Steven E. Lipshultz

Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood.

BACKGROUND Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. METHODS Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. RESULTS Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P less than 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event. CONCLUSIONS Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years.

Female Sex and Higher Drug Dose as Risk Factors for Late Cardiotoxic Effects of Doxorubicin Therapy for Childhood Cancer

BACKGROUND Late cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late cardiotoxicity. METHODS We examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress-velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects. RESULTS All echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female patients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P < or = 0.001), and there was an interaction between these two variables. Independent and significant associations were found between a higher rate of administration of doxorubicin and increased afterload (P < or = 0.001), left ventricular dilatation, and depressed left ventricular function; between a higher cumulative dose and depressed left ventricular function (P < or = 0.001); between a younger age at diagnosis and reduced left-ventricular-wall thickness and mass and increased afterload; and between a longer time since the completion of doxorubicin therapy and reduced left-ventricular-wall thickness and increased afterload (P < or = 0.001). CONCLUSIONS Female sex and a higher rate of administration of doxorubicin were independent risk factors for cardiac abnormalities after treatment with doxorubicin for childhood cancer; the prevalence and severity of abnormalities increased with longer follow-up.

Health Effects of Energy Drinks on Children, Adolescents, and Young Adults

OBJECTIVE: To review the effects, adverse consequences, and extent of energy drink consumption among children, adolescents, and young adults. METHODS: We searched PubMed and Google using “energy drink,” “sports drink,” “guarana,” “caffeine,” “taurine,” “ADHD,” “diabetes,” “children,” “adolescents,” “insulin,” “eating disorders,” and “poison control center” to identify articles related to energy drinks. Manufacturer Web sites were reviewed for product information. RESULTS: According to self-report surveys, energy drinks are consumed by 30% to 50% of adolescents and young adults. Frequently containing high and unregulated amounts of caffeine, these drinks have been reported in association with serious adverse effects, especially in children, adolescents, and young adults with seizures, diabetes, cardiac abnormalities, or mood and behavioral disorders or those who take certain medications. Of the 5448 US caffeine overdoses reported in 2007, 46% occurred in those younger than 19 years. Several countries and states have debated or restricted energy drink sales and advertising. CONCLUSIONS: Energy drinks have no therapeutic benefit, and many ingredients are understudied and not regulated. The known and unknown pharmacology of agents included in such drinks, combined with reports of toxicity, raises concern for potentially serious adverse effects in association with energy drink use. In the short-term, pediatricians need to be aware of the possible effects of energy drinks in vulnerable populations and screen for consumption to educate families. Long-term research should aim to understand the effects in at-risk populations. Toxicity surveillance should be improved, and regulations of energy drink sales and consumption should be based on appropriate research.

Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia

PURPOSE Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare. METHODS Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (-) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively. RESULTS Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to -2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later. CONCLUSION Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.

Cardiovascular Status in Long-Term Survivors of Hodgkin's Disease Treated With Chest Radiotherapy

PURPOSE Cardiovascular status was assessed in 48 Hodgkins disease (HD) survivors at a median of 14.3 years (range, 5.9 to 27.5 years) after diagnosis because they may be at increased risk for cardiovascular abnormalities. PATIENTS AND METHODS Patients completed the Short-Form 36 quality-of-life instrument and were screened by echocardiography, exercise stress testing, and resting and 24-hour ECG. RESULTS All patients received mediastinal irradiation (median, 40.0 Gy; range, 27.0 to 51.7 Gy) at a median age of 16.5 years (range, 6.4 to 25.0 years). Four patients received an anthracycline. Although every patient described their health as good or better, and none had symptomatic heart disease at screening, all but one had cardiac abnormalities on screening. Restrictive cardiomyopathy was suggested by reduced average left ventricular (LV) dimension (P < .001) and mass (P < .001), without increased LV wall thickness. Significant valvular defects were present in 42%; 75% had conduction defects. One survivor developed complete heart block shortly after the study visit. Autonomic dysfunction was suggested by a monotonous heart rate in 57%, persistent tachycardia in 31%, and blunted hemodynamic responses to exercise in 27%. Peak oxygen uptake (VO2max) during exercise, a predictor of mortality in heart failure, was significantly reduced (< 20 mL/kg/m2) in 30% of survivors. VO2max was correlated with increasing fatigue, increasing shortness of breath (both, r = -0.35; P =. 02), and decreasing physical component score on the SF-36 (r = 0.554; P = .00017). CONCLUSION A variety of unsuspected, clinically significant cardiovascular abnormalities are common in long-term survivors of HD who are treated at a young age with mediastinal irradiation. We recommend serial, comprehensive cardiac screening of HD survivors who fit this profile.

Radiation-associated cardiovascular disease

As the number of cancer survivors grows because of advances in therapy, it has become more important to understand the long-term complications of these treatments. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Emphasis is on clinical presentations, recommendations for follow-up, and treatment of patients previously exposed to irradiation. Medline literature searches were performed, and abstracts related to this topic from oncology and cardiology meetings were reviewed. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, valvular disease and conduction abnormalities. Damage appears to be related to dose, volume and technique of chest irradiation. Effects may initially present as subclinical abnormalities on screening tests or as catastrophic clinical events. Estimates of relative risk of fatal cardiovascular events after mediastinal irradiation for Hodgkins disease ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with length of time since exposure. Radiation-associated cardiovascular toxicity may in fact be progressive. Long-term cardiac follow-up of these patients is therefore essential, and the range of appropriate cardiac screening is discussed, although no specific, evidence-based screening regimen was found in the literature.

Protecting against anthracycline-induced myocardial damage: A review of the most promising strategies

Over the last 40 years, great progress has been made in treating childhood and adult cancers. However, this progress has come at an unforeseen cost, in the form of emerging long‐term effects of anthracycline treatment. A major complication of anthracycline therapy is its adverse cardiovascular effects. If these cardiac complications could be reduced or prevented, higher doses of anthracyclines could potentially be used, thereby further increasing cancer cure rates. Moreover, as the incidence of cardiac toxicity resulting in congestive heart failure or even heart transplantation dropped, the quality and extent of life for cancer survivors would improve. We review the proposed mechanisms of action of anthracyclines and the consequences associated with anthracycline treatment in children and adults. We summarise the most promising current strategies to limit or prevent anthracycline‐induced cardiotoxicity, as well as possible strategies to prevent existing cardiomyopathy from worsening.

Predictive Value of Cardiac Troponin T in Pediatric Patients at Risk for Myocardial Injury

BACKGROUND Biochemical markers have not been routinely used in children at risk for myocardial damage. Yet, because of somatic growth and the duration of survival, a low level of myocardial damage may ultimately be of more consequence in children than in adults. METHODS AND RESULTS We investigated the utility of cardiac troponin T (cTnT) blood levels (CARDIAC T ELISA Troponin T, Boehringer Mannheim Corp) in 51 consecutively sampled patients from 1 day to 34 years of age (median=5.7 years) undergoing cardiovascular (n=19) or noncardiovascular (n=17) surgery or who received doxorubicin for acute lymphoblastic leukemia (ALL) (n=15). Minimum detectable cTnT elevations were 0.03 ng/mL. cTnT was measurable in children of all ages with myocyte damage. In patients who underwent cardiovascular surgery, a correlation was noted between a score of increasing surgical severity and the mean level of postoperative cTnT (r=.79, P<.0001). Postoperative cTnT levels were elevated in children who completed cardiovascular surgery with an open chest compared with those with a closed chest (P=.0083). In addition, cTnT levels before cardiovascular surgery predicted postoperative survival (P=.007). cTnT elevations were observed after initial doxorubicin therapy for ALL. The magnitude of elevation predicted left ventricular dilatation (r=.80 when variables were treated as continuous, P=.003) and wall thinning (r=.61, P=.044) 9 months later. CONCLUSIONS Elevations of blood cTnT in children relate to the severity of myocardial damage and predict subsequent subclinical and clinical cardiac morbidity and mortality.

Anthracycline Cardiotoxicity: From Bench to Bedside

Anthracyclines remain among the most widely prescribed and effective anticancer agents. Unfortunately, life-threatening cardiotoxicity continues to compromise their usefulness. Despite more than four decades of investigation, the pathogenic mechanisms responsible for anthracycline cardiotoxicity have not been completely elucidated. In addition, new drugs and combination therapies often exacerbate the toxicity. The First International Workshop on Anthracycline Cardiotoxicity, held in fall 2006, in Como, Italy, focused on the state-of-the-art knowledge and discussed the research needed to address the cardiotoxicity of these drugs. Here, we incorporate these discussions into the framework of a broader review of preclinical and clinical issues.

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease Application to Clinical and Public Health Practice: Report From the Clinical Practice Discussion Group

The Centers for Disease Control and Prevention/American Heart Association (CDC/AHA) Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice was convened on March 14 and 15, 2002, in Atlanta, Ga, to examine the selection and use of inflammatory markers to predict cardiovascular disease (CVD) risk. Three discussion groups on issues related to laboratory, clinical, and population science were organized. The present report contains a summary of the discussions and recommendations of the clinical practice discussion group.This article summarizes epidemiological studies of inflammation markers, particularly C-reactive protein, and cardiovascular disease as of early 2002. Gaps in the research and the public health practice implications are also discussed. Although considerable work has been published since this review was completed, the perspectives and issues presented are still useful in evaluating the use of inflammation markers for risk stratisfication and prevention.