Background-Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity. Methods and Results-Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose Key Words: heart failure Ⅲ apoptosis Ⅲ myocytes A nthracyclines such as doxorubicin, daunomycin, epirubicin, and idarubicin are widely used and highly successful anticancer chemotherapeutic drugs. Unfortunately, these drugs also induce acute cardiotoxicity, which is characterized by hypotension, tachycardia, arrhythmia, and transient depression of left ventricular function. [1][2][3][4] In addition, high cumulative doses are associated with late-onset cardiomyopathy that is refractory to standard treatment. It is widely thought that free radical-induced mitochondrial damage contributes to doxorubicin-induced cardiotoxicity. 5 In addition, doxorubicin can induce DNA damage, inhibit DNA and protein synthesis, promote myofiber degeneration, inhibit transcription of specific gene programs, and induce cardiomyocyte apoptosis via a caspase-3-dependent mechanism. Because doxorubicin can interfere with many different intracellular processes, it has proven difficult to determine the molecular mechanism of its acute and chronic cardiotoxicity. Clinical Perspective p 106Numerous studies have shown that doxorubicin-induced cardiomyocyte apoptosis is associated with increased expression of the p53 tumor suppressor protein. Moreover, reduction of p53 activity via genetic deletion 6 or chemical inhibition 7 is cardioprotective during short-term doxorubicin treatment. To further characterize the role of p53 in acute doxorubicin-induced cardiotoxicity, MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) 8 were studied 7 days after the initiation of treatment. Cardiac function was improved, with a concomitant reduction in cardiomyocyte apoptosis, in the MHC-CB7 mice compared with their doxorubicin-treated nontransgenic siblings. Surprisingly, expression of the MHC-CB7 transgene also markedly blunted the doxorubicin-induced reduction of cardiac mass observed in nontransgenic mice. Western blot analyses indicated that doxorubicin treatment reduced the level of activated mammalian target of rapamycin (mTOR) in nontransgenic mice. mTOR is a serine/threonine protein kinase that regulates protein translation and cell growth. 9 Expression of the MHC-CB7 transgene blocked doxorubicin-induced reduction of mTOR activity. To establish the role of mTOR signaling in doxorubicin-induced cardiotoxicity, mice expressing constitutively active mTOR in the myocardium (MHC-mTORca mice) 10 were subjected to doxorubicin treatment. Expression of the MHC-mTORca transgene was suffi...

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Creation of a competent left atrioventricular valve is a cornerstone in surgical repair of complete atrioventricular septal defects. To identify risk factors for mortality and failure of left atrioventricular valve repair and to determine the impact of cleft closure on postoperative atrioventricular valve function, we retrospectively analyzed hospital records of 203 patients between January 1974 and January 1995. Overall early mortality was 7.9%. Operative mortality decreased significantly over the period of the study from 19% (4/21) before 1980 to 3% (2/67) after 1990 (p = 0.03). Ten-year survival including operative mortality was 91.3% +/- 0.004% (95% confidence limit): all survivors are in New York Heart Association class I or II. Preoperative atrioventricular valve regurgitation was assessed in 203 patients by angiography or echocardiography and was trivial or mild in 103 (52%), moderate in 82 (41%), and severe in 18 (8%). Left atrioventricular valve cleft was closed in 93% (189/203) but left alone when valve leaflet tissue was inadequate and closure of the cleft might cause significant stenosis. Reoperation for severe postoperative left atrioventricular valve regurgitation was necessary in eight patients, five of whom initially did not have closure of the cleft and three of whom had cleft closure. Six patients had reoperation with annuloplasty and two patients required left atrioventricular valve replacement. Five patients survived reoperation and are currently in New York Heart Association class I or II. On most recent evaluation assessed by angiography or echocardiography (a mean of 59 months after repair), left atrioventricular valve regurgitation was trivial or mild in 137 of the 146 survivors (94%) examined; none had moderate or severe left atrioventricular valve stenosis. By multiple logistic regression analysis, strong risk factors for early death and need for reoperation included postoperative pulmonary hypertensive crisis, immediate postoperative severe left atrioventricular valve regurgitation, and double-orifice left atrioventricular valve. These results indicate that complete atrioventricular septal defects can be repaired with low mortality and good intermediate to long-term results. Routine approximation of the cleft is safe and has a low incidence of reoperation for left atrioventricular valve regurgitation.

Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.

Background The course of dilated cardiomyopathy (DCM) leading to heart failure in children varies; survival with conventional treatment is 64% at 5 years. Heart transplantation (HTx) enables improved survival; however, outcomes from listing for transplant are not well described. This study reports survival of patients with DCM from listing with the availability of mechanical bridge to transplant. Methods Patients with a primary diagnosis of DCM (n = 1,098) were identified from a multi-institutional, prospective, registry of patients aged < 18 years listed for HTx from January 1, 1993, to December 31, 2006. Results Characteristics of DCM patients at listing included a mean age of 7.3 years; 51% male, 64% white ethnicity, 77% United Network for Organ Sharing status I, 66% on inotropic support, 28% mechanically ventilated, and 15% on mechanical support. Waitlist mortality was 11%, and 75% underwent HTx at 2 years after listing. Overall 10-year survival after listing was 72%, with higher risk of death associated with arrhythmias, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) support, but not ventricular assist device (VAD) support. Survival at 10 years post-HTx was 72%, with a higher risk of death associated with black race, older age, mechanical ventilation, longer ischemic time, and earlier era of transplant. Conclusions Transplantation for DCM in the pediatric population offers enhanced survival compared with the natural history. Overall waitlist mortality for DCM is low, with the exception of patients on ECMO, mechanically ventilated, or with arrhythmias. DCM patients fared well after transplant, making HTx a key therapeutic intervention.