Juvenile Exposure to Anthracyclines Impairs Cardiac Progenitor Cell Function and Vascularization Resulting in Greater Susceptibility to Stress-Induced Myocardial Injury in Adult Mice

Huang, Cai; Zhang, Xiaoxue; Ramil, Jennifer; Rikka, Shivaji; Kim, Lucy; Lee, Youngil; Gude, Natalie; Thistlethwaite, Patricia A.; Sussman, Mark A.; Gottlieb, Roberta A.; Gustafsson, Åsa B.

doi:10.1161/circulationaha.109.902221

Cited by 175 publications

(160 citation statements)

References 42 publications

(41 reference statements)

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“…However, Huang recently demonstrated that anthracycline causes depletion of the cardiac stem cells in mice exposed to anthracycline as "juveniles." 31 This destruction of cardiomyocyte progenitors in the young heart may lead to inadequate myocardial mass as the child grows. 31,48 Low myocardial mass results in a pathological increase in afterload, even in normotensive patients.…”

Section: Clinical Risk Factorsmentioning

confidence: 99%

“…31 This destruction of cardiomyocyte progenitors in the young heart may lead to inadequate myocardial mass as the child grows. 31,48 Low myocardial mass results in a pathological increase in afterload, even in normotensive patients. Other important cardiac stressors may include pregnancy for women, surgery, myocarditis, or ischemia.…”

Section: Clinical Risk Factorsmentioning

confidence: 99%

See 1 more Smart Citation

Cardiovascular Disease

Chen

Colan

Diller

2011

Circulation Research

105

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Although important advances have been made in curing childhood cancer in the last several decades, long-term survivors face considerable morbidity and mortality because of late effects from their initial anticancer therapy. By 30 years after treatment, the cumulative mortality from treatment-related medical illness actually exceeds that of mortality from cancer recurrence. Cardiovascular disease, in particular, is a leading threat to the well-being of adult survivors of childhood cancers. Unfortunately, the mechanisms of these late cardiac effects are understudied and poorly understood. This article reviews cardiotoxicity associated with 2 major anticancer regimens used in treating childhood cancer patients: anthracycline treatment and radiation therapy. The known pathophysiology and clinical cardiac risk factors that further predispose these patients to late-onset cardiac events are discussed. Basic and translational research is urgently needed to clarify pathophysiologic mechanisms of late cardiac effects and to develop therapies to improve both long-term survival and quality of life of adults cured of pediatric cancers. (Circ Res. 2011;108:619-628.) Key Words: anthracycline Ⅲ radiation Ⅲ cardiotoxicity Ⅲ cancer survivor Ⅲ childhood T he great majority of children who develop childhood cancer today are cured. In the last 40 years, the 5-year survival for childhood cancers has increased from 30% to 80%. 1 Currently, there are an estimated 328 000 childhood cancer survivors in the United States, 2 and it is estimated that 1 in 640 young adults between the ages of 20 and 39 is a survivor of childhood cancer. 1,3 This ever-increasing population of young adult cancer survivors is a testament to the enormous progress made by modern anticancer therapeutics and medical care.Despite a high cure rate, childhood cancer survivors exhibit a long-term survival rate that significantly lags behind ageand gender-matched population controls ( Figure 1A). These patients face considerable mortality during adulthood; excess risks in patients may shorten the lifespan of a survivor by an average of 10 years, as compared with the general population of the United States. 4 Surprisingly, it is not recurrence of the original cancer that is the cause; instead, the intensity of anticancer therapy to achieve cure increases the risk of treatment-related medical illnesses, organ dysfunction, andOriginal received August 27, 2010; resubmission received August 27, 2010; revised resubmission received October 30, 2010; accepted November 16, 2010. In October 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.9 days. secondary cancers. These "late effects," defined as medical complications occurring greater than 5 years after cancer treatment, significantly reduce the long-term health of childhood cancer survivors. The risk of late effects progressively increases with time following completion of anticancer therapy so that, at 30 years after cancer therapy,...

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Section: Clinical Risk Factorsmentioning

confidence: 99%

Section: Clinical Risk Factorsmentioning

confidence: 99%

Cardiovascular Disease

Chen

Colan

Diller

2011

Circulation Research

105

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“…Huang et al [30] demonstrated that anthracyclines induce a loss of cardiac progenitor cells in young mice at doses of anthracyclines that might be considered more in line with those used clinically. They exposed young "juvenile" mice to repeated low doses of doxorubicin and found that the number of cardiac progenitor cells decreased in hearts after exposure.…”

Section: Lessons From Oncology -Could Anthracyclines Be Used To Regrementioning

confidence: 99%

How Can we Improve Non-Surgical Septal Reduction for Hypertrophic Obstructive Cardiomyopathy?

Cleator¹,

Kasasbeh²

2016

J Cardiovasc Dis Diagn

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The goal for treatment of medical refractory Hypertrophic Obstructive Cardiomyopathy (HCM) is reduction of the hypertrophied left ventricular septum which obstructs blood flow. A surgical approach consists of an open-heart myomectomy, while the less invasive percutaneous approach involves creating a myocardial infarction by injecting 95 to 100% ethanol through a septal artery, a procedure termed alcohol septal ablation (ASA). Although less invasive than myomectomy, there are several limitations of alcohol septal ablation. The most important appears to be full thickness infarction that is often complicated by heart block and ventricular tachycardia/fibrillation. The ideal therapy for septal hypertrophy would be to find an agent that induces a less severe injury and/or atrophy of the hypertrophied septum. We review several alternative techniques for selective injury of the septum and describe the ideal characteristics of such an ideal agent. Our central hypothesis is that the anthracycline antibiotic such as doxorubicin may be the perfect agent. Anthracycline-based chemotherapies have been used in the treatment of solid and hematological tumors for many years. These agents have known cardiotoxic side effects that are related to cumulative dose which can lead to heart failure. Although the mechanism of action of doxorubicin cardiotoxicity is controversial, it is very clear that these agents cause atrophy of the myocardium, induce apoptosis and necrosis, as well as anti-angiogenic effects. We propose that selectively treating the hypertrophied septum of HCM patients with injection of the anthracycline doxorubicin will lead to superior outcomes compared to ASA.

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“…A recent study proposed that impairment of cardiac progenitor cells was involved in the pathogenesis of late-onset cardiotoxicity. 15 Currently, early diagnosis and intensive treatment have greatly improved the prognosis of anthracycline-related cardiac failure. Nonetheless, certain patients with late-onset cardiomyopathy require cardiac transplantation.…”

Section: Minami M Et Almentioning

confidence: 99%