Robert J. Boucek

Assessment of ventricular size and function in congenitally corrected transposition of the great arteries

Twenty-four quantitative cineangiographic studies were performed in 19 patients with congenitally corrected transposition of the great arteries to assess right and left ventricular size and function. Ages ranged from 7 days to 44 years and associated lesions included ventricular septal defect (13 of 19), pulmonary stenosis (9 of 19), and systemic (tricuspid) valvular insufficiency (7 of 19). Systemic (anatomically right) ventricular end-diastolic volume was within normal limits in most patients and averaged 119% of predicted normal. Pulmonary (anatomically left) ventricular end-diastolic volume also was normal in most patients, averaged 112% of predicted, and was not different from systemic (right) ventricular end-diastolic volume. Systemic ventricular ejection fraction (RVEF) averaged 0.61 +/- 0.02 and was not different from pulmonary ventricular ejection fraction (LVEF) (0.65 +/- 0.02), but important differences were apparent when age was considered. With exclusion of 2 patients with hypoplastic systemic ventricles and 2 studies performed less than 6 months after open heart surgery, all 12 patients aged less than 10 years had a normal RVEF, whereas 2 of 5 patients aged greater than 17 years had a definitely low RVEF and 1 of 5 had a value at the lower limit of normal. In children, systemic and pulmonary ventricular pump function is usually normal in congenitally corrected transposition of the great arteries and any deviation from normal should suggest ventricular hypoplasia or an increase in afterload. After childhood, systemic ventricular dysfunction is more common and may reflect the inability of the anatomic right ventricle to function as the systemic pumping chamber over a normal lifetime in most patients with congenitally corrected transposition of the great arteries.

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

The Marfan Syndrome: A Deficiency in Chemically Stable Collagen Cross-Links

THE reduced tensile strength of tissues supporting the ocular lenses, cardiac valves, and aorta in heritable connective-tissue diseases is probably due to a defective organization of collagen. Sinc...

Right ventricular volume characteristics before and after palliative and reparative operation in tetralogy of Fallot.

SUMMARY Right heart volume data were obtained in 63 patients with tetralogy of Fallot. The patients were divided into three groups: 1) preoperative tetralogy (N = 34); 2) post shunt procedure (N = 14); 3A) post repair without outflow patch (N = 10); 3B) post repair with an outflow patch (N = 8). In Group 1 right ventricular end-diastolic volume (RVEDV), RV ejection fraction (EF), and RV systolic output (SO) were all mildly depressed. In post shunt patients, RVEDV was normal but RVEF remained depressed. RVEDV and RVSO increased following a shunt procedure, and these variables were larger in patients with a large versus a small shunt. In Group 3A RVEDV, RVEF, and RVSO were normal. In contrast in patients in Group 3B, RVEDV was increased averaging 177 ± 15% of normal, RVEF was depressed averaging 0.45 ± 0.04, and RVSO was normal. RV size and pump function are abnormal in patients whose operation requires an outflow tract patch and the factors which may contribute to these abnormalities include a higher RV peak pressure, pulmonary incompetence, and a larger noncontractile outflow tract. Longitudinal studies relating these variables to clinical performance and exercise testing will be important in assessment of the importance of these abnormalities.

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1 The present study evaluated the time‐dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C‐13 hydroxy metabolite, doxorubicinol. 2 Following addition of doxorubicin (175 μm) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 μm) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 μm), however, failed to produce time‐related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration‐response experiments with doxorubicinol (0.9–7.2 μm) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin‐treated than in doxorubicinol‐treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 μm doxorubicinol promoted a 15 fold greater release rate than 3 μm doxorubicin. 8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+ loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time‐dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Pediatric heart transplantation.

Pediatric heart transplantation has improved to the point that the initially restricted ages and indications have expanded considerably. The number of annual pediatric cardiac transplants has remained stable, but the number of centers performing transplants continues on a downward trend. Currently the half-life (50% still alive) for children who underwent transplantation in the early 1980s is 11.5 years, with a conditional half-life of more than 14 years. An era effect in improved survival is evident for the first time. There is an association between morbidity and the type of immunosuppression regimen employed. The early posttransplant period continues to be the highest risk time. Early rejection correlates with poor late outcome. Transplant coronary disease continues to be the most significant cause of late mortality. Detection of transplant coronary disease may be improved by adjunctive noninvasive imaging such as dobutamine stress echocardiography. There may be dramatic changes in clinical transplant protocols as a result of experience and new technology. This review focuses on key advances in knowledge reported in the past year.

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.

Induction immunotherapy in pediatric heart transplant recipients: a multicenter study

BACKGROUND The efficacy and safety of induction immunotherapy with antithymocyte antibody preparations (IND) in pediatric heart transplantation is controversial. Experimentally, recipient age is an important determinant of immune responses. The effects on induction immunotherapy were determined by an analysis of outcomes of 465 pediatric (age <18 years) heart recipients that either did or did not receive IND in the first week post-transplant. METHODS The outcomes of 2 groups who received either OKT3 (n = 101) or rabbit polyclonal antithymocyte serum (N/R-ATS, n = 105) were compared with 255 recipients who did not receive antithymocyte antibodies. The study population were all heart recipients enrolled in the Pediatric Heart Transplant Study Group (PHTS) between January 1993 and December 1995 and followed up to 36 months. RESULTS Overall mortality and death due to rejection were lowest with N/R-ATS IND (8/105 and 1/105, respectively) compared with the no-induction group (58/255 and 8/ 255, respectively) or the OKT3 group (22/101 and 7/101, respectively) with significance of p = 0.001 and 0.06 respectively. Late mortality beyond 30 days after transplant was lowest with N/R-ATS IND compared with the OKT3 and no IND (p = 0.01). Induction did not affect cumulative infections, deaths due to infection, or the frequency of malignancies. Patients excluded from N/R-ATS induction had the highest mortality (18/ 43), suggesting that the protocols exclusion criteria identified a high-risk group. To minimize potential effect(s) of exclusion bias, patients transplanted at centers participating in the N/R-ATS induction trial were reanalyzed with a post hoc intent-to-treat analysis assigning patients by center (IND or no IND) irrespective of actual treatment. With this analysis overall mortality was 18% for N/R-ATS centers, 21% for OKT3 centers, and 26% for centers not using IND (p = 0.3). The mortalities of recipients <6 months old at transplant were lowest at centers using N/R-ATS and OKT3 IND compared to centers not using IND (p = 0.04). Cumulative rejection (0.8 vs 1.2 rejection/pt/year, p = 0.01) and freedom from rejection death (99% vs. 93% at year 1, p = 0.02) of the N/R-ATS centers were lower compared to OKT3 centers but were not different from centers not using IND. CONCLUSION Following orthotopic transplantation, induction immunotherapy can exert the enduring benefit of reducing late deaths, a possible surrogate for rejection severity, in recipients less than 6 months of age, while not being associated with higher rates of infectious or malignant complications. Since polyclonal anti-T cell antibody preparations appears superior to OKT3 induction in pediatric recipients, the efficacy of ATS induction should be further evaluated in a randomized prospective study in pediatric heart recipients.

Comparative effects of verapamil, nifedipine, and diltiazem on contractile function in the isolated immature and adult rabbit heart.

Summary: The effects of postnatal development on the systolic and diastolic responses to pharmacologic blockade of the slow inward calcium current were investigated in blood-perfused hearts isolated from immature (14-21-day-old) and adult rabbits. Isovolumic left ventricular developed pressure, resting pressure, and maximal rate of pressure development (+ dP/dt) at cumulative doses of either verapamil, nifedipine, or diltiazem were determined by means of an intracavitary balloon. Myocardial contractile function in the immature heart was more sensitive to pharmacologic blockade of the slow inward calcium current than is the adult heart. Doses of verapamil, or nifedipine, that comparably reduced pretreatment developed pressure and + dP/dt were approximately 10-fold less in immature as compared to the adult heart. The dose of diltiazem which reduced developed pressure and dP/dt by 50% was 3-fold less in immature as compared to the adult heart. Verapamil and nifedipine decreased resting pressure in the adult but not in the immature heart. Conversely, diltiazem decreased resting pressure in the immature while not affecting resting pressure in adult hearts. Thus, postnatal cardiac development affects both the systolic and diastolic responses to calcium channel blockade. In addition, diltiazem appears to be qualitatively and quantitatively different from verapamil and nifedipine with respect to the age-related cardiac effects of calcium channel blockade.

Myocardial dysfunction in children with acute meningococcemia

Acute meningococcemia is frequently associated with cardiovascular collapse of uncertain cause. Review of the records of 12 consecutive children revealed clinical evidence of myocardial dysfunction in six (50%). Subsequently myocardial function was prospectively assessed clinically and echocardiographically in 12 children. Seven (58%) of the 12 children had echocardiographic evidence of myocardial dysfunction as defined by a depressed left ventricular shortening fraction (LVSF). The mean LVSF in these seven children was 0.25 +/- 0.03, as compared with the mean LVSF of 0.39 +/- 0.7 in the remaining children. The LVSF estimate of myocardial function strongly correlated with cardiac output as measured by standard thermodilution (r = 0.98, P less than 0.01). Acute meningococcemia was not fatal in those children without evidence of myocardial dysfunction. In contrast, three of the seven children with evidence of myocardial dysfunction died. In four children, echocardiographic evidence of left ventricular dysfunction preceded cardiovascular collapse and clinical recognition of myocardial dysfunction. In children with an initially low LVSF, recovery of LVSF was associated with survival. Children with acute meningococcemia may have impaired myocardial function as indicated by depressed LVSF, resulting in low cardiac output despite normal intravascular volume. Thus, in addition to restoring intravascular volume, knowledge of the status of myocardial function may help direct therapy toward optimizing myocardial contractility.