Woo-Baek Chung

Bio: Woo-Baek Chung is an academic researcher from Catholic University of Korea. The author has contributed to research in topics: Cardiotoxicity & Candesartan. The author has an hindex of 9, co-authored 40 publications receiving 242 citations. Previous affiliations of Woo-Baek Chung include St Mary's Hospital.

Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity

Abstract: Cardiotoxicity is a well-known complication following treatment with anthracyclines. However, they are still widely used in chemotherapy for breast cancer, lymphoma, leukemia, and sarcoma, among others. Patient clinical characteristics, such as age, sex, comorbidities, anthracycline dose and infusion schedule, and the combined anti-cancer agents used, are diverse among cancer types. It is difficult to recommend guidelines for the prevention or management of anthracycline-induced cardiotoxicity applicable to all cancer types. Therefore, anthracycline-induced cardiotoxicity remains a major limitation in the proper management of cancer patients treated with an anthracycline-combined regimen. Efforts have been extensive to determine the mechanism and treatment of anthracycline-induced cardiotoxicity. Because cardiotoxicity causes irreversible damage to the myocardium, prevention is a more effective approach than treatment of cardiotoxicity after symptomatic or asymptomatic cardiac dysfunction develops. This article will review the pathophysiological mechanisms of anthracycline-induced cardiotoxicity and strategies for protecting the myocardium from anthracycline.

Early cardiac function monitoring for detection of subclinical Doxorubicin cardiotoxicity in young adult patients with breast cancer.

Abstract: PURPOSE: As doxorubicin cardiotoxicity is considered irreversible, early detection of cardiotoxicity and prevention of overt heart failure is essential. Although there are monitoring guidelines for cardiotoxicity, optimal timing for early detection of subclinical doxorubicin cardiotoxicity is still obscure. The purpose of this study is to determine optimal timing of cardiac monitoring and risk factors for early detection of doxorubicin cardiotoxicity in young adult patients with breast cancer. METHODS: Medical records of 1,013 breast cancer patients diagnosed from January 2009 to December 2010 is being reviewed and analyzed. Properly monitored patients are defined as patients who underwent transthoracic echocardiography before and after the chemotherapy. The definition of subclinical cardiotoxicity (SC) either decreases left ventricular ejection fraction (LVEF) more than 10% or the LVEF declines under 55% from baseline without heart failure symptoms. RESULTS: Twenty-nine out of 174 (16.7%) properly monitored young adult female patients (mean age, 52±10 years old) developed SC. The mean interval of cardiac evaluation of SC group was 5.5±3.0 months. Among the risk factors, the history of coronary artery disease, cumulative dose of doxorubicin ≥300 mg/m(2) and use of trastuzumab after doxorubicin therapy were associated with development of SC. At cumulative dose of doxorubicin 244.5 mg/m(2), SC can be predicted (sensitivity, 71.4%; specificity, 70.9%; area under the curve, 0.741; 95% confidence interval, 0.608-0.874; p=0.001). CONCLUSION: In young adult patients with breast cancer, SC was common at cumulative dose of doxorubicin <300 mg/m(2) and early performance of cardiac monitoring before reaching the conventional critical dose of doxorubicin might be a proper strategy for early detection of SC.

A case of chloroquine-induced cardiomyopathy that presented as sick sinus syndrome.

Abstract: A 52-year-old woman with rheumatoid arthritis who had been treated with prednisone and hydroxychloroquine for >12 years presented with chest discomfort and a seizure. She was diagnosed with restrictive cardiomyopathy combined with sick sinus syndrome. A myocardial muscle biopsy was performed to identify the underlying cardiomyopathy, which showed marked muscle fiber hypertrophy, fiber dropout, slightly increased interstitial fibrous connective tissue, and extensive cytoplasmic vacuolization of the myocytes under light microscopy. Electron microscopy of the myocytes demonstrated dense, myeloid, and curvilinear bodies. The diagnosis of hydroxychloroquine-induced cardiomyopathy was made based on the clinical, hemodynamic, and pathologic findings. This is the first case report describing chloroquine-induced cardiomyopathy involving the heart conduction system.

Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature

Abstract: Chloroquine and hydroxychloroquine are widely used in the long-term treatment of connective tissue disease and usually considered safe. However, chloroquine- or hydroxychloroquine-related cardiac disorder is a rare but severe adverse event, which can lead to death. This systematic review investigates cardiac complications attributed to chloroquine and hydroxychloroquine. PubMED, EMBASE, and Cochrane database searches were conducted using keywords derived from MeSH terms. Reports published prior to 31 July, 2017 were eligible for inclusion, without restriction to study design. Searches were also conducted on reference lists of included studies. Eighty-six articles were identified, reporting individual cases or short series, providing information on 127 patients (65.4% female). A majority of patients were treated with chloroquine (58.3%), with the remaining treated with hydroxychloroquine (39.4%), or both in succession. Most patients had been treated for a long time (median 7 years, minimum 3 days; maximum 35 years) and with a high cumulative dose (median 1235 g for hydroxychloroquine and 803 g for chloroquine). Conduction disorders were the main side effect reported, affecting 85% of patients. Other non-specific adverse cardiac events included ventricular hypertrophy (22%), hypokinesia (9.4%), heart failure (26.8%), pulmonary arterial hypertension (3.9%), and valvular dysfunction (7.1%). For 78 patients reported to have been withdrawn from treatment, some recovered normal heart function (44.9%), while for others progression was unfavorable, resulting in irreversible damage (12.9%) or death (30.8%). The risk of cardiac complications attributed to chloroquine/hydroxychloroquine was not quantified because of the lack of randomized controlled trials and observational studies investigating the association. Clinicians should be warned that chloroquine- or hydroxychloroquine-related cardiac manifestations, even conduction disorders without repercussion, may be initial manifestations of toxicity, and are potentially irreversible. Therefore, treatment withdrawal is required when cardiac manifestations are present.

Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention.

Abstract: Atrial fibrillation (AF) is associated with significant morbidity and mortality. It is also a progressive disease secondary to continuous structural remodelling of the atria due to AF itself, to changes associated with ageing, and to deterioration of underlying heart disease. Current management aims at preventing the recurrence of AF and its consequences (secondary prevention) and includes risk assessment and prevention of stroke, ventricular rate control, and rhythm control therapies including antiarrhythmic drugs and catheter or surgical ablation. The concept of primary prevention of AF with interventions targeting the development of substrate and modifying risk factors for AF has emerged as a result of recent experiments that suggested novel targets for mechanism-based therapies. Upstream therapy refers to the use of non-antiarrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. Such agents include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins, n-3 (ω-3) polyunsaturated fatty acids, and possibly corticosteroids. Animal experiments have compellingly demonstrated the protective effect of these agents against electrical and structural atrial remodelling in association with AF. The key targets of upstream therapy are structural changes in the atria, such as fibrosis, hypertrophy, inflammation, and oxidative stress, but direct and indirect effects on atrial ion channels, gap junctions, and calcium handling are also applied. Although there have been no formal randomized controlled studies (RCTs) in the primary prevention setting, retrospective analyses and reports from the studies in which AF was a pre-specified secondary endpoint have shown a sustained reduction in new-onset AF with ACEIs and ARBs in patients with significant underlying heart disease (e.g. left ventricular dysfunction and hypertrophy), and in the incidence of AF after cardiac surgery in patients treated with statins. In the secondary prevention setting, the results with upstream therapies are significantly less encouraging. Although the results of hypothesis-generating small clinical studies or retrospective analyses in selected patient categories have been positive, larger prospective RCTs have yielded controversial, mostly negative, results. Notably, the controversy exists on whether upstream therapy may impact mortality and major non-fatal cardiovascular events in patients with AF. This has been addressed in retrospective analyses and large prospective RCTs, but the results remain inconclusive pending further reports. This review provides a contemporary evidence-based insight into the role of upstream therapies in primary (Part I) and secondary (Part II) prevention of AF.

Overweight and Obesity as Risk Factors for Atrial Fibrillation or Flutter: The Danish Diet, Cancer, and Health Study

Abstract: Purpose We examined the association between the body mass index analyzed as a continuous variable and by categorization according to World Health Organization criteria (normal weight, overweight and obesity) and the risk of a hospital (inpatient as well as outpatient) diagnosis of atrial fibrillation or flutter. Methods Population-based prospective cohort study conducted from December 1993 to December 2001 among 47589 participants (22482 men and 25107 women) without preexisting cardiovascular or endocrine disease and with a mean age at baseline of 56 years (range 50-64 years) in the Danish Diet, Cancer, and Health Study. Subjects were followed up in the Danish National Registry of Patients and in the Danish Civil Registration System. Results During follow-up (mean, 5.7 years) atrial fibrillation or flutter developed in 553 subjects (372 men and 181 women). The adjusted hazard ratio for atrial fibrillation or flutter per unit of increase in the body mass index was 1.08 (95% confidence interval [CI]: 1.05 to 1.11) in men and 1.06 (95% CI: 1.03 to 1.09) in women. When using normal weight as a reference, the adjusted hazard ratio for atrial fibrillation or flutter by overweight was 1.75 (95% CI: 1.35 to 2.27) in men and 1.39 (95% CI: 0.99 to 1.94) in women. The adjusted hazard ratio by obesity was 2.35 (95% CI: 1.70 to 3.25) in men and 1.99 (95% CI: 1.31 to 3.02) in women. Conclusion Overweight and obesity are associated with an increased risk of a diagnosis of atrial fibrillation or flutter.

MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2.

Abstract: Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity.