Heart transplantation in children with congenital heart disease.

OBJECTIVES: The aim of this study was to describe heart transplantation in children with congenital heart disease and to compare the results with those in children undergoing transplantation for other cardiac diseases. BACKGROUND: Reports describe decreased survival after heart transplantation in children with congenital heart disease compared with those with cardiomyopathy. However, transplantation is increasingly being considered in the surgical management of children with complex congenital heart disease. Present-day results from this group require reassessment. METHODS: The diagnoses, previous operations and indications for transplantation were characterized in children with congenital heart disease. Pretransplant course, graft ischemia time, post-transplant survival and outcome (rejection frequency, infection rate, length of hospital stay) were compared with those in children undergoing transplantation for other reasons (n = 47). RESULTS: Thirty-seven children (mean [+/- SD] age 9 +/- 6 years) with congenital heart disease underwent transplantation; 86% had undergone one or more previous operations. Repair of extracardiac defects at transplantation was necessary in 23 patients. Causes of death after transplantation were donor failure in two patients, surgical bleeding in two, pulmonary hemorrhage in one, infection in four, rejection in three and graft atherosclerosis in one. No difference in 1- and 5-year survival rates (70% vs. 77% and 64% vs. 65%, respectively), rejection frequency or length of hospital stay was seen between children with and without congenital heart disease. Cardiopulmonary bypass and donor ischemia time were significantly longer in patients with congenital heart disease. Serious infections were more common in children with than without congenital heart disease (13 of 37 vs. 6 of 47, respectively, p = 0.01). CONCLUSIONS: Despite the more complex cardiac surgery required at implantation and longer donor ischemic time, heart transplantation can be performed in children with complex congenital heart disease with success similar to that in patients with other cardiac diseases.

Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs.

To better define the mechanisms of blood pressure control in states of catecholamine excess, we infused norepinephrine for 28 days using subcutaneously implanted osmotic pumps in dogs previously instrumented for monitoring left ventricular dynamics and cardiac output. Plasma norepinephrine rose from 238 +/- 27 to 4346 +/- 952 pg/ml at 21 days, while epinephrine and dopamine levels did not change. Heart rate fell from 85 +/- 4 to 63 +/- 6 beats/min, while arterial pressure was unchanged from baseline. Total peripheral resistance rose 0.011 +/- 0.003 mm Hg/ml/min from a control value of 0.029 +/- 0.002 mm Hg/ml/min, and cardiac output decreased 1093 +/- 292 ml/min from a baseline level of 3575 +/- 156 ml/min. Since stroke volume did not change, the maintenance of arterial pressure is related to decreases in cardiac output secondary to bradycardia. Buffering mechanisms are responsible for maintenance of systemic arterial pressure because hexamethonium and atropine caused hypertension. Although left ventricular end-diastolic pressure, end-diastolic diameter, shortening, rate of change of pressure, velocity of myocardial shortening, cardiac work, stroke work, and the double product did not change significantly during the study, postmortem examination demonstrated biventricular hypertrophy. Thus, despite markedly elevated catecholamine levels and no elevation of systemic arterial pressure, myocardial hypertrophy developed. These studies lend support to the hypothesis that norepinephrine may be a direct myocardial tropic hormone and suggest that intense activation of reflex buffering mechanisms maintains blood pressure in the normal range during chronic catecholamine infusion.

Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts.

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.

Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts.

Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.

Incidence and outcome of primary Epstein-Barr virus infection and lymphoproliferative disease in pediatric heart transplant recipients.

BACKGROUND: The objective of this study was to assess the relationship between Epstein-Barr virus (EBV) infection and posttransplantation lymphoproliferative disease (PTLD) in pediatric heart transplant recipients. EBV is implicated in the development of PTLD. However, the relationship between primary EBV infection and PTLD is not well understood. METHODS: Serial EBV titers were determined prospectively in 50 children before and after heart transplantation. Results were correlated with the development of PTLD. The clinical presentation, management, and outcome of PTLD were characterized. RESULTS: Before transplantation, EBV titers were positive in 19 and negative in 31 patients. After transplantation, all EBV-positive patients remained positive; 1 developed PTLD. Among EBV-negative patients, 12 of 31 remained negative; none developed PTLD. Nineteen patients demonstrated serologic evidence of primary EBV infection after heart transplantation; 12 developed PTLD. Mean follow-up after heart transplantation was 3.3 years (range 0.4 to 8.4 years). Mean time from heart transplantation to histologic confirmation of PTLD was 29 months (range 3 to 72 months). Survival with PTLD was 92%. CONCLUSIONS: Twelve of 13 pediatric heart transplant recipients who developed PTLD had evidence of primary EBV infection. Serial monitoring of EBV titers may lead to earlier identification and improved treatment of PTLD.

Biventricular assist device as a bridge to transplantation in a pediatric patient.

A 5 1/2-year-old boy with idiopathic cardiomyopathy and rapidly worsening hemodynamic parameters underwent placement of a biventricular assist device as a bridge to transplantation. Direct anastomoses to both the aorta and pulmonary artery with Dacron grafts attached to Carmeda-coated tubing facilitated the support period. Inflow was provided by right atrial appendage and left ventricular apex cannulas. A centrifugal pump provided support for 2 days until a suitable donor was identified. The technique is simple, reproducible, and effective for patients with small body surface areas.

Regression of pulmonary arteriovenous malformations following heart transplantation.

Pulmonary arteriovenous malformations (PAVMs) can occur following caval to pulmonary artery connection, Glenn and/or Fontan procedure, leading to severe cyanosis and exercise intolerance. It is unknown whether these abnormalities regress or persist following heart transplantation (HTx). Twenty patients with failed Fontan or Glenn procedures were screened for PAVMs prior to HTx by contrast echocardiography, selective pulmonary angiography, and pulmonary venous desaturation. Age at transplant, diagnosis, previous operations, time from Glenn to transplant, systemic oxygenation, hemoglobin level, and ventricular function were determined. The clinical course after HTx was characterized in three patients with significant PAVMs. Indications for HTx were exercise intolerance and severe cyanosis in one patient, and cyanosis and ventricular dysfunction in two. Pre-HTx, mean systemic saturation was 67%; mean pulmonary venous wedge saturation was 81%. Post-HTx, oxygen saturations were normal (> 96%) at 14, 40, and 180 days. Contrast echocardiography, performed 1 month to 3.3 yrs after HTx, showed no intrapulmonary shunting in two patients and minimal shunting in one. One patient suffered an embolic stroke from right-to-left shunting post-HTx. All patients are alive and well 35, 71, and 73 months post-HTx. In patients with single ventricle physiology, PAVMs are not an absolute contraindication to HTx. Heart-lung transplant may not be required for these patients.

Regulation of nitric oxide production in human coronary microvessels and the contribution of local kinin formation.

BACKGROUND: The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium. METHODS AND RESULTS: Ten hearts from humans with end-stage heart failure and two hearts from patients without heart failure were harvested at the time of orthotopic cardiac transplantation. Microvessels were sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused dose-dependent increases in nitrite, a response that was blocked by NG-nitro-L-arginine methyl ester and receptor-specific antagonists (atropine and HOE 140, respectively). In addition, the production of nitrite by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with norepinephrine or the alpha2-adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B2-receptor antagonist HOE 140. This implicated local kinin synthesis as an intermediate step in the production of nitric oxide in response to alpha2-adrenoceptor stimulation. The production of nitric oxide was also prevented by the addition of serine protease inhibitors, which blocked the action of local kallikrein, again suggesting a role for local kinin synthesis. CONCLUSIONS: Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.

Decreasing incidence of coronary disease in pediatric cardiac transplant recipients using increased immunosuppression.

BACKGROUND: Coronary artery disease (CAD) is a limiting factor to long-term survival in cardiac transplant recipients, affecting from 30% to 50% of patients by 4 years after surgery. Can the incidence of CAD be lowered with augmentation of immunosuppression? METHODS AND RESULTS: We compared the incidence of CAD in our pediatric transplant population with nine potential risk factors, including immunosuppressive regimen. The study group consisted of 55 patients who survived more than 1 year (or to first angiogram) or had autopsies. Coronary angiograms were performed yearly and compared sequentially. The mean follow-up of 55 patients was 36 months. Mean age was 10.3 +/- 6 years (range, 4 months to 18 years). Thirteen patients received double immunosuppression with cyclosporine and prednisone, and 42 received triple therapy with cyclosporine, prednisone, and azathioprine. Significant CAD occurred in 10 grafts (6 deaths and 3 retransplants). Cause for graft loss in 6 patients with CAD was acute rejection. CAD was detected by angiogram in only 2 patients. Nine of 10 patients received double therapy (P < .001). There was no difference in mean follow-up between immunosuppression groups. There was a higher rejection frequency for double therapy (0.19 +/- 0.16 rejections per patient month) compared with triple therapy (0.07 +/- 0.11). Ten patients were rejection free in the triple therapy group. CONCLUSIONS: We experienced a significant decrease in the incidence of CAD in our pediatric cardiac transplant recipients using increased immunosuppressive therapy. Type of immunosuppressive regimen (double) and rejection frequency were independent predictors for CAD by multivariate analysis.

Outcome after orthotopic cardiac transplantation in adults with congenital heart disease.

BACKGROUND: Advances in surgical and medical management have greatly improved long-term survival rates in patients with congenital heart disease (CHD). As these patients reach adulthood, myocardial dysfunction can occur, leading to cardiac transplantation. METHODS AND RESULTS: We reviewed the pretransplantation and posttransplantation courses of 24 patients >18 years old (mean age, 26 years; range, 18 to 56 years) with CHD who received a transplant between January 1985 and September 1998. The relation between preoperative and perioperative risk factors for complications and death was assessed. Single ventricle was the pretransplantation diagnosis for 12 patients (50%), and d-transposition of the great vessels was the diagnosis for 4 patients (16%). Twenty-two patients had a mean of 2 previous operations. At cardiac transplantation, additional surgical procedures were required to correct extracardiac lesions in 18 patients (75%). Refractory heart failure was present in 22 patients, significant cyanosis was present in 7, and protein-losing enteropathy was present in 4. There were 5 early deaths due to bleeding (n=3) and infection (n=2). The Kaplan-Meier survival rate after cardiac transplantation was 79% at 1 year and 60% at 5 years. No anatomic or surgical risk factor was predictive of death. The outcome of patients with CHD who received a transplant was compared with that for patients without CHD (n=788). Mean bypass and ischemic times were significantly longer in patients with CHD than in patients without CHD. Survival rates after transplantation did not differ significantly between patients with and those without CHD (P=0.83). CONCLUSIONS: Successful cardiac transplantation is obtainable in adults with complex CHD, with an outcome similar to that of patients without CHD. A detailed assessment of cardiac anatomy and careful surgical planning are essential to the pretransplantation and posttransplantation management of these patients.