Cardiovascular Complications of Novel Anti-Cancer Immunotherapy: Old Problems from New Agents?

Many novel anti-cancer therapies have dramatically improved outcomes of various cancer patients. However, it also poses a risk for cardiovascular complications as well. For the novel anti-cancer agent with which physicians does not have enough clinical experiences to determine the characteristics of cardiovascular complications, it is important to assess risk factors for cardiotoxicity before starting anti-cancer therapy. High-risk patient should be consulted to cardiologist before initiating anti-cancer therapy and pre-emptive cardiac function monitoring plan might be prepared in advance. The biomarkers, electrocardiography and echocardiography are useful tools for the detection of subclinical cardiotoxicity during anti-cancer therapy. This review article tried to suggest the cardiac function monitoring strategies for newly encountered potential cardiotoxic anti-cancer agents and to summarize the cardiovascular complications of novel anti-cancer immunotherapies including immune checkpoint inhibitor (ICI) and chimeric antigen receptor (CAR) T-cell therapy. ICIs can cause fatal myocarditis, which usually occurs early after initiation, and prompt treatment with high-dose corticosteroid is necessary. CAR T-cell therapy can cause cytokine release syndrome, which may result in circulatory collapse. Supportive treatment as well as tocilizumab, an anti-interleukin-6 receptor antibody are cornerstones of treatment.

Diagnosis, Treatment, and Prevention of Cardiovascular Toxicity Related to Anti-Cancer Treatment in Clinical Practice: An Opinion Paper from the Working Group on Cardio-Oncology of the Korean Society of Echocardiography

Cardiovascular (CV) toxicity associated with anti-cancer treatment is commonly encountered and raises critical problems that often result in serious morbidity or mortality. Most cardiac toxicities are related to the cumulative dose of chemotherapy; however, the type of chemotherapy, concomitant agents, and/or conventional CV risk factors have been frequently implicated in CV toxicity. Approximately half of the patients exhibiting CV toxicity receive an anthracycline-based regimen. Therefore, serologic biomarkers or cardiac imagings are important during anti-cancer treatment for early detection and the decision of appropriate management of cardiotoxicity. However, given the difficulty in determining a causal relationship, a multidisciplinary collaborative approach between cardiologists and oncologists is required. In this review, we summarize the CV toxicity and focus on the role of cardiac imaging in management strategies for cardiotoxicity associated with anti-cancer treatment.

Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity

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.

Thrombosis in the Left Ventricle after Implantable Cardioverter-Defibrillator Implantation: A Rare Cause of Systemic Thromboembolism / 대한구급학회지

This report describes a case of systemic thromboembolism caused by left ventricular (LV) thrombosis that developed after placement of an implantable cardioverter-defibrillator (ICD). A 27-year-old male patient was diagnosed with idiopathic dilated cardiomyopathy and ventricular tachycardia, and underwent ICD implantation for the primary prevention of sudden cardiac death. Two weeks after ICD implantation, the patient experienced renal infarction. Transthoracic echocardiography revealed a mobile thrombus at the LV apex, and automated function imaging demonstrated deteriorated LV function after ICD implantation. The RV was not placed by ICD and the mechanical force which was occurred by ICD that led to induced dyssynchronous motion of the LV apex may have resulted in a systemic thromboembolism.

Early Repolarization Syndrome with Idiopathic Ventricular Fibrillation / 이화의대지

Early repolarization is a common electrocardiographic (ECG) feature found in young adults, men and athletes, and has been considered to be a benign feature for the last several decades. But recent studies suggest that early repolarization may be related to idiopathic ventricular fibrillation and sudden cardiac death. We report a young man, 35 years old, who had life threatening ventricular fibrillation and sudden cardiac arrest. He was evaluated for cardiac causes of ventricular fibrillation. There was no explanation other than that his ECG showed an early repolarization pattern so we treated him with implantable cardioverter defibrillator. Thus, we suggest that early repolarization may be related with life threatening ventricular arrhythmia.

Early Cardiac Function Monitoring for Detection of Subclinical Doxorubicin Cardiotoxicity in Young Adult Patients with Breast Cancer / 한국유방암학회지

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 > or =300 mg/m2 and use of trastuzumab after doxorubicin therapy were associated with development of SC. At cumulative dose of doxorubicin 244.5 mg/m2, 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/m2 and early performance of cardiac monitoring before reaching the conventional critical dose of doxorubicin might be a proper strategy for early detection of SC.

Eosinophilic Myocarditis Associated with Visceral Larva Migrans Caused by Toxocara Canis Infection

A 41-year-old woman who was diagnosed with myocarditis presented eosinophilia. Since the antibody against Toxocara canis (T. canis) was positive, we diagnosed that she had visceral larva migrans due to T. canis associated with myocarditis. She was treated with oral albendazole and prednisolone for two weeks, eosinophil count and hepatic enzymes were normalized after completion of treatment. This is the first report of myocarditis caused by T. canis infection in Korea.

Exercise Treadmill Test for Evaluation of Cardiovascular Disease in Diabetic Patients / 임상당뇨병

Patients with diabetes mellitus have a greater risk for coronary artery disease (CAD) than the general population, and CAD is the major cause of morbidity and mortality in this population. Therefore, its early detection is very important to improve the prognosis. Especially, in asymptomatic patients, a proper screening test to detect occult CAD is needed. The Treadmill Test, in this sense, is a useful tool which can be easily performed with low cost for screening for the presence of myocardial ischemia associated with diabetes mellitus.

Positive Result in the Early Passive Phase of the Tilt-table Test: A Predictor of Neurocardiogenic Syncope in Young Men

BACKGROUND/AIMS: This study elucidated the prognostic factors for neurocardiogenic syncope in males in their late teens and early twenties. METHODS: Tilt-table testing (TTT) was performed on 665 males (age range, 17 to 27 years) following the Italian protocol. The subjects were tilted head-up at a 70degrees angle on a table for 30 minutes during the passive phase. If the passive phase was negative, the subjects were given sublingual nitroglycerin and tilted to the same angle for 20 minutes during the drug-provocation phase. The subjects with positive results were followed without medication. We analyzed factors related to the recurrence rate of syncope. RESULTS: Of 305 subjects (45.8%) with positive results, 223 (age range, 18 to 26 years) were followed for 12 months. The frequency of previous syncopal episodes > or = 4 (p = 0.001) and a positive result during the passive phase (p = 0.022) were significantly related to a high recurrence rate. A positive result during the early passive phase ( 12 minutes; p = 0.011). CONCLUSIONS: A positive result during the early passive phase of TTT and frequent previous syncopal episodes were prognostic factors for neurocardiogenic syncope in men in their late teens and early twenties.

A Case of Acute Purulent Pericarditis Complicated by Severe Left Ventricular Systolic Dysfunction and Cardiac Tamponade / 대한내과학회지

An 85-year-old male visited our hospital because of dyspnea. Chest radiography showed marked cardiomegaly and pneumonic infiltration. Transthoracic echocardiography showed moderate pericardial effusion, which resulted in effusive constrictive pericarditis and severe left ventricular systolic dysfunction. During the hospital course, the patient developed cardiogenic shock and was treated with an inotropic agent and intra-aortic balloon pump. The patient's vital signs were stabilized after pericardiocentesis and drainage. A yellowish purulent pericardial effusion was drained and Streptococcus pneumoniae was isolated. Bacterial purulent pericarditis was not uncommon before the antibiotics era, but it is extremely rare nowadays. Here, we report a case of purulent bacterial pericarditis presenting with severe left ventricular systolic dysfunction and cardiac tamponade.

Pulmonary Hypertension Associated with Acute Hypoxic Pulmonary Vasoconstriction in a Patient with Acute Myeloid Leukemia / 대한내과학회지

Hypoxic pulmonary vasoconstriction is a unique response of the pulmonary circulation to hypoxia. It constitutes part of the self-regulatory mechanism by which pulmonary capillary blood flow is adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, hypoxic pulmonary vasoconstriction may occur as an acute episode or as a sustained response with pulmonary hypertension and vascular remodeling. We report a case of reversible pulmonary hypertension induced by acute hypoxic pulmonary vasoconstriction in an 18-year-old man with relapsed acute myeloid leukemia, complicated with severe anemia and pneumonia.

A Case of Acute Purulent Pericarditis Complicated by Severe Left Ventricular Systolic Dysfunction and Cardiac Tamponade / 대한내과학회지

An 85-year-old male visited our hospital because of dyspnea. Chest radiography showed marked cardiomegaly and pneumonic infiltration. Transthoracic echocardiography showed moderate pericardial effusion, which resulted in effusive constrictive pericarditis and severe left ventricular systolic dysfunction. During the hospital course, the patient developed cardiogenic shock and was treated with an inotropic agent and intra-aortic balloon pump. The patient's vital signs were stabilized after pericardiocentesis and drainage. A yellowish purulent pericardial effusion was drained and Streptococcus pneumoniae was isolated. Bacterial purulent pericarditis was not uncommon before the antibiotics era, but it is extremely rare nowadays. Here, we report a case of purulent bacterial pericarditis presenting with severe left ventricular systolic dysfunction and cardiac tamponade.

Association Between Plaque Thickness of the Thoracic Aorta and Recurrence of Atrial Fibrillation After Ablation

BACKGROUND AND OBJECTIVES: Several predictors of recurrence of atrial fibrillation (AF) after ablation have been identified, including age, type of AF, hypertension, left atrial diameter and impaired left ventricular ejection fraction. The aim of this study was to investigate whether the atherosclerotic plaque thickness of the thoracic aorta is associated with a recurrence of AF after circumferential pulmonary vein ablation (CPVA). SUBJECTS AND METHODS: Among patients with drug-refractory paroxysmal or persistent AF, 105 consecutive (mean age 58+/-11 years, male : female=76 : 29) patients who underwent transesophageal echocardiography and CPVA were studied. The relationships between the recurrence of AF and variables, including clinical characteristics, plaque thickness of the thoracic aorta, laboratory findings and echocardiographic parameters were evaluated. RESULTS: A univariate analysis showed that the presence of diabetes {hazard ratio (HR)=3.425; 95% confidence interval (CI), 1.422-8.249, p=0.006}, ischemic heart disease (HR=4.549; 95% CI, 1.679-12.322, p=0.003), duration of AF (HR=1.010; 95% CI, 1.001-1.018, p=0.025), type of AF (HR=2.412, 95% CI=1.042-5.584, p=0.040) and aortic plaque thickness with > or =4 mm (HR=9.514; 95% CI, 3.419-26.105, p or =4 mm) was an independent predictor of recurrence of AF after ablation (HR=7.250, 95% CI=1.906-27.580, p=0.004). CONCLUSION: Significantly increased aortic plaque thickness can be a predictable marker of recurrence of AF after CPVA.

A Case of Chloroquine-Induced Cardiomyopathy That Presented as Sick Sinus Syndrome

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.

A Case of Left Ventricular Pseudoaneurysm in the Left Atrioventricular Groove after Mitral Valve Replacement

Left ventricle-coronary sinus fistula and left ventricular pseudoaneurysm are unusual and frightening complications after mitral valve replacement. A 27-year-old female patient underwent mitral valve replacement 5 years previously and trans-thoracic echocardiography showed an outpouching lesion at the atrioventricular groove. It was difficult to differentiate whether the lesion was a left ventricle-coronary sinus fistula or a left ventricular pseudoaneurysm by two-dimensional echocardiography. Cardiac computed tomography confirmed a left ventricular pseudoaneurysm compressing the coronary sinus.

Effect of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Patients Following Ablation of Atrial Fibrillation

BACKGROUND AND OBJECTIVES: It is known that angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers (ACEIs and ARBs, respectively) are effective in preventing atrial fibrillation (AF) in high-risk patients. However, it is not known whether ACEIs and ARBs are effective in preventing the recurrence of AF after catheter ablation. SUBJECTS AND METHODS: One hundred fifty-two patients (mean age, 57+/-10 years; M : F=94 : 58) who underwent catheter ablation due to drug-refractory paroxysmal (mean age, 57+/-10 years; M : F=58 : 43) or persistent AF (mean age, 56+/-10 years; M : F=36 : 15) were enrolled. We compared the recurrence rates between the groups with and without ACEIs or ARBs use in paroxysmal and persistent AF. The mean duration of follow-up was 18+/-14 months. RESULTS: The overall recurrence rate after ablation therapy was 26% (n=39). The recurrence rate was significantly decreased in the patients with persistent AF with the use of ACEIs or ARBs (12.1% vs. 61.1%, p<0.01), but this difference was not observed in the patients with paroxysmal AF (24.2% vs. 22.9%, p=0.87). In patients with persistent AF with and without recurrence, the size of the left atrium (44.2+/-8.4 mm vs. 44.3+/-5.8 mm, respectively, p=0.45) and the ejection fraction (62+/-6.5% vs. 61.5+/-6.2%, respectively, p=0.28) were not significantly different. In multivariate analysis, the use of ACEIs or ARBs was independently associated with recurrence after adjusting for the size of the left atrium and the ejection fraction {odds ratio (OR)=0.078, 95% confidence interval (CI)=0.02-0.35, p<0.01}. CONCLUSION:ACEIs and ARBs were shown to be effective in preventing AF recurrence after catheter ablation in patients with persistent AF.

The Expression of Transforming Growth Factor-beta1 and alpha-Smooth Muscle Actin is Increased in the Human Myxomatous Valve

BACKGROUND: In vitro experimental studies have reported that transforming growth factor-beta1 (TGF-beta1) stimulates the production of alpha-smooth muscle actin (alpha-SMA) in porcine valves. However, the relation between TGF-beta1 and alpha-SMA in myxomatous valves has not been elucidated. METHODS: We classified 27 subjects into two groups: 1) myxomatous group (M:F=11:12, mean age=55+/-15 years) and 2) rheumatic group (M:F=3:1, mean age=41+/-17 years) according to preoperative echocardiographic and postoperative histologic findings. Twenty-seven valve specimens from the patients who underwent valve replacement were obtained. Tissue samples were analyzed by immunohistochemistry for TGF-beta1 and alpha-SMA. The positively stained areas were measured using an image analysis program (Image Pro-Plus 4.5), and then the TGF-beta1 volume fraction (TGF-VF) and alpha-SMA volume fraction (alpha-SMA-VF) were calculated. RESULTS: TGF-VF in myxomatous valves was higher than in rheumatic valves (2,759+/-2,294 vs 864+/-276, p=0.04). alpha-SMA-VF in myxomatous valves was higher than in rheumatic valves (4,122+/-2,275 vs 2,421+/-844, p=0.002). There was a significant correlation between TGF-beta1 and alpha-SMA in myxomatous valves (r=0.38, p=0.04). There was no significant correlation between TGF-beta1 and alpha-SMA in rheumatic valves (r=-0.50, p=0.67). CONCLUSIONS: TGF-beta1 and alpha-SMA may be related to the pathogenesis of myxomatous valves. The activation of TGF-beta1 might increase the expression of alpha-SMA in human myxomatous valves.

The Expression of Cardiac Ankyrin Repeat Protein in an Animal Model of Adriamycin-Induced Cardiomyopathy

BACKGROUND AND OBJECTIVES: Cardiac ankyrin repeat protein (CARP) is an embryonic nuclear protein, and its expression is increased under conditions of pressure or volume overload and also in the failing heart. Adriamycin is a cardiotoxic chemotherapeutic agent, and it suppresses the expression of CARP. We compared the expressions of CARP in the myocardium of normotensive rats and spontaneously hypertensive rats (SHRs) that suffered with adriamycin-induced cardiomyopathy. MATERIALS AND METHODS: 36 Wistar-Kyoto rats (WKYs) and 36 SHRs were divided into the adriamycin-administered and saline-administered groups. Adriamycin (2.5 mg/kg) and saline were injected intraperitoneally twice a week for 3 weeks. All the animals were sacrificed 3 weeks after the last injection. Immunohistochemical staining was performed on the left ventricles with using synthesized polyclonal CARP antibody. The positively stained areas were measured by using an image analysis program, and the CARP volume fractions (CaVF) were calculated. RESULTS: CARP was diffusely expressed in the cytoplasm of the myocytes in all the groups. The number of CARP expressing cells was increased in the SHRs. The CaVFs was 5.96+/-5.11% in the WKYs and it was 9.04+/-6.26% in the SHRs (p=0.014). The CaVF was 2.26+/-4.74% in the adriamycin-administered WKYs and it was 1.24+/-4.32% in the adriamycin-administered SHRs (p=0.32). The adriamycin-administered WKYs and SHRs showed significantly decreased CARP expressions, as compared to the saline-administered groups (p<0.001 and p<0.001, respectively). CONCLUSION: These results suggest that CARP is closely related to the pathogenesis of adriamycin-induced cardiomyopathy and it probably plays a pivotal role for the adriamycin cardiac toxicity observed in hypertensive rats.

Echocardiographic Characteristics Related to Chronic Iron Overload in Patient with Aplastic Anemia

BACKGROUND AND OBJECTIVES: In patients with aplastic anemia, chronic iron overload due to multiple blood transfusions, leads to secondary hemochromatosis. Cardiac involvement in hemochromatosis is the leading cause of death. The goal of this study was to find the echocardiographic characteristics of patients with aplastic anemia and chronic iron overload. SUBJECTS AND METHODS: Echocardiography was performed on 33 patients with aplastic anemia (age 33+/-10, M:F=14:19) and 15 controls (age 34+/-8, M:F=6:9). The regions of interest on digitalized 2-D images of the papillary muscle (PM) in the parasternal short-axis view and the interventricular septum (IVS) in the apical 4-chamber view were analyzed using histograms, which quantified the echoreflectiveness (256 gray scales; black=0, white=255) of the myocardium. The echocardiographic parameters of each group were compared, including wall thickness, chamber dimensions, systolic, diastolic function indexes and echoreflectiveness. The aplastic anemic patients were divided into two groups (22 with serum ferritin level> or =2,000 microgram/L vs. 11 with<2,000 microgram/L) and then compared. RESULTS: The right ventricular (RV) wall was thicker in the patients than the controls (4.1+/-1.2 mm vs. 2.6+/-0.5 mm, p<0.01). In the patients, the echoreflectiveness of the PM was typically higher than in the controls (gray scale, 173.9+/-40.9 vs. 80.72+/-34.1, p<0.01), with IVS showing higher reflectivity, but this was not statistically significant (80.4+/-16.6 vs. 75.2+/-13.7, p=0.41). Patients with a ferritin level (2,000 microgram/L had a thicker RV wall (4.4+/-1.2 mm vs. 3.3+/-0.6 mm, p=0.01) and larger left atrium (LA) dimension (38.1+/-1.4 mm vs. 32.2+/-1.9 mm, p=0.02) than those with a ferritin level<2,000 microgram/L. No considerable difference was found between the echoreflectiveness of each group. CONCLUSION: The echocardiographic findings, such as high echoreflectiveness in the PM, RV wall hypertrophy and LA dilation, might be characteristics suggestive of early myocardial changes due to chronic iron overload as a result of multiple transfusions.

A Case of Metastatic Hepatocellular Carcinoma of the Ovary / 대한소화기학회지

Although advances in imaging technology have allowed for earlier detection of disease, hepatocellular carcinoma is usually asymptomatic and discovered at an advanced stage with metastasis. The most common sites of metastasis include lung, peritoneum, adrenal gland, and bone, but rarely, the nasal cavity, orbit, gallbladder, and ovary can be metastatic sites. We experienced a case of metastatic hepatocellular carcinoma of the ovary in a living patient. The differential diagnosis includes hepatoid yolk sac tumor of the ovary, primary or metastatic hepatoid carcinoma and primary or metastatic oxyphil cell tumor of the ovary. To the best of our knowledge, there have been eight cases of metastatic hepatocellular carcinoma of the ovary in the English literature and only six cases discovered in living patients. This is the first report of a metastatic hepatocellular carcinoma of the ovary in Korea.