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We report three patients who presented with chest pain after receiving either the BNT162b2 Pfizer/BioNTech or mRNA-1273 Moderna/NIH vaccine. Clinical presentation, biomarker, and cardiac MRI supported myocarditis. It is imperative that potential side effects of COVID-19 vaccine are reported to improve our knowledge about COVID-19 and mRNA vaccines.

Anthracycline-associated cardiomyopathy and peripartum cardiomyopathy are nonischemic cardiomyopathies that often afflict previously healthy young patients; both diseases have been well described since at least the 1970s and both occur in the settings of predictable stressors (ie, cancer treatment and pregnancy). Despite this, the precise mechanisms and the ability to reliably predict who exactly will go on to develop cardiomyopathy and heart failure in the face of anthracycline exposure or childbirth have proven elusive. For both cardiomyopathies, recent advances in basic and molecular sciences have illuminated the complex balance between cardiomyocyte and endothelial homeostasis via 3 broad pathways: reactive oxidative stress, interference in apoptosis/growth/metabolism, and angiogenic imbalance. These advances have already shown potential for specific, disease-altering therapies, and as our mechanistic knowledge continues to evolve, further clinical successes are expected to follow.

Ventricular assist device (VAD) pump thrombosis is a known complication and while the preferred standard treatment is surgical pump exchange this procedure is not without risk and for some patients the risks are prohibitive. This is a case of a 68-year-old female with bilateral HeartWare ventricular assist devices (HVAD) implanted as destination therapy who presented with signs of recurrent pump thrombosis. Surgical pump exchange was deemed to confer prohibitive risk due to her underlying medical co-morbidities and therefore not an option for treatment. After careful consideration of possible options for treatment, she received systemic thrombolysis (Alteplase 5 mg IV bolus followed by 3 mg/hour infusion for 10 hours through a central line) which was successful. This case highlights, not only the rarity of bilateral VADs as destination therapy, but also demonstrates the safety and efficacy of using systemic thrombolytics in patients with bilateral HVADs for treatment of pump thrombosis.

BACKGROUND: Hypertension (HTN) is an established class effect of vascular endothelial growth factor receptor (VEGFR) inhibition. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, HTN was the most frequent adverse event of lenvatinib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, platelet-derived growth factor receptor (PDGFR), ret proto-oncogene (RET), and stem cell factor receptor (KIT). This exploratory analysis examined treatment-emergent hypertension (TE-HTN) and its relation with lenvatinib efficacy and safety in SELECT. METHODS: In the multicenter, double-blind SELECT trial, 392 patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to lenvatinib (24 mg/d on a 28-day cycle) or placebo. Survival endpoints were assessed with Kaplan-Meier estimates and log-rank tests. The influence of TE-HTN on progression-free survival (PFS) and overall survival (OS) was analyzed with univariate and multivariate Cox proportional hazards models. RESULTS: Overall, 73% of lenvatinib-treated patients and 15% of placebo-treated patients experienced TE-HTN. The median PFS for lenvatinib-treated patients with (n = 190) and without TE-HTN (n = 71) was 18.8 and 12.9 months, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39-0.88; P = .0085). For lenvatinib-treated patients, the objective response rate was 69% with TE-HTN and 56% without TE-HTN (odds ratio, 1.72; 95% CI, 0.98-3.01). The median change in tumor size for patients with and without TE-HTN was -45% and -40%, respectively (P = .2). The median OS was not reached for patients with TE-HTN; for those without TE-HTN, it was 21.7 months (HR, 0.43; 95% CI, 0.27-0.69; P = .0003). CONCLUSIONS: Although HTN is a clinically significant adverse event that warrants monitoring and management, TE-HTN was significantly correlated with improved outcomes in patients with RR-DTC, indicating that HTN may be predictive for lenvatinib efficacy in this population. (C) 2018 American Cancer Society.

Purpose Cancer and cardiovascular disease (CVD) are common causes of morbidity and mortality, and measurement and interpretation of their co-occurrence rate have important implications for public health and patient care. Here, we present the raw and adjusted co-occurrence rates of cancer and CVD in the overall population by using a visually intuitive network approach. Methods By using baseline survey and linked health outcome data from 490,842 individuals age 40 to 69 years from the UK Biobank, we recorded diagnoses between 1997 and 2014 of specific cancers and specific CVDs ascertained through hospital claims. We measured raw and adjusted rates of CVD for the following groups: individuals with Hodgkin or non-Hodgkin lymphoma, lung and trachea cancer, uterus cancer, colorectal cancer, prostate cancer, breast cancer, or no recorded diagnosed cancer during this time period. Analysis accounted for age, sex, and behavioral risk factors, without regard to the order of occurrence of cancer and CVD. Results A significantly increased rate of CVD was found in patients with multiple types of cancers, including Hodgkin and non-Hodgkin lymphoma and lung and trachea, uterus, colorectal, and breast cancer, compared with patients without cancer by using age and sex-adjusted models. Increased co-occurrence for many CVD categories remained after correction for behavioral risk factors. Construction of co-occurrence networks highlighted heart failure as a shared CVD diagnosis across multiple cancer types, including breast cancer, lung cancer, non-Hodgkin lymphoma, and colorectal cancer. Smoking, physical activity, and other lifestyle factors accounted for some but not all of the increased co-occurrence for many of the CVD diagnoses. Conclusion Increased co-occurrence of several common CVD conditions is seen widely across multiple malignancies, and shared diagnoses, such as heart failure, were highlighted by using network methods.

Despite its challenges, a "big data" approach offers a unique opportunity within the field of cardio-oncology. A pharmacovigilant approach using large data sets can help characterize cardiovascular toxicities of the rapidly expanding armamentarium of targeted therapies. Creating a broad coalition of data sharing can provide insights into the incidence of cardiotoxicity and stimulate research into the underlying mechanisms. Population health necessitates the use of big data and can help inform public health interventions to prevent both cancer and cardiovascular disease. As a relatively new discipline, cardio-oncology is poised to take advantage of big data.

To evaluate the efficiency and safety of emergency department (ED) coronary computed tomography angiography (CTA) during a 3-year clinical experience. Single-center registry of coronary CTA in consecutive ED patients with suspicion of acute coronary syndrome (ACS). The primary outcome was efficiency of coronary CTA defined as the length of hospitalization. Secondary endpoints of safety were defined as the rate of downstream testing, normalcy rates of invasive coronary angiography (ICA), absence of missed ACS, and major adverse cardiac events (MACE) during follow-up, and index radiation exposure. One thousand twenty two consecutive patients were referred for clinical coronary CTA with suspicion of ACS. Overall, median time to discharge home was 10.5 (5.7-24.1) hours. Patient disposition was 42.7 % direct discharge from the ED, 43.2 % discharge from emergency unit, and 14.1 % hospital admission. ACS rate during index hospitalization was 9.1 %. One hundred ninety two patients underwent additional diagnostic imaging and 77 underwent ICA. The positive predictive value of CTA compared to ICA was 78.9 % (95 %-CI 68.1-87.5 %). Median CT radiation exposure was 4.0 (2.5-5.8) mSv. No ACS was missed; MACE at follow-up after negative CTA was 0.2 %. Coronary CTA in an experienced tertiary care setting allows for efficient and safe management of patients with suspicion for ACS. • ED Coronary CTA using advanced systems is associated with low radiation exposure. • Negative coronary CTA is associated with low rates of MACE. • CTA in ED patients enables short median time to discharge home. • CTA strategy is characterized by few downstream tests including unnecessary ICA.

Anthracycline-associated cardiomyopathy and peripartum cardiomyopathy are nonischemic cardiomyopathies that often afflict previously healthy young patients; both diseases have been well described since at least the 1970s and both occur in the settings of predictable stressors (ie, cancer treatment and pregnancy). Despite this, the precise mechanisms and the ability to reliably predict who exactly will go on to develop cardiomyopathy and heart failure in the face of anthracycline exposure or childbirth have proven elusive. For both cardiomyopathies, recent advances in basic and molecular sciences have illuminated the complex balance between cardiomyocyte and endothelial homeostasis via 3 broad pathways: reactive oxidative stress, interference in apoptosis/growth/metabolism, and angiogenic imbalance. These advances have already shown potential for specific, disease-altering therapies, and as our mechanistic knowledge continues to evolve, further clinical successes are expected to follow.

Background: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. Methods: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. Results: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (–5.8%, P =0.017), and noninfarct myocardial fibrosis (–5.6%, P =0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. Conclusions: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00729430.

BACKGROUND: Myocardial atrophy and left ventricular (LV) mass reductions are associated with fatigue and exercise intolerance. The relationships between the receipt of anthracycline-based chemotherapy (Anth-bC) and changes in LV mass and heart failure (HF) symptomatology are unknown, as is their relationship to LV ejection fraction (LVEF), a widely used measurement performed in surveillance strategies designed to avert symptomatic HF associated with cancer treatment. METHODS AND RESULTS: We performed blinded, serial assessments of body weight, LVEF and mass, LV-arterial coupling, aortic stiffness, and Minnesota Living with Heart Failure Questionnaire measures before and 6 months after initiating Anth-bC (n=61) and non–Anth-bC (n=15), and in 24 cancer-free controls using paired t and χ(2) tests and multivariable linear models. Participants averaged 51±12 years, and 70% were women. Cancer diagnoses included breast cancer (53%), hematologic malignancy (42%), and soft tissue sarcoma (5%). We observed a 5% decline in both LVEF (P

The OMEGA-REMODEL (Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction) trial of patients with acute myocardial infarction (MI) reported significant attenuation of adverse left ventricular (LV) remodeling and noninfarct myocardial fibrosis after 6

Anthracyclines are an important component of cancer treatments; however, their use is limited by the occurrence of cardiotoxicity. There are limited data on the occurrence of heart failure and the value of baseline and follow-up measurements of left ventricular (LV) ejection fraction (EF) in the current era. Therefore, the objectives of the present study were twofold: (1) to characterize the occurrence of and risk factors for major adverse cardiac events (MACEs: symptomatic heart failure and cardiac death) in a large contemporaneous population of adult patients treated with anthracyclines and (2) to test the value of LVEF and LV dimensions obtained using echocardiography in the prediction of MACE. Five thousand fifty-seven patients were studied, of whom 124 (2.4%) developed MACE. Of the total cohort, 2,285 patients had an available echocardiogram pre-chemotherapy. Patients with MACE were older (p0.0001), predominantly men (p = 0.03), and with a higher incidence of cardiovascular risk factors and cardiac treatments. Patients with hematologic cancers had a higher incidence of cardiac events than patients with breast cancer (4.2% vs 0.7%, p0.0001). Baseline LVEF, LVEF ≤5 points above the lower limits of normal, and LV internal diameter were predictive of the rate of occurrence of MACE. In conclusion, older patients with hematologic cancers and patients with a baseline LVEF ≤5 points above the lower limit of normal have higher incidence of MACE and should be closely monitored.

10.2217/FON.15.128 © 2015 Future Medicine Ltd In the USA and in most industrialized nations the two leading causes of death are heart disease and cancer [1]. CardioOncology or Onco-Cardiology is a specialty that focuses on the intersection of cancer and cardiovascular disease. There are many points along the spectrum of cancer where cardiovascular risk factors or disease may influence the shortand longterm course of patients. From the interplay of shared risk factors between cancer and cardiovascular disease to the use of potentially cardiotoxic therapies that may cause acute or late toxicities; cardiovascular disease impacts overall morbidity and mortality in patients with cancer. Along this spectrum there are several potential points where interventions may lead to improved cardiovascular outcomes and overall health (Figure 1). Chemotherapy can cause direct effects on the heart leading to left ventricular dysfunction (cardiomyopathy). Anthracyclines are the prototypical cardiotoxic chemotherapy and have been used effectively in a variety of cancers for the past five decades. The incidence of cardiotoxicity varies among different studies in part related to different patient populations (survivors of childhood vs adult cancers), different methods of surveillance and different definitions of cardiotoxicity [2,3]. A contemporary prospective study reported an incidence of anthracycline associated cardiotoxicity of 9% [4]. Preventative strategies including prophylactic treatment with ACE inhibitors and β-blockers have shown some promise though further studies are necessary [5,6]. There has also been exciting research into the molecular mechanisms of anthracycline cardiotoxicity, which may allow for more sophisticated drug design or novel approaches to minimize the risk of cardiotoxicity [7,8]. The importance of prompt recognition and management of cardiotoxicity is supported by several studies. An important recent study by Cardinale et al. demonstrated in a large prospective cohort of patients being treated with anthracyclines that 9% of patients developed cardiac dysfunction (defined as a reduction in LVEF of >10% to a value less than 50%) and the overwhelming majority of these patients developed LV dysfunction within the first year after treatment [4]. The majority of these (82%) patients had a partial or full recovery of LV function. This finding challenges the previously held dogma that anthracycline associated LV dysfunction is irreversible. Importantly in this prospective study there was prompt institution of therapy with ACE inhibitors and β-blockers. Unraveling the molecular mechanisms of many cancer types has led to the rapid development of numerous targeted therapies. Many of these are tyrosine kinase inhibitors that have the potential for a OPINION Special Focus Issue: Cardio-oncology

Anthracyclines are one of the most commonly used antineoplastic agent classes, and a core part of the treatment in breast cancers, hematological malignancies, and sarcomas. Their benefit is decreased by their well-recognized cardiotoxicity. The purpose of this review is to outline the presentation, mechanisms, diagnosis, and treatment of anthracyclines-induced cardiotoxicity. Symptomatic heart failure occurs in 2% to 5% of patients treated with anthrayclines and may be higher in older patients or patients with cardiovascular risk factors. The mechanisms involved in anthracycline-induced cardiotoxicity involve myocyte loss by apoptosis in the presence of a limited regenerative capacity. Once symptomatic, anthracycline-induced cardiotoxicity is associated with markedly decreased survival. Left ventricular ejection fraction (LVEF), mostly determined using echocardiography, is used to monitor patients treated with anthracyclines. As more than 1/3 of patients treated with anthracyclines do not recover their baseline LVEF once it is decreased, more sensitive echocardiographic indices of LV function such as myocardial deformation or biomarkers have been studied in patients monitoring. Cardioprotective treatments such as angiotensin-converting enzyme inhibitors, beta-blockers, iron chelators, statins, and metformin are also the topic of research efforts.

Survivors of childhood and adult cancers face increased risk of cardiovascular disease. We review the current evidence base and guidelines for this rapidly growing population. Research continues to show that cardiovascular disease is an important cause of morbidity and mortality in cancer survivors. Cardiotoxicity related to chemotherapy and radiotherapy accounts for part of this increased risk. There is emerging evidence that cancer and cardiovascular disease share a similar biology and risk factors. At present, there are several guidelines and consensus recommendations for the management of cardiovascular risk in cancer survivors. The evidence base is accumulating though additional research is necessary to demonstrate improved outcomes and comparative effectiveness.

Despite its challenges, a "big data" approach offers a unique opportunity within the field of cardio-oncology. A pharmacovigilant approach using large data sets can help characterize cardiovascular toxicities of the rapidly expanding armamentarium of targeted therapies. Creating a broad coalition of data sharing can provide insights into the incidence of cardiotoxicity and stimulate research into the underlying mechanisms. Population health necessitates the use of big data and can help inform public health interventions to prevent both cancer and cardiovascular disease. As a relatively new discipline, cardio-oncology is poised to take advantage of big data.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3–4·0% in studies in relapsed/refractory MM and 1·2–4·7% in previously untreated MM (2·0–7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3–5·9% grade ≥2; 0·6–4·1% grade ≥3), IHD (1·2–2·9% all grades; 0·4–2·7% grade ≥3) and cardiac death (0–1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events., JPL receives research funding from Celgene Corporation, Millennium, Novartis, and Onyx; and is a consultant for Janssen Pharmaceuticals, and Novartis, and has participated in advisory boards for Janssen and Millennium. JJM is a consultant for Millennium Pharmaceuticals Inc., Novartis, Pfizer, Acceleron, and Alnylam. SAF is a consultant for Clovis Oncology, Inc. and ARIAD pharmaceuticals; and receives honoraria from Medtronic. JFSM is a consultant/advisor and receives honoraria from Janssen, Celgene Corporation, Millennium Pharmaceuticals Inc., Novartis, Onyx Pharmaceuticals, and Bristol-Myers Squibb. PS is a consultant/advisor, and receives research funding from Janssen Pharmaceuticals, Celgene Corporation, and Onyx Pharmaceuticals; and receives honoraria from Janssen Pharmaceuticals, and Celgene Corporation. RZO receives research funding from Bristol-Myers Squibb, Celgene Corporation, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals, and Resverlogix; receives honoraria from Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals; and is a member of advisory boards for Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Merck, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals. PM receives honoraria from Janssen, and is a member of advisory boards for Janssen, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals. LR receives honoraria from Janssen, and Celgene Corporation. EAF is a consultant and receives honoraria from Celgene Corporation, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals, and SanofiAventis. PV receives research funding from Takeda Pharmaceuticals, Celgene Corporation, Janssen, GlaxoSmithKline, Acetylon, Oncopeptides, and Amgen; is a consultant for Novartis and Takeda, and has participated in advisory boards for Celgene Corporation, Bristol-Meyers Squibb, and Janssen. M-VM receives honoraria from Janssen, Millennium, and Celgene Corporation. LM is employed by Janssen Research & Development LLC; and has ownership at Johnson & Johnson. HF is employed by Janssen Research & Development LLC. AD is employed by Janssen Global Services LLC; and has ownership at Johnson & Johnson. HvdV is employed by Millennium Pharmaceuticals Inc., Formerly Janssen Research & Development, Division of Janssen Pharmaceuticals NV; and has ownership with Johnson & Johnson. JE, D-LE, LN, HS, and NJ are employed by Millennium Pharmaceuticals Inc. ED was formerly employed by Millennium Pharmaceuticals Inc. KCA is a consultant for Celgene Corporation, Onyx Pharmaceuticals, Sanofi-Aventis, and Gilead; and has equity ownership at Acetylon Pharmaceuticals, and Oncopep. SL is a consultant for Millennium Pharmaceuticals Inc., Celgene Corporation, Novartis, Bristol-Myers Squibb, Onyx Pharmaceuticals, and Merck. PGR is a member of advisory committees for Millennium Pharmaceuticals Inc., Janssen, Novartis, and Celgene Corporation, and has received research funding from Millennium, Celgene, and Bristol Myers Squibb. Writing support during the development of the manuscript was provided by Steve Hill PhD of FireKite, an Ashfield Company, part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals Inc., and Janssen Global Services LLC.

Objective— In addition to an extensively characterized role of high-density lipoprotein (HDL) in reverse cholesterol transport, bioactive lipids bound to HDL can also exert diverse vascular effects. Despite this, integration of HDL action in the vasculature with pathways that metabolize HDL and release bioactive lipids has been much less explored. The effects of HDL on endothelial cells are mediated in part by HDL-associated sphingosine 1-phosphate (S1P), which binds to S1P 1 receptors and promotes activation of endothelial NO synthase (eNOS) and the kinase Akt. In these studies, we characterized the role of endothelial lipase (EL) in the control of endothelial signaling and biology, including those mediated by HDL-associated S1P. Approach and Results— HDL-induced angiogenesis in aortic rings from EL-deficient (EL −/− ) mice was markedly decreased compared with wild-type controls. In cultured endothelial cells, small interfering RNA–mediated knockdown of EL abrogated HDL-promoted endothelial cell migration and tube formation. Small interfering RNA–mediated EL knockdown also attenuated HDL-induced phosphorylation of eNOS 1179 and Akt 473 . S1P stimulation restored HDL-induced endothelial migration and Akt/eNOS phosphorylation that had been blocked by small interfering RNA–mediated EL knockdown. HDL-induced endothelial cell migration and Akt/eNOS phosphorylation were completely inhibited by the S1P 1 antagonist W146 but not by the S1P 3 antagonist CAY10444. Conclusions— EL is a critical determinant of the effects of HDL on S1P-mediated vascular responses and acts on HDL to promote activation of S1P 1 , leading to Akt/eNOS phosphorylation and subsequent endothelial migration and angiogenesis. The role of EL in HDL-associated S1P effects provides new insights into EL action, the responses seen through EL and HDL interaction, and S1P signaling.

We aimed to describe the cardiac magnetic resonance (CMR) findings and determine the prognostic variables in patients with a cardiomyopathy after treatment with anthracyclines. CMR imaging was performed in 91 patients (58% men, mean age 43 ± 18 years, and mean anthracycline dose of 276 ± 82 mg/m(2)) with a reduced ejection fraction after anthracycline-based chemotherapy. Major adverse cardiovascular events were defined as cardiovascular death, appropriate implantable cardioverter-defibrillator therapy, and admission for decompensated heart failure. Patients presented a median of 88 months (interquartile range 37 to 138) after chemotherapy and were followed for 27 months (interquartile range 22 to 38). Late gadolinium enhancement was an uncommon finding (5 patients, 6%) despite a reduced ejection fraction (36 ± 8%). An inverse association was found between the anthracycline dose and the indexed left ventricular (LV) mass by CMR (r = -0.67, p0.001). A total of 52 adverse cardiac events occurred (event rate of 22%/year). When the patients were grouped according to the presence or absence of a major adverse cardiovascular event, the indexed LV mass and glomerular filtration rate were lower and the anthracycline dose was greater among the patients who experienced an adverse event. In a multivariate model, the indexed LV mass demonstrated the strongest association with major adverse cardiovascular events (hazard ratio 0.89, chi-square 26, p0.001). In conclusion, myocardial scar by late gadolinium enhancement-CMR is infrequent in patients with anthracycline-cardiomyopathy despite a reduced ejection fraction, the event rate in patients with established anthracycline-cardiotoxicity is high, and indexed LV mass by CMR imaging is a predictor of adverse cardiovascular events.

Objective— To investigate the effects of pioglitazone (PIO), a peroxisome proliferator–activated receptor γ agonist, on plaque matrix metalloproteinase (MMP) and macrophage (Mac) responses in vivo in a molecular imaging study. Methods and Results— In vitro, PIO suppressed MMP-9 protein expression in murine peritoneal Macs ( P −/− mice receiving a high-cholesterol diet (HCD) were administered an MMP-activatable fluorescence imaging agent and a spectrally distinct Mac-avid fluorescent nanoparticle. After 24 hours, mice underwent survival dual-target intravital fluorescence microscopy of carotid arterial plaques. These mice were then randomized to HCD or HCD plus 0.012% PIO for 8 weeks, followed by a second intravital fluorescence microscopy study of the same carotid plaque. In the HCD group, in vivo MMP and Mac target-to-background ratios increased similarly ( P P r ≥0.75). Microscopy demonstrated MMP and Mac reductions in PIO-treated mice and a PIO-modulated increase in plaque collagen. Conclusion— Serial optical molecular imaging demonstrates that plaque MMP and Mac activity in vivo intensify with hypercholesterolemia and are reduced by PIO therapy.

The traditional in-class face-to-face lectures have been the mainstay in medical education, but the major drawback of this model includes passive learning experience. A new pedagogic model, in form of flipped classroom, offers advantage of self-paced review of educational material and promotes

There have been tremendous technological advances in noninvasive cardiovascular imaging, offering the clinician unparalleled information from a variety of modalities. Cardiovascular magnetic resonance imaging (MRI) has the advantages of superior spatial resolution, detailed tissue characterization, and accurate quantitative assessment of cardiac structure and function, without the need for radiation exposure. Recent advances in image acquisition and postimage processing have led to clinically validated protocols for myocardial perfusion, late gadolinium enhancement, and coronary angiography. The following collection of images was selected to demonstrate the typical appearance of various cardiovascular conditions using MRI. There is, of course, much heterogeneity in both the phenotypic severity of a given condition as well as its appearance on MRI. This article, while not intended to be a comprehensive collection, aims to serve as an introduction to the current applications of cardiac MRI.

Cardiac toxicity of cancer therapies remains an important clinical problem, despite decades of investigation. The prevention, surveillance, and treatment of cardiac toxicity are areas of active research, stimulated by recent attention from the National Institutes of Health.1 This has brought new energy and novel methods to the table. For patients facing treatment of cancer, no one size fits all, and several teams of investigators have tried to identify genetic variables or biomarkers that might predict the risk for cardiac injury by anthracyclines and allow for a more personalized approach that allows for a cancer patient to receive the maximal benefit of these powerful chemotherapies at minimal risk. These studies have identified many molecular pathways that may be important determinants of cardiotoxicity and have led to recent proposals for use of genetic testing in this setting.2 Article, see p 1135 Beer et al,3 in this issue of Circulation Research , have taken an alternative agnostic approach to identify biomarkers that might be used to evaluate risk for chemotherapy-associated cardiac injury and heart failure. Serial plasma samples were collected from a carefully characterized group of breast cancer patients treated with anthracycline and trastuzumab. Through the use of label-free …

Summary: In this report, we describe the first chronic case of Q fever endocarditis in a 72-year-old woman in Iran. The patient developed radiation-associated heart disease status post (s/p) coronary artery bypass surgery, mitral and aortic valve replacements, and tricuspid valve repair. Endocarditis was also suspected due to a history of heart valve surgery. Blood cultures were negative, but a diagnosis of Q fever endocarditis was confirmed based on serologic titers (IgG phase I 1:32,768). The patient was treated with doxycycline and hydroxychloroquine. Keywords: Q fever, Coxiella burnetii, Endocarditis, Female, Iran

Survival in cancer has improved, shifting some of the focus of care to minimizing the long term complications of cancer therapy. Cardiovascular disease is a leading long-term cause of morbidity and mortality in patients who survive cancer. In the review we will focus on imaging techniques that are used to detect the cardiovascular consequences of chemotherapy. We will differentiate cardiotoxicity and cardiac injury from cardiac dysfunction and cardiomyopathy. We will discuss the current clinical measures that are used to monitor patients, the limitations of each technique, and then detail research into novel methods for tracking and detecting the cardiac toxicity and cardiac dysfunction that may occur as a result of chemotherapy.

Bevacizumab treatment is associated with tumor shrinkage and hearing improvement in about 50 % of neurofibromatosis 2 (NF2) patients with progressive vestibular schwannomas. Hypertension and proteinuria are common side effects of treatment. However, the long-term toxicity of bevacizumab in this population has not been reported.We reviewed the medical records of all NF2 patients treated with compassionate care bevacizumab at our institution. Hypertension was defined as a systolic blood pressure ≥140 or a diastolic blood pressure ≥90. Proteinuria was measured by urine dipstick. Time-to-event analyses were conducted for hypertension and proteinuria. The relationship of cumulative dose of bevacizumab to mean arterial pressure (MAP) was examined using mixed model analysis, while the relationship to urine protein was examined using generalized estimating equations.Thirty-three patients (median age 28 years) were included in the study, with a median treatment time of 34.1 months. 15/26 (58 %) patients became hypertensive and 18/29 (62 %) developed proteinuria during treatment. Median time to develop hypertension was 12.8 months. Median time to develop 1+ and 2+ proteinuria was 23.7 and 31.9 months, respectively. Eight patients required treatment holidays for proteinuria (median length 3.2 months). A significant positive relationship existed between cumulative bevacizumab dose and MAP (p0.0001) but not between cumulative dose and proteinuria (p0.30).In our cohort of NF2 patients, extended use of bevacizumab was associated with manageable toxicity. However, bevacizumab treatment still requires careful monitoring of blood pressure and proteinuria, and future studies should investigate optimal dosing schedules to minimize long-term toxicity.

Occludin and 18 distinct members of the claudin family are tetra-span transmembrane proteins that are localized in cell-specific tight junctions (TJs). A previous study showed that expression of chick occludin in Madin-Darby canine kidney (MDCK) cells raised transepithelial electrical resistance (TER) and, paradoxically, increased mannitol flux. In the present study, we employed epitope tagged canine occludin expression, under the control of the tetracycline repressible transactivator, to determine the extent to which the unexpected parallel increase in TER and mannitol flux was related to a structural mismatch between avian and canine occludins, which are only 50% identical. To determine whether the paradoxical changes in permeability was specific to occludin, we assessed the effect of over-expressing epitope tagged murine claudin-1. Our data revealed that over-expression of either of the epitope tagged mammalian tight junction proteins increased TER, mannitol and FITC-dextran flux. We observed a 2- and up to 5.6-fold over-expression of occludin-VSV-G and claudin-1-myc, respectively, with no change in ZO-1, endogenous occludin or claudin-1 expression. Confocal microscopy revealed that occludin-VSV-G, claudin-1-myc and ZO-1 co-localized at the TJ. In addition, claudin-1-myc formed aberrant strands along the lateral cell surface without an underlying ZO-1 scaffold. In fracture labeled replicas these strands consisted of claudin-1-myc with little accompanying occludin. These observations suggest that in epithelial cells claudin-1 can assemble into TJ strands without the participation of either ZO-1 or occludin. The proximity of the myc tag to the COOH-terminal YV sequence of claudin-1 appeared to interfere with its interaction with ZO-1, since over-expression of non-tagged claudin-1 increased TER but had a minimal effect on solute flux and no aberrant strands formed. From our data we conclude that differences in structure between avian and mammalian occludin do not account for the observed paradoxical increase in mannitol flux. Levels of ZO-1 remained unchanged despite substantial increases in induced TJ integral protein expression, suggesting that an imbalance between levels of ZO-1 and occludin or claudin-1 leads to altered regulation of pores through which non-charged solute flux occurs. We suggest that ion and solute flux are differentially regulated at the TJ.

A 58-year-old black woman with a past medical history of recurrent presyncope, hypertension, depression, and breast cancer with right lumpectomy was admitted with symptoms of palpitations, chest pressure accompanied by numbness, and exertional dyspnea. An admission resting ECG revealed sinus rhythm without evidence of a prior myocardial infarction associated with occasional premature ventricular beats. A telemetry surveillance rhythm strip demonstrated nonsustained ventricular tachycardia with a left bundle block pattern (Figure 1). Transthoracic echocardiography examination was performed that showed normal biventricular morphology, size, and systolic function with no regional wall motion abnormalities (Movie I in the online-only Data Supplement). To further investigate the cause of the nonsustained ventricular tachycardia and to exclude any possible structural heart disease, a cardiac magnetic resonance (CMR) study with gadolinium contrast was performed. The CMR confirmed the normal biventricular size and systolic function (Movie II in the online-only Data Supplement) and, interestingly, revealed a region of intramyocardial fatty …

The antimetabolite chemotherapeutic agent 5-fluorouracil is used to treat a variety of cancers. Although 5-fluorouracil is generally well tolerated, its toxicity profile includes potential cardiac ischemia, vasospasm, arrhythmia, and direct myocardial injury. These actual or potential toxicities are thought to resolve upon cessation of the medication; however, information about the long-term cardiovascular effects of therapy is not sufficient. We present the case of a 58-year-old man who had 2 ventricular fibrillation cardiac arrests, with evidence of coronary vasospasm and myocarditis, on his 4th day of continuous infusion with 5-fluorouracil. External defibrillation and cessation of the 5-fluorouracil therapy resolved the patient's electrocardiographic abnormalities. In addition to reporting the clinical manifestations of 5-fluorouracil–associated cardiotoxicity in our patient, we discuss management challenges in patients who develop severe 5-fluorouracil–induced ventricular arrhythmias.

Background— A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. Methods and Results— In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P P P =0.04; adjusted hazard ratio=7.37; P Conclusions— Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01821924.

Objectives This study sought to determine feasibility and prognostic performance of stress cardiac magnetic resonance (CMR) in obese patients (body mass index [BMI] ≥30 kg/m2). Background Current stress imaging methods remain limited in obese patients. Given the impact of the obesity epidemic on cardiovascular disease, alternative methods to effectively risk stratify obese patients are needed. Methods Consecutive patients with a BMI ≥30 kg/m2 referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes. Results Of 285 obese patients, 272 (95%) completed the CMR protocol, and among these, 255 (94%) achieved diagnostic imaging quality. Mean BMI was 35.4 ± 4.8 kg/m2, with a maximum weight of 200 kg. Reasons for failure to complete CMR included claustrophobia (n = 4), intolerance to stress agent (n = 4), poor gating (n = 4), and declining participation (n = 1). Sedation was required in 19 patients (7%; 2 patients with intravenous sedation). Sixteen patients required scanning by a 70-cm–bore system (6%). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (0.3% vs. 6.3% for those with ischemia and 6.7% for those with ischemia and LGE). Median follow-up of the cohort was 2.1 years. In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, inducible ischemia (hazard ratio 7.5; 95% confidence interval: 2.0 to 28.0; p = 0.002) remained independently associated with MACE. When patients with early coronary revascularization (within 90 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Conclusions Stress CMR is feasible and effective in prognosticating obese patients, with a very low negative event rate in patients without ischemia or infarction.

We aimed to determine whether the myocardial extracellular volume (ECV), measured using T1 measurements obtained during cardiac magnetic resonance imaging were increased in patients treated with anthracyclines. We performed cardiac magnetic resonance imaging and echocardiography and measured the ECV in 42 patients treated with anthracyclines. The data from the cardiac magnetic resonance study were compared to those from healthy volunteers. The anthracycline-treated cohort consisted of 21 men and 21 women with a mean age of 55 ± 17 years, who presented a median of 84 months after chemotherapy with a cumulative anthracycline exposure of 282 ± 65 mg/m(2) and a mean left ventricular ejection fraction of 52 ± 12%. The ECV was elevated in the anthracycline-treated patients compared to the age- and gender-matched controls (0.36 ± 0.03 vs 0.28 ± 0.02, p

Summary To test the hypothesis that fibrotic burden in remote myocardium quantified by CMR during early period of infarct healing is a strong determinant of the cardiac remodeling outcome. Background After acute myocardial infarction (AMI), co-existing myocardial stunning, ischemia, and architectural alteration may yield variable patterns of ventricular remodeling with potential long-term prognostic implications. We hypothesize that CMR quantification of fibrotic content, based on R1 (1/T1) assessment, in non-infarct myocardium early after infarction and during the infarct healing phases may provide novel prediction of the final infarct size and alteration of ventricular functions during infarct healing. Methods

In patients with recent MI, elevated fibrotic burden within the remote myocardium quantified by CMR is strongly associated with post-exercise heart rate variability (HRV) and QT dispersion (QTD). In contrast, infarct tissue heterogeneity demonstrated strong association with prolonged mean QRS duration at rest and during exercise. We postulate that these patterns of ischemic structural/arrhythmogenic affiliations during convalescent infarct healing, likely reflect differences in depolarization/repolarization characteristics of different post-ischemic myocardium and sympathetic innervation.

The intersection of cancer and cardiovascular disease occurs on several levels. The present miniseries, within Circulation ’s Contemporary Reviews in Cardiovascular Medicine series, will highlight important areas within the emerging discipline of cardio-oncology. The miniseries will straddle a number of topics, as outlined …

ObjectivesThe major aim of this study is to test the hypothesis that stress cardiac magnetic resonance (CMR) imaging can provide robust prognostic value in women presenting with suspected ischemia, to the same extent as in men.BackgroundCompelling evidence indicates that women with coronary artery disease (CAD) experience worse outcomes than men owing to a lack of early diagnosis and management. Numerous clinical studies have shown that stress CMR detects evidence of myocardial ischemia and infarction at high accuracy. Compared to nuclear scintigraphy, CMR is free of ionizing radiation, has high spatial resolution for imaging small hearts, and overcomes breast attenuation artifacts, which are substantial advantages when imaging women for CAD.MethodsWe performed stress CMR in 405 patients (168 women, mean age 58 ± 14 years) referred for ischemia assessment. CMR techniques included cine cardiac function, perfusion imaging during vasodilating stress, and late gadolinium enhancement imaging. All patients were followed for major adverse cardiac events (MACE).ResultsAt a median follow-up of 30 months, MACE occurred in 36 patients (9%) including 21 cardiac deaths and 15 acute myocardial infarctions. In women, CMR evidence of ischemia (ISCHEMIA) demonstrated strong association with MACE (unadjusted hazard ratio: 49.9, p < 0.0001). While women with ISCHEMIA(+) had an annual MACE rate of 15%, women with ISCHEMIA(−) had very low annual MACE rate (0.3%), which was not statistically different from the low annual MACE rate in men with ISCHEMIA(−) (1.1%). CMR myocardial ischemia score was the strongest multivariable predictor of MACE in this cohort, for both women and men, indicating robust cardiac prognostication regardless of sex.ConclusionsIn addition to avoiding exposure to ionizing radiation, stress CMR myocardial perfusion imaging is an effective and robust risk-stratifying tool for patients of either sex presenting with possible ischemia.