Kenneth O. Schowengerdt

Association of Parvovirus B19 Genome in Children With Myocarditis and Cardiac Allograft Rejection Diagnosis Using the Polymerase Chain Reaction

BACKGROUND Inflammatory diseases of the heart, including myocarditis and cardiac transplant rejection, are important causes of morbidity and mortality in children. Although viral infection may be suspected in either of these clinical conditions, the definitive etiology is often difficult to ascertain. Furthermore, the histology is identical for both disorders. Coxsackievirus has long been considered the most common cause of viral myocarditis; however, we previously demonstrated by polymerase chain reaction (PCR) analysis that many different, and sometimes unexpected, viruses may be responsible for myocarditis and cardiac rejection. In this study, we describe the association of parvovirus genome identified through PCR analysis of cardiac tissue in the clinical setting of myocarditis and cardiac allograft rejection. METHODS AND RESULTS Myocardial tissue from endomyocardial biopsy, explant, or autopsy was analyzed for parvovirus B19 using primers designed to amplify a 699-base pair PCR product from the VP1 gene region. Samples tested included those obtained from patients with suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects (n=250). Parvoviral genome was identified through PCR in 9 patients (3 myocarditis; 6 transplant) and no control patients. Of the 3 patients with myocarditis, 1 presented with cardiac arrest leading to death, 1 developed dilated cardiomyopathy, and the other gradually improved. Four of the 6 transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection. CONCLUSIONS Parvovirus is associated with myocarditis in a small percentage of children and may be a potential contributor to cardiac transplant rejection. PCR may provide a rapid and sensitive method of diagnosis.

Heart transplantation in children: Indications*

Abstract: This review details the indications for heart transplantation in children. Contraindications have evolved from absolute to relative. Controversial issues remain and this paper represents a consensus of more than a dozen centers that have programs that remain active performing pediatric heart transplants.

Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients

BACKGROUND Hyperlipidemia is common after cardiac transplantation and it is a risk factor for post-transplantation coronary artery disease. Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia. Pravastatin, a HMG-CoA reductase inhibitor, has been shown to be effective and safe for cholesterol reduction in adult heart transplant recipients. To our knowledge the safety and efficacy of pravastatin therapy in pediatric and adolescent heart transplant populations have not been previously analyzed. Therefore, we evaluated lipid profiles, liver transaminases, rejection data, and possible side effects in pediatric and adolescent cardiac transplant recipients treated with pravastatin. METHODS The study group consisted of 40 cardiac transplant recipients 10 to 21 years old (mean age 16.9 years). Twenty-two patients received pravastatin in addition to an immunosuppressive regimen of either cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Serial determinations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides were available for all pravastatin-treated patients. Pre-treatment lipid values and hepatic transaminases were compared with those measured after therapy with pravastatin. Comparison of pravastatin-induced lipid reduction between groups treated with cyclosporine vs tacrolimus was also made. RESULTS Patients receiving pravastatin experienced a mean 32 mg/dl decrease in TC (p < 0.005) and a mean 31 mg/dl decrease in LDL (p < 0.005), regardless of their immunosuppressive regimen. No statistical differences occurred in the magnitude of mean lipid reduction induced by pravastatin between the groups treated with cyclosporine vs tacrolimus. No significant changes in hepatic transaminase levels were noted, and no clinical evidence of pravastatin-induced myositis occurred in any subjects. CONCLUSION Pravastatin therapy is effective and safe when used in pediatric and adolescent cardiac transplant recipients. Although the pravastatin-induced reduction in TC and LDL was more pronounced in patients receiving cyclosporine, the reduction was not statistically different from that in the tacrolimus group. No evidence of hepatic dysfunction or rhabdomyolysis in patients treated with pravastatin was noted. Long-term studies are required to evaluate the effect of pravastatin therapy on the incidence of accelerated coronary atherosclerosis in this population.

Intermediate follow-up of pediatric heart transplant recipients with elevated pulmonary vascular resistance index

OBJECTIVES This study examined perioperative and intermediate outcomes in pediatric cardiac transplant recipients who had elevated pulmonary vascular resistance indexes preoperatively. BACKGROUND Elevated pulmonary vascular resistance was associated with poor outcome in previous studies and constitutes a relative contraindication to transplantation. Few studies have evaluated this poor outcome risk factor in pediatric patients. METHODS To evaluate outcomes of nonneonatal transplant recipients, records were reviewed and divided into Group I (preoperative pulmonary vascular resistance index > or = 6 units.m2) and Group II (pulmonary vascular resistance index < 6 units.m2). Donor/recipient weight ratios, ischemic times, length of intensive care unit stay, posttransplantation infection rates, arrhythmia, response to pretransplantation vasodilator infusions and pulmonary vascular resistance indexes at the first and most recent posttransplantation biopsies were analyzed. RESULTS Group I (8 patients) had a mean (+/- SEM) pulmonary vascular resistance index of 11.5 +/- 3.5 units,m2; Group II (29 patients) had a mean pulmonary vascular resistance index of 2.3 +/- 0.4 units,m2 (p < 0.002). Pulmonary vascular resistance index decreased from 12.3 +/- 3.9 to 3.9 +/- 0.9 units.m2 (p < 0.05) in 7 Group I patients undergoing vasodilator infusion during pretransplantation catheterization. Thirty-six orthotopic heart transplantations were performed and one heterotopic transplantation. Donor weights exceeded recipient weights by 13% and 31% for Groups I and II, respectively (p > 0.25). Donor ischemic time was 215 min for Group I and 225 min for Group II (p > 0.75). Intensive care unit stay was 11.5 days in Group I and 15.1 days in Group II (p = 0.20). Infection rate was 38% in both groups (p > 0.80). Arrhythmias occurred in 90% of Group I and 42% in Group II (p < 0.03) patients. Pulmonary resistance index in Group I decreased from 11.5 +/- 3.5 to 3.3 +/- 1.2 units.m2 (p < 0.03) by the first posttransplantation biopsy and have not changed subsequently. During 2.3 years (range 0.3 to 8.5) of follow-up, the mortality rate was 25% and 21% for Groups I and II, respectively (p > 0.80). CONCLUSIONS Group I patients did not require significantly oversized donors, restricted donor locations or longer intensive care unit stays or have higher infection rates; however, arrhythmias were more frequent. Pulmonary resistance index normalized early after transplantation. Pulmonary vascular reactivity may be more important for survival than absolute resistance index.

Tacrolimus-based triple-drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients.

BACKGROUND Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia, a risk factor for post-transplant coronary artery disease. The recent development of tacrolimus has created an alternative to cyclosporine-based triple drug immunotherapy. One potential benefit that has been reported in patients receiving tacrolimus is a minimization of elevation of both total and LDL cholesterol, compared to those increases observed in patients receiving cyclosporine-based immunosuppression. It is unclear in previous studies whether this beneficial effect is related to tacrolimus directly or to its corticosteroid sparing potential. To study this relationship, we compared lipid profiles from pediatric cardiac transplant recipients treated with corticosteroids, and either cyclosporine or tacrolimus. METHODS The study group consisted of 23 patients (mean age = 12.3 years) with pre-transplant and serial post-transplant determinations of total cholesterol, LDL, HDL, and triglycerides. Patients were separated into 4 study groups, defined by immunosuppressive regimen (cyclosporine vs. tacrolimus) and prednisone dose (>0.10 mg/kg/day vs. < or =0.10 mg/kg/day). RESULTS Patients who received cyclosporine and higher doses of prednisone experienced a mean 74 mg/dl increase from baseline in total cholesterol (p = .0001). None of the other 3 treatment groups demonstrated a statistically significant elevation. Similar trends were observed in LDL and triglyceride alterations between the 4 study groups. Interestingly, patients treated with tacrolimus and higher doses of prednisone demonstrated a significant rise in HDL from baseline (p = .0001), although those who received cyclosporine and higher dose prednisone failed to exhibit this rise. CONCLUSION The minimal degree of lipid alteration seen in patients receiving tacrolimus and higher doses of prednisone indicates that this effect was not solely based upon the steroid-sparing properties of tacrolimus therapy. The data also suggests a possible synergistic effect between cyclosporine and higher doses of prednisone on hyperlipidemia. Therefore, in pediatric patients requiring higher corticosteroid doses late after transplantation, use of tacrolimus rather than cyclosporine may lead to more favorable lipid profiles and help minimize the risk of post-transplant coronary arteriopathy.

Prenatal diagnosis of congenital heart disease.

This article presents advancements in the field of fetal echocardiography and the significant impact of these within the fields of pediatric cardiology, perinatology, and neonatology. A prenatal diagnosis of congenital heart disease allows for improved counseling of the parents, guides the timing and optimal location of delivery, and allows appropriate planning and consultation between the cardiologist and neonatologist. It also facilitates accurate diagnosis and management of fetal arrhythmias, identifies potential candidates for in utero cardiac intervention, and serves as the imaging guidance technique for these procedures. The goals, indications, advantages, limitations, and spectrum of congenital heart disease that can be diagnosed are reviewed.

Decreased functional caspase-3 expression in umbilical cord blood neutrophils is linked to delayed apoptosis.

Resolution of inflammatory processes depends on the efficient removal of aging neutrophils by the reticuloendothelial system. Neutrophil apoptosis is key to this process, and its impairment may contribute to the pathogenesis of chronic inflammation. We recently discovered that Fas-mediated apoptosis in umbilical cord blood neutrophils was significantly delayed as compared with those of adults. Because execution of apoptosis relies on caspases, we used reverse transcription PCR, immunoblots, and enzymatic assays to study the integrity of several members of those proteases known to mediate Fas-induced apoptosis in neutrophils. Our results indicate that diminished expression of caspase-3 mRNA and the precursor form of the protein, as well as a lower functional enzymatic activity of caspase-3, correlates with delayed apoptosis in umbilical cord blood neutrophils. Our data suggest that functional expression of caspase-3 in neutrophils may be regulated during ontogeny.

Genetic basis of inherited cardiomyopathies.

Cardiomyopathies are a major cause of morbidity and mortality worldwide, and currently are the most common group of disorders leading to cardiac transplantation. Recent advances in the field of molecular medicine have provided significant molecular genetic insight into a variety of both primary and secondary cardiomyopathies. The purpose of this review is to briefly describe the known primary and secondary causes of cardiomyopathy; describe the molecular genetic abnormalities associated with them, if known; and describe the current progress being made within this area of molecular cardiology.

A Comparison of the Modified Blalock-Taussig Shunt With the Right Ventricle-to-Pulmonary Artery Conduit

BACKGROUND This study compared the modified Blalock-Taussig (MBT) shunt with the right ventricle-to-pulmonary artery (RVPA) conduit with respect to outcome and PA growth. METHODS PA growth was assessed in 19 MBT patients and in 15 RVPA patients before stage 2 palliation for hypoplastic left heart syndrome. The RVPA was done with a ringed Gore-Tex tube (W. L. Gore and Assoc, Flagstaff, AZ) at each anastomosis. RESULTS The two cohorts had similar pre-Glenn demographic and hemodynamic data. No patient required transcatheter or surgical intervention on the shunt or PAs after stage 1 palliation. The branch PA growth was better in RVPA (McGoon ratio: MBT, 1.5±0.2 vs RVPA, 2.0±0.6; p<0.003) and was significantly more balanced (right-to-left PA area ratio: MBT, 1.5±0.5 vs RVPA, 0.9±0.6; p=0.002). The Nakata index trended higher in RVPA (MBT, 242A±90 mm2/m2 vs RVPA, 267±95 mm2/m2, p=0.2). After stage 2 palliation, oxygen saturation trended higher in the RVPA (81%±5%) vs MBT cohort (77%±8%, p<0.08). CONCLUSIONS The Norwood operation using a RVPA nonvalved conduit is associated with improved branch PA growth.

An institutional review of the value of computed tomographic angiography in the diagnosis of congenital cardiac malformations.

The ultra-fast, thin-cut computerised tomographic angiogram is an efficient method to diagnose extracardiac lesions associated with congenital cardiac disease. For the purposes of this review, we evaluated various facets of the technique as used in 30 patients who were referred for diagnosis of congenital cardiac disease. The technique had high diagnostic accuracy, with a sensitivity of 93 percent in 15 of these patients referred for either interventional catheterisation or surgery. There were no immediate side-effects associated with the scanning procedure. The scan was also found to be more cost-effective as compared to an alternative noninvasive modality for imaging modality, namely magnetic resonance imaging. The angiographic technique, however, does expose the child to between 2 and 2.5 rems of radiation, despite the short period of scanning, of 10 plus or minus 2 seconds.