen in the coculture were significantly reduced. Monocytes cultured alone contained low levels of [35S]fibronectin and [14C]collagen but when added to the coculture there was up to a 22-fold increase in [35S]fibronectin and a 1.9-fold increase in [14C]collagen compared to the coculture alone. The increase in fibronectin was prevented in the presence of neutralizing antibody to interleukin 1 and antibody to interleukin 6 by 45% and 67%, respectively. Addition of monocytes to cocultures also induced the levels of mRNA for connexin43 by 2.8-fold. We conclude that the interaction of HAEC, HASMC, and monocytes in coculture can result in marked increases in the levels of several biologically important molecules and that increased gap junction formation between the cells and interleukins 1 and 6 may be partially responsible for these changes.

Longitudinal analysis of fibroblast growth factor expression after transplantation and association with severity of cardiac allograft vasculopathy.

BACKGROUND: Vascular smooth muscle cell growth factors are postulated to contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively address the timing, location, or stimuli for growth factor expression and relationship to CAV. METHODS AND RESULTS: Acidic fibroblast growth factor (aFGF) mRNA expression was determined in serial endomyocardial biopsies during the first year after transplantation. Patients with high levels of aFGF mRNA and elevations after the early posttransplant period had significantly more severe CAV than patients with low aFGF and no late elevations. CONCLUSIONS: Parenchymal aFGF expression varies between patients and in the same patient over time and correlates with development of CAV.

Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses.

BACKGROUND: Great arteries in congenital heart disease (CHD) may dilate, become aneurysmal, or rupture. Little is known about medial abnormalities in these arterial walls. Accordingly, we studied 18 types of CHD in patients from neonates to older adults. METHODS AND RESULTS: Intraoperative biopsies from ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk in 86 patients were supplemented by 16 necropsy specimens. The 102 patients were 3 weeks to 81 years old (average, 32+/-6 years). Biopsies were examined by light (LM) and electron (EM) microscopy; necropsy specimens by LM. Positive aortic controls were from 15 Marfan patients. Negative aortic controls were from 11 coronary artery disease patients and 1 transplant donor. Nine biopsies from acquired trileaflet aortic stenosis were compared with biopsies from bicuspid aortic stenosis. Negative pulmonary trunk controls were from 7 coronary artery disease patients. A grading system consisted of negative controls and grades 1, 2, and 3 (positive controls) based on LM and EM examination of medial constituents. CONCLUSIONS: Medial abnormalities in ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk were prevalent in patients with a variety of forms of CHD encompassing a wide age range. Aortic abnormalities may predispose to dilatation, aneurysm, and rupture. Pulmonary trunk abnormalities may predispose to dilatation and aneurysm; hypertensive aneurysms may rupture. Pivotal questions are whether these abnormalities are inherent or acquired, whether CHD plays a causal or facilitating role, and whether genetic determinants are operative.

Intraoperative measurement of pericardial constraint: role in ventricular diastolic mechanics.

The pressure of pericardial constraint was measured in 20 patients undergoing elective cardiac surgery (10 in Group I with normal cardiac size; 10 in Group II with cardiomegaly) using a catheter with a collapsible latex end balloon. Right atrial pressure and other hemodynamic variables including right ventricular stroke work index were also measured before and after the pericardium was widely opened. The pericardium was grossly normal in all patients and only small physiologic effusions were present. In Group I mean pericardial pressure was 8 +/- 2 mm Hg as was mean right atrial pressure. In Group II mean pericardial pressure was 6 +/- 2 mm Hg versus mean right atrial pressure of 10 +/- 5 mm Hg (p less than 0.05). Excluding 2 of the 20 patients with outlying data, pericardial pressure showed linear correlation with right atrial pressure (r = 0.689). In Group I right ventricular stroke work index rose from 5.0 +/- 2.0 to 6.4 +/- 2.1 g-m/m2 (p less than 0.01) after pericardiotomy with no significant increase in mean right atrial pressure; similar findings in Group II were consistent with removal of external constraint. Thus, even in the absence of an abnormal effusion the normal pericardium exerts a significant pressure on the heart, which is often similar in magnitude to right atrial pressure. In certain notable exceptions, however, right atrial pressure far exceeds pericardial pressure. Such pericardial constraint has important implications for ventricular diastolic mechanics.

Repair of conotruncal abnormalities with the use of the valved conduit: improved early and midterm results with the cryopreserved homograft.

Repair of complex cardiac lesions has been facilitated by the availability of valved conduits to reestablish right ventricular to pulmonary artery continuity. From 1977 to June 1991, 148 patients underwent repair with insertion of a conduit. Their mean age was 6.6 years (11 days to 45 years). The diagnosis was transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction in 51, truncus arteriosus in 36, pulmonary atresia with ventricular septal defect in 25, tetralogy of Fallot in 19, double-outlet right ventricle in 10, pulmonary atresia with intact ventricular septum in 6 and atrioventricular canal with pulmonary atresia in 1. A Dacron porcine-valved conduit was used in 37, a homograft conduit in 106 and a nonvalved conduit in 5. There were 13 early deaths overall (8.8%); 8 (22%) of the early deaths occurred in the 37 patients who received a Dacron graft, 4 (3.8%) occurred in the 106 patients who received a homograft and 1 occurred in a patient with a nonvalved Gore-Tex conduit. An additional patient underwent orthotopic heart transplantation in the early postoperative period. In 117 patients operated on from January 1985 to June 1991 the early mortality rate was 2.6% (3 of 117). Among 28 patients receiving a Dacron porcine-valved graft there were two late deaths (7.1%) after a mean follow-up interval of 93 months, and 8 patients required reoperation for conduit obstruction. Among 102 homograft recipients there were two late deaths (1.9%).(ABSTRACT TRUNCATED AT 250 WORDS)

Benefits of early surgical repair in fixed subaortic stenosis.

OBJECTIVES: We sought to determine whether early resection can improve outcome in fixed subaortic stenosis. BACKGROUND: The diagnosis of subaortic stenosis (SAS) is often made before significant gradients occur. Whereas resection is the accepted treatment, it remains uncertain whether surgical intervention at this early stage can reduce the incidence of recurrence or influence the progression of aortic valve damage. METHODS: Follow-up was available for 75 of 83 consecutive patients operated on for fixed SAS; the average duration of follow-up was 6.7 years. The lesion was discrete in 68 patients (91%) and of a tunnel type in 7, with associated ventricular septal defect in 28 (37%). All underwent transaortic resection. RESULTS: There were no deaths. There were 18 recurrences of SAS in 15 patients (20%). Thirteen patients (17%) underwent 17 reoperations for recurrence or aortic valve disease. The cumulative hazard of recurrence was 8.9%, 16.1% and 29.4% +/- 2.3% (mean +/- SEM), and the hazard of events, including recurrence and reoperation, was 9.2%, 18.4% and 35.1% +/- 3.5% at 2, 5 and 10 years, respectively. Residual end-operative left ventricular outflow tract (LVOT) gradients (> 10 mm Hg, n = 8) and tunnel lesions were univariate predictors of recurrence (p = 0.0006 and p = 0.003, respectively). Multivariate predictors included higher preoperative LVOT gradient (p < 10(-4)) and younger patient age (p = 0.002). Only two recurrences (0.87 per 100 patient-years of follow-up) were noted in patients with a preoperative peak LVOT gradient < or = 40 mm Hg (n = 40), whereas higher gradients (n = 35) were associated with a greater than sevenfold recurrence rate (6.45 events per 100 patient-years, p = 0.002). The aortic valve required concomitant repair in 17 cases in the high gradient group (48.6%) but in only 8 in the low gradient group (20%, p = 0.018). Despite relief of the obstruction, progressive aortic regurgitation was noted at follow-up after 14 procedures in the high gradient group (40%) but after only 5 procedures in the low gradient group (12.5%, p = 0.014). CONCLUSIONS: The data suggest that surgical resection of fixed subaortic stenosis before the development of a significant (> 40 mm Hg) outflow tract gradient may prevent recurrence, reoperation and secondary progressive aortic valve disease.

Is intravenous glucocorticoid therapy better than an oral regimen for asymptomatic cardiac rejection? A randomized trial.

OBJECTIVES: This study assessed whether treatment with oral prednisone (bolus plus tapered doses) is comparable to intravenous methylprednisolone sodium succinate (Solu-Medrol) therapy in patients with asymptomatic moderate cardiac allograft rejection episodes without hemodynamic compromise. BACKGROUND: Intravenous Solu-Medrol therapy is frequently administered for moderate rejection episodes after heart transplantation but has not previously been compared with an oral prednisone therapy for asymptomatic cardiac rejection in a randomized trial. Compared with oral prednisone therapy, the administration of intravenous Solu-Medrol is more costly and resource intensive, and it can require loss of work time for patients and the family members who accompany them to treatment. METHODS: Forty-one heart transplant patients with 43 episodes of asymptomatic moderate cardiac rejection were randomized to receive 3 days of 1,000 mg of intravenous Solu-Medrol (20 episodes) or prednisone as a bolus dose of 100 mg orally for 3 days, tapering to the previous maintenance dosage over 14 days (23 episodes). Follow-up endomyocardial biopsies were performed at 2 and 4 weeks. Infectious complications were monitored and the cost of the two forms of therapy was assessed. RESULTS: Resolution of moderate rejection occurred within 4 weeks in 19 (95%) of 20 patients treated with intravenous steroids and in 21 (91%) of 23 patients treated with oral prednisone. No significant difference in infectious complications occurred between the two groups in the ensuing 3 months after therapy. The cost of the oral prednisone therapy was $6.30 compared with the cost of $180 to $966 for administration of intravenous Solu-Medrol. CONCLUSIONS: Oral prednisone (bolus plus tapered doses) appears to be as effective and to have similar infectious complication rates as intravenous Solu-Medrol for the treatment of asymptomatic cardiac rejection. The convenience and lower cost of oral prednisone therapy may warrant its routine use for this type of cardiac rejection.

Improvement in exercise capacity of candidates awaiting heart transplantation.

OBJECTIVES: This study determined the frequency of improvement in peak oxygen uptake and its role in reevaluation of candidates awaiting heart transplantation. BACKGROUND: Ambulatory candidates for transplantation usually wait > 6 months to undergo the procedure, and during this period symptoms may lessen, and peak oxygen uptake may improve. Whereas initial transplant candidacy is based increasingly on objective criteria, there are no established guidelines for reevaluation to determine who can leave the active waiting list. METHODS: All ambulatory transplant candidates with initial peak oxygen uptake < 14 ml/kg per min were identified. Of 107 such patients listed, 68 survived without early deterioration or transplantation to undergo repeat exercise. A strategy of reevaluation using specific clinical criteria and exercise performance was tested to determine whether patients with improved oxygen uptake could safely be followed without transplantation. RESULTS: In 38 of the 68 patients, peak oxygen uptake increased by > or = 2 ml/kg per min to a level > or = 12 ml/kg per min after 6 +/- 5 months, together with an increase in anaerobic threshold, peak oxygen pulse and exercise heart rate reserve and a decrease in heart rate at rest. Increased peak oxygen uptake was accompanied by stable clinical status without congestion in 31 of 38 patients, and these 31 were taken off the active waiting list. At 2 years, their actuarial survival rate was 100%, and the survival rate without relisting for transplantation was 85%. CONCLUSION: Reevaluation of exercise capacity and clinical status allowed removal of 31 (29%) of 107 ambulatory transplant candidates from the waiting list with excellent early survival despite low peak oxygen uptake on initial testing. The ability to increase peak oxygen uptake, particularly with increased peak oxygen pulse, may indicate improved prognosis as well as functional capacity and, in combination with stable clinical status, may be an indication to defer transplantation in favor of more compromised candidates.

Molecular heterogeneity of protein kinase C expression in human ventricle.

OBJECTIVE: Although activation of protein kinase C (PKC) modulates the function of normal cardiac myocytes and likely plays a role in the pathogenesis of cardiomyopathic disease states, the molecular basis of PKC expression in human ventricle has not been examined in detail. METHODS: We have performed Western analysis and immunohistochemistry on explanted human cardiac tissue from nondiseased and diseased specimens using isoform-specific antibodies directed against all known PKC isozymes. RESULTS: In homogenates from left and right ventricle, all isoforms except PKC-gamma and theta were detected by immunoblotting, with confirmation using a second antibody directed against a different epitope when possible. For PKC-betaII, delta, and epsilon, data indicated that these isoforms were variably phosphorylated in vivo, resulting in multiple bands during immunoblotting. Because of potential antibody cross-reactivity, reverse transcriptase polymerase chain reaction (RT-PCR) was performed which confirmed expression of PKC-alpha, betaI, and zeta. Immunohistochemistry demonstrated that all isoforms detected in ventricular homogenate by Western analysis could be localized to cardiac myocytes. From a methodologic standpoint, significant degradation of PKC isoforms could be demonstrated when samples were either frozen or allowed to remain at room temperature, compared to immediate subcellular fractionation. CONCLUSIONS: These findings indicate that the PKC expression in human ventricular myocytes is remarkably diverse, with multiple conventional, novel, and atypical isoforms present, and highlight the importance of sample preparation in comparative studies of PKC isoform expression.

Prolongation of second heart transplants in rats.

Second clinical kidney grafts often survive longer than first grafts. Using a rat cardiac allograft model, we examined the conditions under which survival of a second graft can be longer than first graft survival. In the BUF-to-LEW combination, following rejection of the first transplant, second cardiac allografts from the same donor strain implanted immediately survived longer than the first grafts (P = 0.047). Although the mean survival time of first grafts was 9.0 days, second grafts implanted in the same animals survived 19.5 days. In contrast, when ACI donors were used for the same LEW recipients, the second grafts were rejected in 3 days compared with 6.6 days for first grafts. Donor-specific spleen cell transfusions in these combinations resulted in prolonged survival in the BUF to LEW combination, but had no effect when the donor strain was ACI. Second grafts from BUF had prolonged survival following rejection of the first graft. Thus the histocompatibility difference was a determining factor of whether or not prolongation would be obtained. Another factor was timing of the second transplant. If 7 days were allowed to elapse following rejection of the first graft before implantation of the second, the enhancement effect was lost. Moreover, in the LEW-to-ACI combination in which second grafts were rejected rapidly, removal of the first graft after 7 days (before rejection), resulted in prolonged survival of the second graft. There is, therefore, a window of time before rejection of first grafts and shortly thereafter, when the enhancement effect can be obtained. Passive transfer of serum in the BUF-to-LEW combination resulted in enhancement, but transfer of splenic cells was ineffective. We conclude that graft rejection can result in induction of enhancement during a specific period, after which this effect is lost; and that enhancement can be obtained only in certain strain combinations. This suggests that human patients with heart transplants that reject might benefit from a second graft, even from a donor with a mismatch similar to the first graft.

Anomalous origin of the left main pulmonary artery from the ascending aorta associated with DiGeorge syndrome.

We place on record 2 infants with the DiGeorge syndrome and anomalous origin of the left pulmonary artery from the ascending aorta. We postulate that: (1) embryogenesis of anomalous origin of the left pulmonary artery from the ascending aorta might be due to the persistent fifth aortic arch connecting both arterial systems; (2) an anomalous pulmonary artery arising from the ascending aorta is part of the aortic arch abnormality accompanied by normal conotruncal septation; and (3) in the DiGeorge syndrome, cardiac anomalies that originate from the conotruncus or aortic arch, or both, may have the same embryologic mechanisms.

The influence of coronary anatomy on the arterial switch operation in neonates.

To determine whether coronary anatomy influences the outcome of the neonatal arterial switch operation, we examined the results in all newborn infants (n = 70) with D-transposition of the great arteries who had a corrective operation at our institution between March 1987 and April 1991. The origin and distribution of coronary arteries were identified preoperatively by echocardiography, aortic root angiography, or selective coronary arteriography and intraoperatively by direct inspection. However, the arterial switch operation was performed independent of the coronary anatomy in all but two candidates for the operation. Four early deaths occurred and five surviving patients had symptoms of impaired cardiac function. No late deaths have occurred in patients followed up for 2 to 50 months. Evidence of myocardial ischemia was present in three of the four deaths and in four of the five patients with cardiovascular symptoms. Patients with commissural or intramural coronary origins between the great arteries had significantly greater cardiovascular morbidity and mortality because of coronary ischemia than patients with the most common coronary pattern. Thus coronary anatomy may influence surgical management and the postoperative course of newborn infants with transposition.

A new simplified method of optimizing cardioplegic delivery without right heart isolation. Antegrade/retrograde blood cardioplegia.

We report our initial experience with antegrade/retrograde cardioplegia using a self-inflating/deflating balloon cannula that allows rapid transatrial retrograde cannulation of the coronary sinus (10 to 15 seconds) without right heart isolation and permits routine single venous cannulation. We subjected 141 consecutive adult patients and nine children to antegrade/retrograde cardioplegia using rapid transatrial insertion of the Retroplegia cannula (Research Medical, Inc., Salt Lake City, Utah). Single venous cannulation was used in 116 patients having coronary artery bypass grafting or aortic valve replacement, or both. Initial antegrade blood cardioplegia caused immediate arrest (less than 1 minute) and the cardioplegic dose was divided equally between antegrade and retrograde delivery. Included are 95 patients having isolated bypass grafting (34 with extending infarction, cardiogenic shock, or ejection fraction less than 20%); 19 having coronary reoperations, 42 with aortic or mitral valve procedures, or both; and nine children having repair of congenital defects (e.g., repair of ventricular septal defect, Rastelli operation, Konno operation). Septal temperature in patients with occlusion of the left anterior descending coronary artery fell to 11.5 degrees +/- 0.5 degrees C after retrograde cardioplegia versus only 16 degrees +/- 3 degrees C after antegrade cardioplegia (p less than 0.05). The overall hospital mortality rate was 2% and no complications followed transatrial retrograde cannulation of the coronary sinus.

Synchronously stimulated skeletal muscle graft for myocardial repair. An experimental study.

We studied the feasibility of augmentation of impaired myocardium with synchronously paced skeletal muscle grafts. The short contractile period of skeletal muscle required development of a new stimulator to ensure that the pedicle graft contraction would simulate that of the myocardium. In four dogs each, rectus and diaphragmatic muscles were wrapped around a balloon and electrically stimulated in synchrony with the electrocardiogram, varying stimulation currents and frequency of discharge during systole. For this purpose, a prototype hybrid stimulator was developed which senses the cardiac R wave and modulates the electrical output to the skeletal muscle by delivering a train of impulses of varying frequencies within the systolic intervals. The contraction characteristics in response to such stimulation were similar in rectus and diaphragmatic muscles, but the former developed higher maximum tensions because of the greater muscle bulk. Square-wave output was found to be more effective than sine-wave stimulation, and a single stimulating electrical pulse of 40 msec duration produced a maximum tension of 60 mm Hg lasting for 120 msec, whereas a train of 4 pulses within a 320 msec period was able to achieve a maximum tension of 100 mm Hg lasting nearly 400 msec, the latter approximating that of the myocardium. In six other dogs, the rectus muscle pedicle graft was used to replace a segment of the left ventricle (25.5% +/- 2.1% of left ventricular mass) excised under cardiopulmonary bypass. Left ventricular isometric contraction was studied using a left ventricular balloon with stimulators turned on and off. Significant augmentations of left ventricular maximum tension (+19.3% +/- 2.5%, p less than 0.001, paired t test) and left ventricular contractility (+38.3% +/- 9.4%, p less than 0.001) were achieved when the skeletal muscle grafts were stimulated. Thus, in this preliminary study, skeletal muscle graft properly oriented and stimulated is able to augment the left ventricular isometric contractile function after significant loss of left ventricular myocardial mass.

The use of combined antegrade-retrograde infusion of blood cardioplegic solution in pediatric patients undergoing heart operations.

The benefits of combined antegrade-retrograde infusion of blood cardioplegic solution are becoming well known in adult coronary and valvular heart operations. Many of these advantages relate directly to the pediatric patient. They include prompt arrest and even distribution, particularly with aortic insufficiency or open aortic root, avoiding or limiting ostial cannulation, allowing uninterrupted surgical procedures, and flushing air/debris from the coronary arteries. We therefore report on the first 123 pediatric patients at the University of California, Los Angeles, to receive myocardial protection with antegrade (aortic) infusion in conjunction with retrograde (coronary sinus) infusion of blood cardioplegic solution. We employed a retroplegia catheter with a self-inflating and deflating occlusion balloon on the tip of a pressure-monitored infusion cannula that remains in the coronary sinus during the operation. Induction blood cardioplegic solution, 30 ml/kg in equally divided doses, is administered in the coronary sinus first antegrade at an aortic pressure less than 80 mm Hg, followed by retrograde infusion at less than 40 mm Hg. Maintenance cardioplegic solution (15 ml/kg) is administered every 20 minutes through one or both of the infusion cannulas, depending on the surgical procedure. Patients' ages ranged from 1 week to 16 years with a mean of 4.6 years. The following procedures were included in descending order: Fontan 20, atrioventricular valve repair/replacement (and complete atrioventricular canal) 16, aortic root/Konno/Ross 16, Rastelli 13, aortic valve repair/replacement 13, ventricular septal defect (and double-outlet right ventricle) 13, tetralogy of Fallot 10, coronary artery reimplantation/fistula repair 6, truncus arteriosus 4, arterial switch 3, bidirectional Glenn 2, sinus venosus 2, and aortopulmonary window, Senning, Stansel, interrupted aortic arch, and Ebstein's, 1 each. Aortic crossclamp times ranged from 6 to 219 minutes with a mean of 87 minutes. Myocardial oxygen consumption data for a series of six patients indicated the supplemental benefit for retrograde infusion of cardioplegic solution along with antegrade infusion, particularly in hypertrophied myocardium. Three deaths occurred (2.4% 30-day mortality), in the following patients: the first with truncus arteriosus and interrupted aortic arch, the second with complete atrioventricular canal and pulmonary hypertension, and the third with truncal valve regurgitation and replacement. There were no complications related to the retroplegia catheter. From this initial positive experience, we conclude that (1) combined antegrade-retrograde infusion of blood cardioplegic solution can be safely used in an expanding number of pediatric heart operations in all age groups, and (2) combined antegrade-retrograde infusion of blood cardioplegic solution may provide additional myocardial protection, with excellent surgical outcome, in complex congenital heart repairs.

Management of the left atrioventricular valve in the repair of complete atrioventricular septal defects.

Left atrioventricular valve regurgitation in atrioventricular canal defects is usually due to malalignment of the edges of the cleft or to annular dilatation. Intraoperative assessment and correction of left atrioventricular valve incompetence is critical for successful outcome in the surgical management of complete atrioventricular canal defects. Although some have elected not to suture the cleft in the setting of minimal incompetence, we have found that this often results in significant left atrioventricular valve insufficiency, necessitating reoperation. From January 1982 through December 1990, 105 patients with complete atrioventricular canal underwent definitive repair. Repair was performed with a single pericardial patch technique in 86 patients (82%). Intraoperative assessment of left atrioventricular valve competence was performed in all cases. Ninety-six patients (91%) required suturing of the cleft and 63 (60%) required annuloplasty to establish satisfactory competence of the left atrioventricular valve. The overall early mortality rate was 10.5% (11/105 patients). From 1986 to 1990, the early mortality rate decreased to 7.7% (6/78 patients). In a mean follow-up of 39 months (range 1 to 106 months), late survival was 96% (90/94 operative or early survivors). Reoperation was performed on eleven (11.5%) patients; six (6.3%) for failure of the atrioventricular valve repair, three for patch dehiscence, and two for residual ventricular septal defects. These data demonstrate that routine approximation of the cleft and aggressive use of left atrioventricular valve annuloplasty is safe and results in an excellent outcome with a low incidence of reoperation for failure of left atrioventricular valve repair.