Cancer therapy-related cardiac dysfunction and the role of cardiovascular imaging: systemic review and opinion paper from the Working Group on Cardio-Oncology of the Korean Society of Cardiology.

Cardio-oncology is a critical field due to the escalating significance of cardiovascular toxicity as a side effect of anticancer treatments. Cancer therapy-related cardiac dysfunction (CTRCD) is a prevalent condition associated with cardiovascular toxicity, necessitating effective strategies for prediction, monitoring, management, and tracking. This comprehensive review examines the definition and risk stratification of CTRCD, explores monitoring approaches during anticancer therapy, and highlights specific cardiovascular toxicities linked to various cancer treatments. These include anthracyclines, HER2-targeted agents, vascular endothelial growth factor inhibitors, immune checkpoint inhibitors, chimeric antigen receptor T-cell therapies, and tumor-infiltrating lymphocytes therapies. Incorporating the Korean data, this review offers insights into the regional nuances in managing CTRCD. Using systematic follow-up incorporating cardiovascular imaging and biomarkers, a better understanding and management of CTRCD can be achieved, optimizing the cardiovascular health of both cancer patients and survivors.

Breast Cancer and Therapy-Related Cardiovascular Toxicity.

The global incidence of breast cancer is on the rise, a trend also observed in South Korea. However, thanks to the rapid advancements in anticancer therapies, survival rates are improving. Consequently, post-treatment health and quality of life for breast cancer survivors are emerging as significant concerns, particularly regarding treatment-related cardiotoxicity. In this review, we delve into the cardiovascular complications associated with breast cancer treatment, explore surveillance protocols for early detection and diagnosis of late complications, and discuss protective strategies against cardiotoxicity in breast cancer patients undergoing anticancer therapy, drawing from multiple guidelines.

Double-chambered left ventricle with a thrombus in an asymptomatic patient: A case report.

BACKGROUND: Double-chambered left ventricle (DCLV) is an extremely rare congenital disease in which the left ventricle (LV) is divided by abnormal muscle tissue. Due to its rarity, there is a lack of data on the disease, including its diagnosis, treatment, and prognosis. Accordingly, we report a case in which DCLV was diagnosed and followed up. CASE SUMMARY: A 45-year-old man presented to our hospital due to abnormal findings on an electrocardiogram recorded during a health check. He had no specific cardiac symptoms, comorbidities or relevant past medical history. Echocardiography revealed that the LV was divided into two by muscle fibers. There were no findings of ischemia on coronary angiography and coronary computed tomography angiography performed to exclude differential diagnoses. After comprehensive analysis of the images, DCLV was diagnosed. As it seemed to be asymptomatic DCLV, we decided the patient was to be observed without administering any medication. However, follow-up echocardiography revealed a thrombus in the accessory chamber (AC). Anticoagulant medication was initiated, the thrombus resolved, and the patient is currently undergoing follow-up without any specific symptoms. CONCLUSION: Asymptomatic, uncomplicated DCLV was diagnosed through multimodal imaging; however, a thrombus in the AC occurred during the follow-up. The findings highlight that multimodal imaging is essential in diagnosing DCLV, and that anticoagulation is important in its management.

Sodium-glucose cotransporter-2 inhibitors improve clinical outcomes in patients with type 2 diabetes mellitus undergoing anthracycline-containing chemotherapy: an emulated target trial using nationwide cohort data in South Korea.

Novel hypoglycemic agents, sodium-glucose cotransporter 2 inhibitors (SGLT2i), have shown protective effects against anthracycline (AC)-induced cardiotoxicity and exhibit partial anticancer effects in animal models. However, clinical evidence for this is scarce. This study aimed to evaluate whether SGLT2i improve the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) undergoing AC-containing chemotherapy. A total of 81,572 patients who underwent AC chemotherapy between 2014 and 2021 were recruited from a nationwide Korean cohort. Patients were classified into three groups: patients with T2DM taking SGLT2i (n = 780) and other hypoglycemic agents excluding SGLT2i (non-SGLT2i; n = 3,455) during AC chemotherapy, and the non-DM group (n = 77,337). The clinical outcome was a composite of heart failure hospitalization, acute myocardial infarction, ischemic stroke, and death. After propensity score matching, 779 SGLT2i users were compared with 7800 non-DM patients and 2,337 non-SGLT2i users. The SGLT2i group had better composite outcomes compared with the non-DM group (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [95% CI] = 0.25-0.51) and compared with the non-SGLT2i group (adjusted HR = 0.47, 95% CI = 0.32-0.69). In conclusion, SGLT2i may contribute to improving clinical outcomes in patients with T2DM undergoing AC-containing chemotherapy, through an emulated target trial using Korean nationwide cohort data.

Impact on clinical outcomes of renin-angiotensin system inhibitors against doxorubicin-related toxicity in patients with breast cancer and hypertension: A nationwide cohort study in South Korea.

BACKGROUND: Although doxorubicin (DOX) is a commonly used potent chemotherapeutic agent in patients with breast cancer, its cardiotoxic effect is a concern, particularly in patients with hypertension. Antihypertensive renin-angiotensin system (RAS) inhibitors may potentially play a role in preventing overt heart failure (HF) due to DOX toxicity. This study aimed to evaluate whether the use of RAS inhibitors improves clinical outcomes in patients with hypertension and breast cancer undergoing DOX-containing chemotherapy. METHODS: A total of 54,344 female patients who were first diagnosed with breast cancer and initiated into DOX therapy between 2008 and 2015 were recruited from a nationwide Korean cohort. Patients were divided into two groups: with and without hypertension (HT, n = 10,789; non-HT, n = 43,555), and the RAS inhibitor group (n = 1,728) was sub-classified from the HT group. Two propensity score-matched cohorts were constructed to compare the clinical outcomes between non-HT and HT groups and between non-HT and RAS inhibitor groups. The primary outcome was the composite of HF and death. RESULTS: After propensity score matching, the HT group had a higher risk for HF (adjusted hazard ratio [HR] = 1.30, 95% confidence intervals [95% CI] = 1.09-1.55) compared to the non-HT group, but there was no significant difference in primary outcome between the two groups. The RAS inhibitor group had a lower risk for primary outcome (adjusted HR = 0.78, 95% CI = 0.65-0.94) and death (adjusted HR = 0.81, 95% CI = 0.66-0.99) compared to the non-HT group. CONCLUSIONS: Hypertension is a risk factor for HF in patients with breast cancer undergoing DOX chemotherapy. However, the RAS inhibitors used to treat hypertension may contribute to decreased mortality and improved clinical outcomes.

Missed a live match? Determinants of League of Legends Champions Korea highlights viewership.

This research aims to explore the determinants of the League of Legends Champions Korea (LCK) highlight views and comment counts. The data of 629 game highlight views and comment counts for seven tournaments were collected from YouTube. The highlight views and comment counts were regressed on a series of before-the-game factors (outcome uncertainty and game quality), after-the-game factors (sum and difference of kills, assists, multiple kills, and upset results), and match-related characteristics (game duration, evening game, and clip recentness). A multi-level least square dummy variable regression was conducted to test the model. Among the before-the-game factors, outcome uncertainty and game quality were significantly associated with highlight views and comment counts. This indicated that fans liked watching games with uncertain outcomes and those involving high-quality teams. Among the after-the-game factors, an upset result was a significant determinant of esports highlight views and comment counts. Thus, fans enjoy watching underdogs win. Finally, the sum of kills and assists only affected view counts, which indicated that fans prefer watching offensive games with more kills and a solo performance rather than teamwork.

Differential Cardiovascular Outcomes of Each Antihypertensive Drug Class in Patients With Hypertension and Breast Cancer Undergoing Doxorubicin-Containing Chemotherapy.

PURPOSE: The preemptive use of renin-angiotensin system (RAS) inhibitors may reduce doxorubicin (DOX)-related cardiotoxicity. Using the national insurance claims data of Korea, this study compared cardiovascular (CV) outcomes following the use of four major antihypertensive drug classes in patients with hypertension and breast cancer who underwent DOX-containing chemotherapy. METHODS: A total of 4,722 patients with hypertension and breast cancer who underwent DOX-containing chemotherapy were included. The outcomes were compared between patients who used RAS inhibitors, calcium channel blockers (CCBs), beta-blockers (BBs), and thiazide and thiazide-like diuretics (TDs). The primary outcome was a composite of incident heart failure and serious ventricular arrhythmias, including ventricular tachycardia and fibrillation, ischemic heart disease, and stroke. RESULTS: In the propensity score-matched population, there were no significant differences in the primary outcome between RAS inhibitor and CCB users; however, patients with diabetes who used CCBs had a worse primary outcome than those who used RAS inhibitors (adjusted hazard ratio [aHR], 1.93; 95% confidence interval [CI], 1.06-3.51). BB and TD users had a worse primary outcome compared with RAS inhibitor (aHR, 1.88; 95% CI, 1.30-2.71 in BB users and aHR, 2.55; 95% CI, 1.37-4.75 in TD users) or CCB (aHR, 1.54; 95% CI, 1.09-2.16 in BB users and aHR, 2.08; 95% CI, 1.13-3.82 in TD users) users. CONCLUSION: RAS inhibitors are preferred for the treating hypertension and improving CV outcomes in patients with hypertension and breast cancer undergoing DOX-containing chemotherapy, particularly in patients with comorbid diabetes. However, CCBs are equivalent to RAS inhibitors and are more favorable than BBs and TDs in terms of improving CV outcomes.

Adherence and clinical outcomes for twice-daily versus once-daily dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: Is dosing frequency important?

BACKGROUND: Twice-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may reduce drug adherence compared with once-daily dosing of NOACs in patients with atrial fibrillation (AF), thus worsening clinical outcomes. We evaluated adherence to apixaban and dabigatran requiring twice-daily dosing compared with edoxaban or rivaroxaban with a once-daily dosing regimen and the subsequent clinical outcomes in patients with AF. METHODS: Adherence to each NOAC and outcomes were compared between patients who were diagnosed with AF and initiated NOACs between 2016 and 2017 using Korean claims data. High adherence was defined as the proportion of days covered (PDC) of the index NOAC ≥80%. The clinical outcomes included stroke, acute myocardial infarction, death, and composite outcome. RESULTS: A total of 33,515 patients were analyzed (mean follow-up, 1.7 ± 1.3 years). The proportion of patients with high adherence to NOACs was 95%, which did not significantly differ according to the dosing regimen. The mean PDC for NOACs was as high as ~96%, which was the highest for apixaban users, intermediate for edoxaban or rivaroxaban users, and lowest for dabigatran users, regardless of the dosing regimen. Adverse outcomes in low adherence patients for each NOAC were higher than that of high adherence patients, regardless of the dosing frequency. CONCLUSIONS: Adherence between once- and twice-daily dosing NOACs in patients with AF was high and similar among both dosing regimens. Patients with low NOAC adherence had poorer clinical outcomes, regardless of the dosing frequency.

Mitochondrial ROS Produced in Human Colon Carcinoma Associated with Cell Survival via Autophagy.

Human colon carcinomas, including HCT116 cells, often exhibit high autophagic flux under nutrient deprivation or hypoxic conditions. Mitochondrial ROS (mROS) is known as a 'molecular switch' for regulating the autophagic pathway, which is critical for directing cancer cell survival or death. In early tumorigenesis, autophagy plays important roles in maintaining cellular homeostasis and contributes to tumor growth. However, the relationships between mROS and the autophagic capacities of HCT116 cells are poorly understood. Ubiquinol cytochrome c reductase binding protein (UQCRB) has been reported as a biomarker of colorectal cancer, but its role in tumor growth has not been clarified. Here, we showed that UQCRB is overexpressed in HCT116 cells compared to CCD18co cells, a normal colon fibroblast cell line. Pharmacological inhibition of UQCRB reduced mROS levels, autophagic flux, and the growth of HCT116 tumors in a xenograft mouse model. We further investigated mutant UQCRB-overexpressing cell lines to identify functional links in UQCRB-mROS-autophagy. Notably, an increasing level of mROS caused by UQCRB overexpression released Ca2+ by the activation of lysosomal transient receptor potential mucolipin 1 (TRPML1) channels. This activation induced transcription factor EB (TFEB) nuclear translocation and lysosome biogenesis, leading to autophagy flux. Collectively, our study showed that increasing levels of mROS caused by the overexpression of UQCRB in human colon carcinoma HCT116 cells could be linked to autophagy for cell survival.

Does diabetes increase the risk of cardiovascular events in patients with negative treadmill stress echocardiography?

Cardiovascular morbidity and mortality rates are considered to be high in patients with diabetes despite negative stress test results; however, little data are available to support this supposition. We compared the long-term cardiovascular events between patients with diabetes and those without diabetes with negative treadmill stress echocardiography and evaluated the predictors for cardiovascular events in patients with diabetes. A total of 1,243 consecutive patients (mean age, 56 ± 10 years; non-diabetics: diabetics, 975:268; mean follow-up of 5 years) with negative treadmill stress echocardiography were evaluated. Clinical data were examined, and major adverse cardiovascular events (MACEs, a composite of coronary revascularization, acute myocardial infarction, and cardiovascular death) were compared between the non-diabetic and diabetic groups. In the population matched by clinical characteristics, the diabetic and non-diabetic groups had similar occurrence of MACEs (non-diabetics vs. diabetics = 5% versus 7%; p = 0.329) and event-free survival. MACEs in the diabetic group were associated with elevated early diastolic velocity of the mitral inflow/mitral annulus (E/e') ratio, indicative of diastolic dysfunction. The absence of statin and dipeptidyl peptidase-4 inhibitor use and use of sulfonylureas were also predictors of more MACEs. In conclusion, long-term cardiovascular events in patients with diabetes and negative stress echocardiography were comparable to those in patients without diabetes. However, appropriate monitoring of diastolic dysfunction, statin use, and individualized antidiabetic drug selection are required to reduce the cardiovascular risk in patients with diabetes.

A natural small molecule induces MAPT clearance via mTOR-independent autophagy.

Autophagy, the process of lysosomal degradation of biological materials within cells, is often halted abnormally in proteopathies, such as tauopathy and amyloidopathy. Thus, autophagy regulators that rescue dysregulated autophagy have great potential to treat proteopathies. We previously reported that the natural small molecule kaempferide (Kaem) induces autophagy without perturbing mTOR signaling. Here, we report that Kaem promotes lysosomal degradation of microtubule-associated protein tau (MAPT) in inducible MAPT cells. Kaem enhanced autophagy flux by mitigating microtubule-associated protein 1 light chain 3 (LC3) accumulation when MAPT expression was induced. Kaem also promoted activation of transcription factor EB (TFEB) without inhibiting mTOR and without mTOR inhibition-mediated cytotoxicity. In addition, Kaem-induced MAPT degradation was abolished in the absence of mitochondrial elongation factor Tu (TUFM), which was previously shown to be a direct binding partner of Kaem. Collectively, these results demonstrate that Kaem could be a potential therapeutic for tauopathy and reveal that TUFM can be a drug target for autophagy-driven disorders.

Coronary sinus endocarditis in a hemodialysis patient: A case report and review of literature.

BACKGROUND: Infective endocarditis is more common in hemodialysis patients than in the general population and is sometimes difficult to diagnose. Isolated coronary sinus (CS) vegetation is extremely rare and has a good prognosis, but complicated CS vegetation may have a poorer clinical course. We report a case of CS vegetation accidentally found via echocardiography in a hemodialysis patient with undifferentiated shock. The CS vegetation may have been caused by endocardial denudation due to tricuspid regurgitant jet and subsequent bacteremia. CASE SUMMARY: A 91-year-old man with dyspnea and hypotension was transferred from a nursing hospital. He was on regular hemodialysis and had a history of severe grade of tricuspid regurgitation. There was no leukocytosis or fever upon admission. Repetitive and sequential blood cultures revealed absence of microorganism growth. Chest computed tomography showed lung consolidation and a large pleural effusion. A mobile band-like mass on the CS, suggestive of vegetation, was observed on echocardiography. We diagnosed him with infective endocarditis involving the CS, pneumonia, and septic shock based on echocardiographic, radiographic, and clinical findings. Infusion of broad-spectrum antibiotics, fluid resuscitation, inotropic support, and ventilator care were performed. However, the patient died from uncontrolled infection and septic shock. CONCLUSION: CS vegetation can be fatal in hemodialysis patients with impaired immune systems, especially when it delays the diagnosis.

Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction.

Disorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem's biological activity, the target protein was identified via combined drug affinity responsive target stability and LC-MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload.

Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein.

Macroautophagy/autophagy (hereafter autophagy), the process of mass degradation of unnecessary elements within the cell, is often dysregulated in many diseases such as cancer, atherosclerosis, and neurodegenerative diseases. Hence, autophagy modulating agents have a great potential to be therapeutic agents for the autophagy-related diseases. Here we report that an anti-depressant drug sertraline (Sert) is an autophagy-inducing agent. Mechanistically, Sert potentially binds to and antagonizes the mitochondrial VDAC1 (voltage dependent anion channel 1), resulting in reduced cellular ATP (adenosine triphosphate) level, activation of AMP-activated protein kinase (AMPK) and inhibition of its downstream, MTOR (mechanistic target of rapamycin kinase)-RPS6KB1 (ribosomal protein S6 kinase B1) signaling pathway. Cells lacking VDAC1 expression completely abrogate the modulatory effect of Sert on AMPK-MTOR pathway and autophagy-inducing activity. We further show that Sert suppresses tauopathy by promoting the autophagic degradation of MAPT (microtubule associated protein tau) protein via inducing autophagy. Our study demonstrates the potential of Sert as a novel small molecule autophagy-inducing agent and provides a new drug candidate to treat autophagy related diseases by targeting VDAC1.Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Baf: bafilomycin A1; BiFC: biomolecular fluorescence complementation; CAMKK2/CAMKKB: calcium/calmodulin dependent protein kinase kinase 2; CC: compound C; DARTS: drug affinity responsive target stability; HUVECs: human umbilical vein endothelial cells; Inda: indatraline; STK11/LKB1: serine/threonine kinase 11; MAPT: microtubule associated protein tau; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; 3-MA: 3-methyladenine; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; Rapa: rapamycin; Sert: sertraline; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; SLC6A4/SERT1: solute carrier family 6 member 4; TFEB: transcription factor EB; VDAC1: voltage dependent anion channel 1; WT: wild-type; WM: wortmannin.

Targeting Autophagy In Disease: Recent Advances In Drug Discovery.

INTRODUCTION: Small molecules targeting autophagy have been highly implicated as new therapeutic agents to treat diseases of interest. With the increasing demand for autophagy-targeting drugs, this review attempts to provide an efficient strategy to explore major autophagy-based human disease interventions with newly explored mechanisms using small molecules and promising therapeutic approaches. AREAS COVERED: Introduced in this review are direct links and applications among autophagy pathways, their modulators, and phenotypic diseases, along with recent approaches. Autophagy-related diseases, machinery, and compounds are introduced to guide the appropriate investigation of autophagy in the pharmaceutical industry. The authors then provide their expert perspectives on the subject. EXPERT OPINION: The self-catabolic intracellular process autophagy occurs in organisms throughout their lifetime, supporting its critical role in organismal health across life stages. Because of the detrimental influence of dysfunctional cells to an organism and their etiology in numerous diseases, maintaining cellular quality control by recycling components through autophagy is essential to prevent health decline.

Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment.

Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors are shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets, we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC-MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.