Publications by authors named "Steven E. Lipshultz"

254 Publications

Disruption of healthcare: Will the COVID pandemic worsen non-COVID outcomes and disease outbreaks?

Prog Pediatr Cardiol 2020 Dec 6;59:101254. Epub 2020 Jun 6.

Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, United States of America.

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http://dx.doi.org/10.1016/j.ppedcard.2020.101254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274978PMC
December 2020

Rethinking COVID-19 in children: Lessons learned from pediatric viral and inflammatory cardiovascular diseases.

Prog Pediatr Cardiol 2020 Jun 22;57:101233. Epub 2020 May 22.

Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, United States of America.

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http://dx.doi.org/10.1016/j.ppedcard.2020.101233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243773PMC
June 2020

Elevated Heart Rate and Survival in Children With Dilated Cardiomyopathy: A Multicenter Study From the Pediatric Cardiomyopathy Registry.

J Am Heart Assoc 2020 08 30;9(15):e015916. Epub 2020 Jul 30.

Department of Pediatrics Jacobs School of Medicine and Biomedical Sciences University at Buffalo NY.

Background In adults with heart failure, elevated heart rate is associated with lower survival. We determined whether an elevated heart rate was associated with an increased risk of death or heart transplant in children with dilated cardiomyopathy. Methods and Results The study is an analysis of the Pediatric Cardiomyopathy Registry and includes baseline data, annual follow-up, and censoring events (transplant or death) in 557 children (51% male, median age 1.8 years) with dilated cardiomyopathy diagnosed between 1994 and 2011. An elevated heart rate was defined as 2 or more SDs above the mean heart rate of children, adjusted for age. The primary outcomes were heart transplant and death. Heart rate was elevated in 192 children (34%), who were older (median age, 2.3 versus 0.9 years; <0.001), more likely to have heart failure symptoms (83% versus 67%; <0.001), had worse ventricular function (median fractional shortening score, -9.7 versus -9.1; =0.02), and were more often receiving anticongestive therapies (96% versus 86%; <0.001) than were children with a normal heart rate. Controlling for age, ventricular function, and cardiac medications, an elevated heart rate was independently associated with death (adjusted hazard ratio [HR] 2.6; <0.001) and with death or transplant (adjusted HR 1.5; =0.01). Conclusions In children with dilated cardiomyopathy, elevated heart rate was associated with an increased risk of death and cardiac transplant. Further study is warranted into the association of elevated heart rate and disease severity in children with dilated cardiomyopathy and as a potential target of therapy.
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http://dx.doi.org/10.1161/JAHA.119.015916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792277PMC
August 2020

Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors.

Cardiooncology 2019 2;5:18. Epub 2019 Dec 2.

11Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children's Hospital, 1001 Main Street, Buffalo, NY 14203 USA.

Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional and newer anti-neoplastic therapies can cause short- and long-term cardiotoxicity. The clinical implications of this cardiotoxicity become more important with the increasing use of cardiotoxic drugs. The implications are especially serious among patients predisposed to adverse cardiac effects, such as youth, the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic radiation. However, the optimal strategy for preventing and managing chemotherapy-induced cardiotoxicity remains unknown. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use. The only United States Food and Drug Administration and European Medicines Agency approved treatment for preventing anthracycline-related cardiomyopathy is dexrazoxane. We advocate administering dexrazoxane during cancer treatment to limit the cardiotoxic effects of anthracycline chemotherapy.
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http://dx.doi.org/10.1186/s40959-019-0054-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048046PMC
December 2019

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group.

Cardiooncology 2019 28;5:15. Epub 2019 Oct 28.

6Department of Pediatrics, University at Buffalo, Oishei Children's Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA.

Background: Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.

Methods: We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.

Results: All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness scores ( < 0.01) and LV mass scores ( < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass scores were significantly smaller for girls ( < 0.01) and marginally smaller for boys ( = 0.06). Girls had significantly smaller LV end-diastolic dimension scores normalized to BSA ( < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.

Conclusions: Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.

Trial Registrations: ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.
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http://dx.doi.org/10.1186/s40959-019-0050-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048050PMC
October 2019

Cardiovascular diseases in survivors of childhood cancer.

Cancer Metastasis Rev 2020 03;39(1):55-68

Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.

Over the past few decades, the diagnosis and management of children with various malignancies have improved tremendously. As a result, there are an increasing number of children who are long-term cancer survivors. With improved survival, however, has come an increased risk of treatment-related cardiovascular complications that can appear decades after treatment. These problems are serious enough that all caregivers of childhood cancer survivors, including oncologists, cardiologists, and other health care personnel, must pay close attention to the short- and long-term effects of chemotherapy and radiotherapy on these children. This review discusses the effects of treatment-related cardiovascular complications from anthracyclines and radiotherapy and the methods for preventing, screening, and treating these complications.
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http://dx.doi.org/10.1007/s10555-020-09859-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123498PMC
March 2020

Left ventricle segmental function in childhood cancer survivors using speckle-tracking echocardiography.

Cardiol Young 2019 Dec 27;29(12):1494-1500. Epub 2019 Nov 27.

Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.

Aim: Anthracycline-associated cardiotoxicity in childhood cancer survivors may relate to global or segmental left ventricular abnormalities from associated thromboembolic events and myocardial microinfarcts. We characterized left ventricular segmental changes by two-dimensional speckle-tracking echocardiography in anthracycline-treated asymptomatic childhood cancer survivors.

Methods And Results: Childhood cancer survivors' echocardiograms with normal left ventricular fractional shortening >1 year after anthracycline chemotherapy were studied. Cancer-free control children had normal echocardiograms. Apical two-, three-, and four-chamber peak systolic left ventricular longitudinal and global longitudinal strain, and peak systolic left ventricular radial and circumferential strain at papillary muscle levels were analyzed. The mean (standard deviation) age was 12.7 (3.8) years in 41 childhood cancer survivors. The median (interquartile range) follow-up after anthracycline chemotherapy was 4.73 (2.15-8) years. The median (range) cumulative anthracycline dose was 160.2 (60-396.9) mg/m2. In childhood cancer survivors, the mean (standard deviation) left ventricular longitudinal strain was lower in two- (-18.6 [3.2] versus -21.3 [2.5], p < 0.001), three- (-16.3 [6.0] versus -21.7 [3.0], p < 0.001), and four- (-17.6 [2.7] versus -20.8 [2.0], p < 0.001) chamber views compared to controls. The left ventricular global longitudinal strain (-17.6 [2.7] versus -21.3 [2.0]) and circumferential strain (-20.8 [4.3] versus -23.5 [2.6], p < 0.001) were lower in childhood cancer survivors. Among childhood cancer survivors, 12 out of 16 left ventricular segments had significantly lower longitudinal strain than controls.

Conclusions: Asymptomatic anthracycline-treated childhood cancer survivors with normal left ventricular fractional shortening had lower global longitudinal and circumferential strain. The left ventricular longitudinal strain was lower in majority of the segments, suggesting that anthracycline cardiotoxicity is more global than regional.
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http://dx.doi.org/10.1017/S1047951119002622DOI Listing
December 2019

Left ventricular diastolic dysfunction in HIV-uninfected infants exposed in utero to antiretroviral therapy.

AIDS 2020 03;34(4):529-537

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Objectives: To longitudinally measure LV diastolic function in HIV-exposed but uninfected (HEU) children perinatally exposed to ART.

Design: HEU children who were perinatally exposed to antiretroviral therapy (ART) may be at risk for adverse cardiac effects. We have previously reported that those children have decreased left ventricular (LV) mass, dimension, and septal thickness with increased contractility.

Methods: Serial echocardiograms were obtained at specific times from birth to 48 months from two groups of HIV-uninfected children: 148 HIV-negative children who were perinatally exposed to ART and 130 non-ART-exposed HIV-unexposed healthy controls. The following LV diastolic indices were obtained: mitral valve early and late diastolic velocity (E and A), tissue Doppler-derived LV-free wall and septal early diastolic velocity (LV e' and sep e').

Results: All echocardiographic indices were significantly different in ART-exposed children compared with ART-unexposed healthy controls. Both E and A were overall lower at all ages by 8.28 cm/s (P = 0.0002) and 13.46 cm/s (P < 0.0001) respectively. E/A ratio was higher by 0.27, 0.46, and 0.28 units at birth, 1 year and 2 years of age, respectively (all P ≤ 0.01). Moreover, LV e' and sep e' were overall lower at all ages by 0.84 cm/s (P = 0.01) and 0.47 cm/s (P = 0.02), respectively.

Conclusion: Children who were exposed to ART in utero have subclinical yet significant differences in specific LV diastolic indices. Follow-up with serial echocardiograms are recommended in this population to further assess the potential cardiac toxicity of perinatal exposure to ART.
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http://dx.doi.org/10.1097/QAD.0000000000002443DOI Listing
March 2020

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

Prog Pediatr Cardiol 2019 Jun 7;53:1-10. Epub 2019 Mar 7.

Department of Pediatrics, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI.

Background: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy.

Study Design: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure.

Results: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years.

Conclusion: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children.

Clinical Trial Registration Nct01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.
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http://dx.doi.org/10.1016/j.ppedcard.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863618PMC
June 2019

Caffeine and Clinical Outcomes in Premature Neonates.

Children (Basel) 2019 Oct 24;6(11). Epub 2019 Oct 24.

Department of Pediatrics, University at Buffalo, Buffalo, NY 14203, USA.

Caffeine is the most widely used drug by both adults and children worldwide due to its ability to promote alertness and elevate moods. It is effective in the management of apnea of prematurity in premature infants. Caffeine for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia in very-low-birth-weight infants and improves survival without neurodevelopmental disability at 18-21 months. Follow-up studies of the infants in the Caffeine for Apnea of Prematurity trial highlight the long-term safety of caffeine in these infants, especially relating to motor, behavioral, and intelligence skills. However, in animal models, exposure to caffeine during pregnancy and lactation adversely affects neuronal development and adult behavior of their offspring. Prenatal caffeine predisposes to intrauterine growth restriction and small growth for gestational age at birth. However, in-utero exposure to caffeine is also associated with excess growth, obesity, and cardio-metabolic changes in children. Caffeine therapy is a significant advance in newborn care, conferring immediate benefits in preterm neonates. Studies should help define the appropriate therapeutic window for caffeine treatment along with with the mechanisms relating to its beneficial effects on the brain and the lung. The long-term consequences of caffeine in adults born preterm are being studied and may depend on the ability of caffeine to modulate both the expression and the maturation of adenosine receptors in infants treated with caffeine.
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http://dx.doi.org/10.3390/children6110118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915633PMC
October 2019

Stakeholder perspectives on addressing adverse events from adjuvant cancer therapy: A qualitative study.

Cancer 2019 Dec 27;125(24):4471-4480. Epub 2019 Aug 27.

Health Policy and Management, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina.

Background: With increasing survival rates, a growing population of patients with cancer have received or will receive adjuvant therapy to prevent cancer recurrences. Patients and caregivers will confront the complexities of balancing the preventative benefits of adjuvant therapy with possible near-term or long-term adverse events (AEs). Adjuvant treatment-related AEs (from minimal to severe) can impact therapeutic adherence, quality of life, emotional and physical health, and survival. However, to the authors' knowledge, limited information is available regarding how stakeholders use or desire to use adjuvant-related AE information to inform the care of patients with cancer.

Methods: A qualitative, purposeful sampling approach was used to elicit stakeholder feedback via semistructured interviews (24 interviews). Drug development, drug regulatory, clinical, payer, and patient/patient advocacy stakeholders were questioned about the generation, dissemination, and use of adjuvant treatment-related AE information to inform the care of patients with cancer. Transcripts were coded independently by 2 senior health care researchers and reconciled to identify key themes.

Results: All stakeholder groups in the current study identified needed improvements in each of the following 4 areas: 1) improving the accessibility and relevance of AE-related information; 2) better integrating and implementing available information regarding AEs for decisions; 3) connecting contemporary cultural and economic value systems to the generation and use of information regarding adjuvant treatment-related AEs; and 4) addressing a lack of alignment and ownership of stakeholder efforts to improve the use of AE information in the adjuvant setting.

Conclusions: Despite commonalities in the overall needs identified by the diverse stakeholders in the current study, broad systemic change has been stymied. The current study identified the lack of alignment and the absence of a central "owner" of these diffuse efforts as a previously unrecognized hurdle to realizing the desired systemic improvements. Future initiatives aimed at improving quality of life and outcomes for patients receiving adjuvant therapy through the improved use of AE information must address this challenge through innovative collectives and novel leadership strategies.
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http://dx.doi.org/10.1002/cncr.32448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916390PMC
December 2019

Short- and long-term safety and efficacy of bariatric surgery for severely obese adolescents: a narrative review.

Pediatr Res 2020 01 11;87(2):202-209. Epub 2019 Aug 11.

Division of Cardiology, Children's Hospital of Michigan, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.

The selection criteria, safety, and efficacy of bariatric surgery are well established in adults but are less well defined for severely obese adolescents. The number of severely obese adolescents who could benefit from weight loss surgery is increasing, although referral rates have plateaued. Surgical options for these adolescents are controversial and raise several questions. Recent studies, including the prospective Teen-Longitudinal Assessment of Bariatric Surgery Study and the Adolescent Morbid Obesity Surgery Study, help answer these questions. Early bariatric surgical intervention improves body mass index but, more importantly, improves cardiovascular and metabolic co-morbidities of severe obesity. A review of the medical, psychosocial, and economic risks and benefits of bariatric surgery in severely obese adolescents is a step toward improving the management of a challenging and increasing population. We describe the current knowledge of eligibility criteria, preoperative evaluation, surgical options, outcomes, and referral barriers of adolescents for bariatric surgery.
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http://dx.doi.org/10.1038/s41390-019-0532-3DOI Listing
January 2020

Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association.

Circulation 2019 07 28;140(1):e9-e68. Epub 2019 May 28.

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
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http://dx.doi.org/10.1161/CIR.0000000000000682DOI Listing
July 2019

Dilated cardiomyopathy.

Nat Rev Dis Primers 2019 05 9;5(1):32. Epub 2019 May 9.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.
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http://dx.doi.org/10.1038/s41572-019-0084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096917PMC
May 2019

Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents.

J Acquir Immune Defic Syndr 2019 06;81(2):238-246

Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI.

Background: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth.

Setting: The Adolescent Master Protocol is a Pediatric HIV/AIDS Cohort Study network study conducted across 14 US sites.

Methods: Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected (PHEU) youth enrolled in the Adolescent Master Protocol, we evaluated associations of vitamin D [measured as 25-hydroxy-vitamin D (25-OHD)], parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function, and concentrations of NT-proBNP, a biomarker of cardiac damage.

Results: Among 485 participants (305 PHIV and 180 PHEU) with echocardiograms and bone mineralization measures, low 25-OHD (<20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (>65 pg/mL) was identified more often among PHIV participants than PHEU participants (9% vs 3%, P = 0.02). After adjusting for HIV status and demographic covariates, both low 25-OHD and elevated PTH were associated with lower mean LV mass z-scores, whereas elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25-OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU participants than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness, both overall and among PHIV participants.

Conclusions: In this cohort of PHIV and PHEU youth, we observed associations of 25-OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.
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http://dx.doi.org/10.1097/QAI.0000000000002007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522268PMC
June 2019

Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series.

Cardiooncology 2019 29;5. Epub 2019 Jan 29.

12Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children's Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA.

Background: Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy.

Methods: Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane.

Results: Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m), and one received daunorubicin (540 mg/m). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure.

Conclusion: The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.
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http://dx.doi.org/10.1186/s40959-019-0036-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048095PMC
January 2019

A randomized controlled laboratory study on the long-term effects of methylphenidate on cardiovascular function and structure in rhesus monkeys.

Pediatr Res 2019 02 17;85(3):398-404. Epub 2018 Dec 17.

Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children's Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.

Background: Whether long-term methylphenidate (MPH) results in any changes in cardiovascular function or structure can only be properly addressed through a randomized trial using an animal model which permits elevated dosing over an extended period of time.

Methods: We studied 28 male rhesus monkeys (Macaca mulatta) approximately 7 years of age that had been randomly assigned to one of three MPH dosages: vehicle control (0 mg/kg, b.i.d., n = 9), low dose (2.5 mg/kg, b.i.d., n = 9), or high dose (12.5 mg/kg, b.i.d., n = 10). Dosage groups were compared on serum cardiovascular and inflammatory biomarkers, electrocardiograms (ECGs), echocardiograms, myocardial biopsies, and clinical pathology parameters following 5 years of uninterrupted dosing.

Results: With the exception of serum myoglobin, there were no statistical differences or apparent dose-response trends in clinical pathology, cardiac inflammatory biomarkers, ECGs, echocardiograms, or myocardial biopsies. The high-dose MPH group had a lower serum myoglobin concentration (979 ng/mL) than either the low-dose group (1882 ng/mL) or the control group (2182 ng/mL). The dose response was inversely proportional to dosage (P = .0006).

Conclusions: Although the findings cannot be directly generalized to humans, chronic MPH exposure is unlikely to be associated with increased cardiovascular risk in healthy children.
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http://dx.doi.org/10.1038/s41390-018-0256-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779032PMC
February 2019

When is early septal myectomy in children with hypertrophic cardiomyopathy justified?

Transl Pediatr 2018 Oct;7(4):362-366

Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.

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http://dx.doi.org/10.21037/tp.2018.09.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212380PMC
October 2018

Risk of Coronary Events 55 Years after Thymic Irradiation in the Hempelmann Cohort.

Cardiooncology 2018 17;4. Epub 2018 Feb 17.

Department of Epidemiology, Schools of Public Health and Health Professions and of Medicine, University of Florida, Gainesville, Florida.

Background: Studies of cancer survivors treated with older radiotherapy (RT) techniques (pre-1990s) strongly suggest that ionizing radiation to the chest increases the risk of coronary heart disease (CHD). Our goal was to evaluate the impact of more modern cardiac shielding techniques of RT on the magnitude and timing of CHD risk by studying a cohort exposed to similar levels of cardiac irradiation years ago.

Methods: Between 2004 and 2008, we re-established a population-based, longitudinal cohort of 2,657 subjects exposed to irradiation for an enlarged thymus during infancy between 1926 and 1957 and 4,388 of their non-irradiated siblings. CHD events were assessed using a mailed survey and from causes of death listed in the National Death Index. We used Poisson regression methods to compare incidence rates by irradiation status and cardiac radiation dose. Results were adjusted for the CHD risk factors of attained-age, sex, diabetes, dyslipidemia hypertension and smoking.

Results: Median age at time of follow-up was 57.5 years (range 41.2 - 88.8 yrs) for irradiated and non-irradiated siblings. The mean estimated cardiac dose amongst the irradiated was 1.45 Gray (range 0.17 - 20.20 Gy), with 91% receiving <3.00 Gy. During a combined 339,924 person-years of follow-up, 213 myocardial infarctions (MI) and 350 CHD events (MI, bypass surgery and angioplasty) occurred. After adjustment for attained age, gender, and other CHD risk factors, the rate ratio for MI incidence in the irradiated group was 0.98 (95%CI, 0.74 - 1.30), and for any CHD event was 1.07 (95%CI, 0.86 - 1.32). Higher radiation doses were not associated with more MIs or CHD events in this dose range, in either the crude or the adjusted analyses.

Conclusions: Radiation to the heart during childhood of <3 Gy, the exposure in most of our cohort, does not increase the lifelong risk of CHD. Reducing cardiac radiation to this amount without increasing other cardiotoxic therapies may eliminate the increased CHD risk associated with radiotherapy for childhood cancer. By extension there is unlikely to be increased CHD risk from relatively higher dose imaging techniques, such as CT, because such techniques use much smaller radiation doses than received by our cohort.
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http://dx.doi.org/10.1186/s40959-018-0027-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205237PMC
February 2018

Lowering the P Value Threshold.

JAMA 2018 09;320(9):936

Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, Michigan.

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http://dx.doi.org/10.1001/jama.2018.8717DOI Listing
September 2018

Cardiovascular disease in survivors of childhood cancer.

Curr Opin Pediatr 2018 10;30(5):628-638

Division of Pediatric Cardiology, Children's Hospital of Michigan, Detroit.

Purpose Of Review: We review the cardiotoxic chemotherapeutic agents, the clinical and subclinical presentations and progression of their cardiotoxicity, and the management of the subsequent cardiovascular disease in survivors of childhood cancer. We discuss various preventive measures, especially the cardioprotectant, dexrazoxane, whose use with anthracycline chemotherapy, including doxorubicin, is based on strong evidence. Most treatment recommendations for this unique population are based on expert opinion, not on empirical evidence.

Recent Findings: As patients with childhood cancers live longer, morbidity from the cardiac side effects of chemotherapy is increasing. Treatment-related cardiac damage is irreversible and often progressive. It is imperative that such damage be prevented with strategies such as limiting the cumulative anthracycline dose, the use of anthracycline structural analogues and the use of cardioprotective agents.

Summary: A deeper understanding of the mechanisms of their cardiotoxicity reveals that there is no 'safe' dose of anthracyclines. However, certain risk factors, such as higher lifetime anthracycline cumulative doses, higher anthracycline dose rates, female sex, longer follow-up, younger age at anthracycline treatment and cardiac irradiation, are associated with more severe cardiotoxicity. We advocate the use of dexrazoxane to limit the cardiotoxic effects of anthracycline chemotherapy.
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http://dx.doi.org/10.1097/MOP.0000000000000675DOI Listing
October 2018

Cardiac status of perinatally HIV-infected children: assessing combination antiretroviral regimens in observational studies.

AIDS 2018 10;32(16):2337-2346

Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA.

Objective: To evaluate potential adverse associations of individual antiretroviral medications used in combination antiretroviral therapy regimens on cardiac structure and function in youth with perinatally-acquired HIV infection (PHIV).

Design: PHIV youth (N = 325) enrolled in a prospective multisite cohort study had a single echocardiogram at age 7-16 years to evaluate cardiac function and structure.

Methods: We applied several statistical approaches to evaluate associations between use of 18 individual antiretroviral medications with Z-scores for 11 measures of left ventricular function and structure. These included simultaneously evaluating all antiretroviral medications in adjusted linear regression models controlling for the false discovery rate (FDR), applying hierarchical models to estimate individual antiretroviral medication effects as deviations from drug class means, and evaluating latent measures of cardiac function and structure underlying multiple echocardiographic parameters.

Results: Youth taking combination regimens with a protease inhibitor (69%) had significantly better cardiac function than those on other regimens. After FDR control and adjustment for other antiretroviral medications, no individual antiretroviral medication was significantly associated with any measure of left ventricular function, but zidovudine was associated with higher adjusted mean Z-scores for one measure of left ventricular structure (end-systolic wall stress). Factor analysis identified three latent factors: heart function, heart size, and heart wall stress. Lopinavir was associated with better heart function scores, whereas zidovudine was associated with higher wall stress scores. Zidovudine and nevirapine were associated with higher heart size factor scores.

Conclusions: Despite cardioprotective effects of combination regimens in PHIV youth, individual antiretroviral medications were associated with altered cardiac structure, which could progress to symptomatic cardiomyopathy in adulthood.
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http://dx.doi.org/10.1097/QAD.0000000000001988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519135PMC
October 2018

Letter by Lipshultz Regarding Article, "Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?"

Circ Res 2018 03;122(7):e62-e63

Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI.

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http://dx.doi.org/10.1161/CIRCRESAHA.118.312918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997275PMC
March 2018

Cardiac and inflammatory biomarkers in perinatally HIV-infected and HIV-exposed uninfected children.

AIDS 2018 06;32(10):1267-1277

Department of Pediatrics, School of Medicine, Wayne State University, Detroit, Michigan.

Objectives: To compare distributions of serum cardiac and inflammatory biomarkers between perinatally HIV-infected (PHIV) and perinatally HIV-exposed uninfected (PHEU) children, to evaluate their associations with echocardiographic measures, and among PHIV youth, with antiretroviral therapy (ART) and HIV disease severity measures.

Design: Cross-sectional analysis of temporally paired serum samples for biomarkers and echocardiograms in a prospective multicenter cohort study of PHIV and PHEU youth.

Methods: Serum samples were analyzed among 402 youth in the PHACS Adolescent Master Protocol (AMP) for high-sensitivity cardiac troponin-T (hs-cTnT, a cardiomyocyte injury marker), N-terminal-pro-brain natriuretic peptide (NT-proBNP, a myocardial stress marker), and inflammatory markers [high-sensitivity C-reactive protein, interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α (TNF-α), and soluble TNF receptor II (sTNF-RII)]. Echocardiograms were centrally measured and parameters converted to z cores to account for differences in age and body size.

Results: Compared with PHEU (N = 156), PHIV youth (N = 246) more often had detectable hs-cTnT and higher levels of sTNF-RII and IL-18. Higher inflammatory biomarkers were generally associated with higher left ventricular (LV) wall stress and lower LV function and LV mass in the two groups. Among PHIV youth, the biomarkers were more strongly associated with current rather than historical immunologic and virologic status.

Conclusion: PHEU and PHIV have modest, significant differences in serum levels of specific inflammatory and active myocardial injury biomarkers. Higher biomarker levels were associated with lower LV mass and shifts in LV structure. Further study is warranted on the longitudinal role of cardiac and inflammatory biomarkers for targeting interventions among PHIV and PHEU youth.
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http://dx.doi.org/10.1097/QAD.0000000000001810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387791PMC
June 2018

Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score.

Clin Genitourin Cancer 2018 08 5;16(4):e761-e769. Epub 2018 Feb 5.

Department of Oncology, Oslo University Hospital Radium Hospital, and Oslo University, Faculty of Medicine Oslo, Norway.

Background: Testicular cancer survivors (TCSs) are at increased risk of cardiovascular disease (CVD) after cisplatin-based chemotherapy (CBCT). Identifying at-risk survivors would allow early intervention, but risk prediction tools such as the Framingham Risk Score (FRS) have not been applied to TCSs given modern chemotherapy.

Methods: TCSs > 1 year post-CBCT were evaluated. Associations between FRS and clinical, socioeconomic, and lifestyle measures and treatment regimen (4 cycles, etoposide and cisplatin [EP × 4]); 3 or 4 cycles, bleomycin plus EP (BEP × 3, BEP × 4) were analyzed with general linear multivariable models. Controls from the National Health and Nutrition Examination Survey were matched 1:1 to TCSs by age, race, and education with differences in mean FRS evaluated with 2-sided t tests.

Results: Of 787 TCSs (median age, 37.3 years; median follow-up, 4.2 years), 284, 342, and 161 received EP × 4, BEP × 3, or BEP × 4, respectively. TCSs had higher median systolic blood pressure (126 vs. 119 mm Hg; P < .001), but fewer were smokers (8.4% vs. 28.2%; P < .001) than controls. In multivariable analysis, no significant differences in FRS between EP × 4, BEP × 3, and BEP × 4 were observed, but less than college education (P < .001) and lack of vigorous exercise (P = .006) were associated with higher FRS. Mean FRS did not differ between TCSs and controls (6.8% vs. 7.3%; P = .67).

Conclusion: This is the first study to apply the office-based FRS to TCSs. Chemotherapy regimen (BEP × 3 vs. EP × 4) was not associated with FRS, but less educated and less vigorously active patients had higher FRS, and present a high-risk subgroup for intense follow-up and counseling.
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http://dx.doi.org/10.1016/j.clgc.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063791PMC
August 2018

No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy.

JACC Heart Fail 2018 03 7;6(3):222-230. Epub 2018 Feb 7.

Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida.

Objectives: This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).

Background: In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.

Methods: The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI] <5% for age ≥2 years or weight-for-length <5% for <2 years), obesity (BMI >95% for age ≥2 years or weight-for-length >95% for <2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (n = 214) were MN, 13.3% (n=120) were obese, and 63.1% (n=570) were NB.

Results: Obese patients were older (9.0 vs. 5.7 years for NB; p < 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p = 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p < 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p = 0.012), cardiac dimension z-scores >2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p < 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p = 0.03), but no difference in transplant rate (p = 0.159).

Conclusions: Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391).
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http://dx.doi.org/10.1016/j.jchf.2017.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834393PMC
March 2018

Anthracycline cardiotoxicity: the importance of horizontally integrating pre-clinical and clinical research.

Cardiovasc Res 2018 02;114(2):205-209

Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, Rockville, MD 20850-9734, USA.

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http://dx.doi.org/10.1093/cvr/cvx246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852510PMC
February 2018

Survival Without Cardiac Transplantation Among Children With Dilated Cardiomyopathy.

J Am Coll Cardiol 2017 Nov;70(21):2663-2673

Department of Pediatrics, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, Michigan.

Background: Studies of children with dilated cardiomyopathy (DCM) have suggested that improved survival has been primarily due to utilization of heart transplantation.

Objectives: This study sought to determine transplant-free survival for these children over 20 years and identify the clinical characteristics at diagnosis that predicted death.

Methods: Children <18 years of age with some type of DCM enrolled in the Pediatric Cardiomyopathy Registry were divided by year of diagnosis into an early cohort (1990 to 1999) and a late cohort (2000 to 2009). Competing risks and multivariable modeling were used to estimate the cumulative incidence of death, transplant, and echocardiographic normalization by cohort and to identify the factors associated with death.

Results: Of 1,953 children, 1,199 were in the early cohort and 754 were in the late cohort. Most children in both cohorts had idiopathic DCM (64% vs. 63%, respectively). Median age (1.6 vs. 1.7 years), left ventricular end-diastolic z-scores (+4.2 vs. +4.2), and left ventricular fractional shortening (16% vs. 17%) at diagnosis were similar between cohorts. Although the rates of echocardiographic normalization (30% and 27%) and heart transplantation (24% and 24%) were similar, the death rate was higher in the early cohort than in the late cohort (18% vs. 9%; p = 0.04). Being in the early cohort (hazard ratio: 1.4; 95% confidence interval: 1.04 to 1.9; p = 0.03) independently predicted death.

Conclusions: Children with DCM have improved survival in the more recent era. This appears to be associated with factors other than heart transplantation, which was equally prevalent in both eras. (Pediatric Cardiomyopathy Registry [PCMR]; NCT00005391).
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http://dx.doi.org/10.1016/j.jacc.2017.09.1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726578PMC
November 2017

Cardiac Effects of Highly Active Antiretroviral Therapy in Perinatally HIV-Infected Children: The CHAART-2 Study.

J Am Coll Cardiol 2017 Oct;70(18):2240-2247

Boston Children's Hospital, Boston, Massachusetts.

Background: Before the introduction of highly active antiretroviral therapy (HAART), cardiac mortality and morbidity were common in HIV-infected children.

Objectives: This study sought to identify long-term cardiovascular effects of HAART in HIV-infected children.

Methods: The CHAART-2 (HAART-Associated Cardiotoxicity in HIV-Infected Children) study prospectively compared 148 echocardiograms from 74 HAART-exposed children to 860 echocardiograms from 140 HAART-unexposed but HIV-infected children from the Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (PC HIV) study. Both studies used similar protocol, centralized echocardiographic interpretation, and measures expressed as z-scores referenced to healthy controls. Associations between HAART exposure and echocardiographic measures were evaluated using generalized estimating equations.

Results: Comparing the HAART-exposed and HAART-unexposed groups, any HAART exposure was positively associated with left ventricular (LV) fractional shortening (z-score for difference = 1.07; p = 0.02) and HAART exposure duration (z-score difference per year = 0.17; p = 0.003. LV mass was negatively associated with any HAART exposure (z-score difference = -0.64; p = 0.01) as was septal thickness (z-score difference = -0.93; p = 0.001). Duration of HAART exposure was negatively associated with LV end-systolic dimension and heart rate (z-score difference per year= -0.11; p = 0.05; and z-score difference per year = -0.10; p = 0.002, respectively). During 11 years of follow-up, in the HAART-exposed group, LV mass and LV end-diastolic septal thickness were lower whereas LV contractility and LV fractional shortening were higher when compared to the HAART-unexposed group.

Conclusions: Cardiac structure and function were better in perinatally HIV-infected children exposed to HAART than in those of similar children from the pre-HAART era but did decline over time. Evidence-based strategies for cardiovascular monitoring are needed to inform treatment decisions to improve long-term cardiovascular health.
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http://dx.doi.org/10.1016/j.jacc.2017.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687306PMC
October 2017

Pediatric Cardiomyopathies.

Circ Res 2017 Sep;121(7):855-873

From the Department of Pediatrics, Columbia University Medical Center, New York, NY (T.M.L., W.K.C., L.J.A.); Department of Pediatrics, Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, NY (D.T.H., J.M.L.); Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, Canada (P.K.); Department of Pediatrics, The Heart Institute, Le Bonheur Children's Hospital, Memphis, TN (J.A.T.); Indiana University School of Medicine, Indianapolis (S.M.W.); Department of Cardiology, Boston Children's Hospital, MA (S.D.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (J.L.J., E.M.M.); Department of Pediatrics, Children's Hospital of Philadelphia, PA (J.W.R.); Department of Pediatrics, Washington University School of Medicine, St. Louis, MO (C.D.C.); Department of Pediatrics, Primary Children's Hospital, Salt Lake City, UT (A.K.L.); Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital, Chicago, IL (P.T.T.); and Department of Pediatrics, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit (J.D.C., H.R., A.H., S.E.L.).

Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657298PMC
September 2017