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1. Cardiotoxicity of venetoclax in patients with acute myeloid leukemia: comparison with anthracyclines

Author

Takeshi Onoue, Andrew H. Matthews, Azin Vakilpour, Yu Kang, Bénédicte Lefebvre, Amanda M. Smith, Shannon R. McCurdy, Michael G. Fradley, Joseph Carver, Jesse Chittams, and Marielle Scherrer-Crosbie

Subjects
Venetoclax, Cardiotoxicity, Heart failure, Atrial fibrillation, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Venetoclax is a promising drug for patients with acute myeloid leukemia (AML) ineligible for anthracycline-based treatments. In rats, venetoclax is reported to cause myocardial injury. Our objectives were to report the frequency of cardiovascular (CV) events in patients treated with venetoclax, and, subsequently, to compare CV outcomes in matched patients treated with venetoclax or anthracyclines. Patients diagnosed with AML and treated with venetoclax or anthracyclines from January 2017 to July 2021 were identified. Major adverse cardiac events (MACE, including new-onset heart failure (HF), acute myocardial infarction, new onset atrial fibrillation (AF)) were recorded. Propensity-score method was then used to compare patients treated with venetoclax or anthracyclines. Patients treated with venetoclax (n=103) were older, with more hyperlipidemia than patients treated with anthracyclines (n=217). However, only 63% of patients treated with venetoclax underwent echocardiographic screening (vs. 93% of patients treated with anthracyclines, P< 0.001). Eighteen patients with venetoclax (17%) and 27 patients with anthracyclines (12%) developed MACE, including 10 % of new HF in each group. The median time to MACE was 8 days (interquartile range 5-98 days). In the matched cohort (n=132 patients), the cumulative incidence of MACE at one year was not different (17.5 % venetoclax, 9.2% anthracyclines, p =0.27). Thus, MACE incidence is similar in matched patients receiving venetoclax or anthracyclines. Close CV monitoring during the early phase of treatment may be helpful in patients treated with venetoclax.

Published
2024
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2. 14,15-Dihydroxyeicosatrienoic acid, a soluble epoxide hydrolase metabolite in blood, is a predictor of anthracycline-induced cardiotoxicity – a hypothesis generating study

Author

Julia Matzenbacher dos Santos, Aby Joiakim, David A. Putt, Marielle Scherrer-Crosbie, and Hyesook Kim

Subjects
Cardiotoxicity, 14,15-DHET, Early blood biomarker, Anthracyclines, Doxorubicin, Soluble epoxide hydrolase, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Early identification of patients susceptible to chemotherapy-induced cardiotoxicity could lead to targeted treatment to reduce cardiac dysfunction. Rats treated with doxorubicin (DOX), a chemotherapeutic agent, have increased cardiac expression of 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), a bioactive lipid implicated in hypertension and coronary artery disease. However, the utility of 14,15-DHET as plasma biomarkers was not defined. The aim of this study is to investigate if levels of 14,15-DHET are an early blood biomarker to predict the subsequent occurrence of cardiotoxicity in cancer patients after chemotherapy. Methods H9c2 rat cardiomyocytes were treated with DOX (1 μM) for 2 h and levels of 14,15-DHET in cell media was quantified at 2, 6 or 24 h in media after DOX treatment. Similarly, female Sprague–Dawley rats were treated with DOX for two weeks and levels of 14,15-DHET was assessed in plasma at 48 h and 2 weeks after DOX treatment. Changes in brain natriuretic peptide (BNP) mRNA, an early cardiac hypertrophy process, were determined in the H9c2 cells and rat cardiac tissue. Results were confirmed in human subjects by assessment of levels of 14,15-DHET in plasma of breast cancer patients before and after DOX treatment and left ventricular ejection fraction (LVEF), a clinical marker of cardiotoxicity. Results Levels of 14,15-DHET in cell media and rat plasma increased ~ 3-fold and was accompanied with increase in BNP mRNA in H9c2 cells and rat cardiac tissue after DOX treatment. In matched plasma samples from breast cancer patients, levels of 14,15-DHET were increased in patients that developed cardiotoxicity at 3 months before occurrence of LVEF decrease. Conclusions Together, these results indicate that levels of 14,15-DHET are elevated prior to major changes in cardiac structure and function after exposure to anthracyclines. Increased levels of 14,15-DHET in plasma may be an important clinical biomarker for early detection of anthracycline-induced cardiotoxicity in cancer patients.

Published
2023
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3. Circulating Cardiovascular Biomarkers in Cancer Therapeutics‐Related Cardiotoxicity: Review of Critical Challenges, Solutions, and Future Directions

Author

Gillian Murtagh, James L. Januzzi, Marielle Scherrer‐Crosbie, Tomas G. Neilan, Susan Dent, Jennifer E. Ho, Vinesh Appadurai, Ray McDermott, and Nausheen Akhter

Subjects
biomarkers, cardiotoxicity, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

ABSTRACT Cardiotoxicity is a growing concern in the oncology population. Transthoracic echocardiography and multigated acquisition scans have been used for surveillance but are relatively insensitive and resource intensive. Innovative imaging techniques are constrained by cost and availability. More sensitive, cost‐effective cardiotoxicity surveillance strategies are needed. Circulating cardiovascular biomarkers could provide a sensitive, low‐cost solution. Biomarkers such as troponins, natriuretic peptides (NPs), novel upstream signals of oxidative stress, inflammation, and fibrosis as well as panomic technologies have shown substantial promise, and guidelines recommend baseline measurement of troponins and NPs in all patients receiving potential cardiotoxins. Nonetheless, supporting evidence has been hampered by several limitations. Previous reviews have provided valuable perspectives on biomarkers in cancer populations, but important analytic aspects remain to be examined in depth. This review provides comprehensive assessment of critical challenges and solutions in this field, with focus on analytical issues relating to biomarker measurement and interpretation. Examination of evidence pertaining to common and serious forms of cardiotoxicity reveals that improved study designs incorporating larger, more diverse populations, registry‐based approaches, and refinement of current definitions are key. Further efforts to harmonize biomarker methodologies including centralized biobanking and analyses, novel decision limits, and head‐to‐head comparisons are needed. Multimarker algorithms incorporating machine learning may allow rapid, personalized risk assessment. These improvements will not only augment the predictive value of circulating biomarkers in cardiotoxicity but may elucidate both direct and indirect relationships between cardiovascular disease and cancer, allowing biomarkers a greater role in the development and success of novel anticancer therapies.

Published
2023
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4. Editorial: Leveraging digital and technological innovations in cardio-oncology: building collaborative networks, implementing education and improving the cardiac outcomes of patients

Author

Abdulaziz Hamid, James MacLeod, Samuel Erb, Generika Berman, Hugo R. Martinez, Marielle Scherrer-Crosbie, Richard K. Cheng, and Sherry-Ann Brown

Subjects
artificial intelligence, telemedicine, precision medicine, digital health, health equity, cardio-oncology, Diseases of the circulatory (Cardiovascular) system, RC666-701
Published
2023
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5. Leveraging innovation, education, and technology for prevention and health equity: Proceedings from the cardiology oncology innovation ThinkTank 2021

Author

Sherry-Ann Brown, Generika Berman, Jim Logan, Diego Sadler, Rohit Moudgil, Brijesh Patel, Marielle Scherrer-Crosbie, Daniel Addison, Richard K. Cheng, and Arco J. Teske

Subjects
innovation, prevention, health equity, cardiology, oncology, artificial intelligence, Diseases of the circulatory (Cardiovascular) system, RC666-701
Published
2022
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6. Women with peripartum cardiomyopathy have normal ejection fraction, but abnormal systolic strain, during pregnancy

Author

Ruth Tamrat, Yu Kang, Marielle Scherrer‐Crosbie, Lisa D. Levine, Zoltan Arany, and Jennifer Lewey

Subjects
Peripartum cardiomyopathy, Strain echocardiography, Heart failure, Maternal morbidity, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract We report a case series of six women with peripartum cardiomyopathy (PPCM) who incidentally underwent echocardiography prior to the clinical presentation of PPCM. For comparison, we identified controls, matched 2:1 on age, race, body mass index, gestational age, and hypertensive disorder. Among the six cases, all were diagnosed with PPCM during the post‐partum period. Pre‐PPCM echocardiograms were performed between 17.7 weeks of gestation and 13 days post‐partum. Baseline left ventricular ejection fraction and size were normal and similar to the 12 matched controls (60% ± 6.6% vs. 61.4% ± 6.3%, P = 0.63) or left ventricular end‐diastolic dimension (4.6 cm ± 0.2 cm vs. 4.5 cm ± 0.4 cm, P = 0.689). There was a trend towards a less negative (more abnormal) mean global longitudinal strain in cases compared with controls (−14% ± 4% vs. −18.3% ± 4.5%, P = 0.0658). Mean global circumferential strain was significantly less negative (more abnormal) in cases compared with controls (−21.5% ± 5% vs. −29.3% ± 7.6%, P = 0.0329). We conclude that women who develop PPCM have normal left ventricular ejection fraction during gestation preceding PPCM, indicating that the disease develops acutely in the peripartum period. Abnormal strain can be detected, however, suggesting that strain imaging could represent a screening method in populations at high risk for PPCM if confirmed in future studies.

Published
2021
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7. Cardiovascular Effects of CAR T Cell Therapy

Author

Bénédicte Lefebvre, MD, Yu Kang, MD, PhD, Amanda M. Smith, MA, Noelle V. Frey, MD, Joseph R. Carver, MD, and Marielle Scherrer-Crosbie, MD, PhD

Subjects
cardio-oncology, cardiovascular, CAR T cells, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Anti-CD19 chimeric antigen receptor (CAR) T cell therapy holds great promise in the treatment of patients with hematologic malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CAR T cell therapy. Objectives: The aim of this study was to define the occurrence of major adverse cardiovascular events (MACE) in adult patients treated with CAR T cell therapy and assess the relationships among clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes. Methods: Baseline clinical, laboratory, and echocardiographic parameters were collected in 145 adult patients undergoing CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis. Results: Thirty-one patients had MACE (41 events) at a median time of 11 days (interquartile range: 6 to 151 days) after CAR T cell infusion. The median follow-up period was 456 days (interquartile range: 128 to 1,214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (interquartile range: 1 to 8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53%, respectively. The Kaplan-Meier estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and grade 3 or 4 CRS were independently associated with MACE. Conclusions: Patients treated with CAR T cell therapy are at an increased risk for MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.

Published
2020
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8. An Initial Evaluation of Human Plasma cMLC-1: A Potential Protein Biomarker for Trastuzumab-Induced Cardiotoxicity, Breast Cancer Screening and Progression

Author

Ling Yu, Read Allen, Lin Jia, Ting Sun, Steven J. Isakoff, Marielle Scherrer-Crosbie, Allison M. Kehlmann, Hui Zheng, Amy Ly, Charlotte S. Walmsley, Katherine Hesler, Ava N. Varasteh, Christopher J. Pinto, Daniel E. McLoughlin, Wenjin Wu, and Xinhui Wang

Subjects
cardiac myosin light chain 1(cMLC-1), biomarkers, trastuzumab-induced cardiotoxicity, breast cancer screening, breast cancer progression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundTrastuzumab is a targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab-induced cardiotoxicity (TIC) has been reported when trastuzumab is administered to patients as a single agent or combined with anthracycline. Currently no means for detecting the early onset of TIC such as a protein biomarker is available. In this regard and based on promising results from a preliminary animal study, the potential of cardiac myosin light chain 1(cMLC-1) as a biomarker to predict TIC, screen patients for breast cancer and monitor tumor progression in breast cancer patients was evaluated.MethodsArchived plasma samples collected before and after trastuzumab treatment at various fixed time points from 15 HER2+ patients with or without cardiotoxicity, recently collected plasma samples from 79 breast cancer patients (40 HER2+, 39 HER2-), and 46 healthy donors were analyzed for cMLC-1 levels using an enzyme-linked immunosorbent assay (ELISA).ResultsAn elevated plasma cMLC-1 level was found to be associated with TIC in 3 out of 7 (43%) trastuzumab-treated HER2+ breast cancer patients. However, this study provided an opportunity for us to study plasma cMCL-1 levels in breast cancer patients. It was demonstrated that elevated plasma cMCL-1 is associated with breast cancer. The cutoff cMLC-1 concentration is estimated to be 44.99 ng/mL with a sensitivity of 59.49% (95%CI: 48.47%-69.63%) and specificity of 71.74% (95%CI: 57.45% -82.68%). We also found a noticeable but not significantly more elevated plasma cMCL-1 level in HER2- than in HER2+ breast cancer patients with the given sample sizes. As a result, improved sensitivity of 79.49% (95%CI: 64.47%-89.22%) with the specificity of 63.04% (95%CI:48.60%-75.48%) were obtained for cMLC-1 to predict HER2- breast cancer with the cutoff at 37.17 ng/mL. Moreover, this study determined that cMLC-1 level was significantly higher in patients with metastatic breast cancer than in patients with non-metastatic breast cancer.ConclusionsWhile the analysis of cMLC-1 levels in the plasma of a limited number of trastuzumab-treated HER2+ breast cancer patients failed to fully support its identification as a blood protein biomarker for predicting TIC, additional analyses of plasma cMLC-1 levels did significantly establish its correlations with breast cancer and disease progression. Our findings shed light on and filled, to some extent, the gap of knowledge of the potential of cMLC-1 as a blood protein biomarker for screening breast cancer and monitoring disease progression of breast cancer.

Published
2022
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9. Artificial intelligence and imaging: Opportunities in cardio-oncology

Author

Nidhi Madan, Julliette Lucas, Nausheen Akhter, Patrick Collier, Feixiong Cheng, Avirup Guha, Lili Zhang, Abhinav Sharma, Abdulaziz Hamid, Imeh Ndiokho, Ethan Wen, Noelle C. Garster, Marielle Scherrer-Crosbie, and Sherry-Ann Brown

Subjects
Imaging, Cardio-oncology, Cancer, Cardiac tumors, Artificial intelligence, Echocardiography, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Cardiovascular disease is a leading cause of death in cancer survivors. It is critical to apply new predictive and early diagnostic methods in this population, as this can potentially inform cardiovascular treatment and surveillance decision-making. We discuss the application of artificial intelligence (AI) technologies to cardiovascular imaging in cardio-oncology, with a particular emphasis on prevention and targeted treatment of a variety of cardiovascular conditions in cancer patients. Recently, the use of AI-augmented cardiac imaging in cardio-oncology is gaining traction. A large proportion of cardio-oncology patients are screened and followed using left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), currently obtained using echocardiography. This use will continue to increase with new cardiotoxic cancer treatments. AI is being tested to increase precision, throughput, and accuracy of LVEF and GLS, guide point-of-care image acquisition, and integrate imaging and clinical data to optimize the prediction and detection of cardiac dysfunction. The application of AI to cardiovascular magnetic resonance imaging (CMR), computed tomography (CT; especially coronary artery calcium or CAC scans), single proton emission computed tomography (SPECT) and positron emission tomography (PET) imaging acquisition is also in early stages of analysis for prediction and assessment of cardiac tumors and cardiovascular adverse events in patients treated for childhood or adult cancer. The opportunities for application of AI in cardio-oncology imaging are promising, and if availed, will improve clinical practice and benefit patient care.

Published
2022
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10. Symptomatic Heart Failure in Acute Leukemia Patients Treated With Anthracyclines

Author

Yu Kang, MD, PhD, Bruna Leal Assuncao, MD, Srinivas Denduluri, PhD, Shannon McCurdy, MD, Selina Luger, MD, Bénédicte Lefebvre, MD, Joseph Carver, MD, and Marielle Scherrer-Crosbie, MD, PhD

Subjects
acute leukemia, anthracycline, cardiotoxicity, global longitudinal strain, heart failure, risk score, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Objectives: The purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. Background: Knowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. Methods: Baseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray’s regression analysis, and from this, a 21-point risk score was generated. Results: Forty patients (8.9%) developed HF. The HF risk score included a baseline GLS >−15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction 60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). Conclusions: We developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

Published
2019
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11. Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice.

Author

Terrence Pong, Marielle Scherrer-Crosbie, Dmitriy N Atochin, Kenneth D Bloch, and Paul L Huang

Subjects
Medicine, Science
Abstract

Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection.We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation.Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.

Published
2014
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12. Soluble guanylate cyclase α1-deficient mice: a novel murine model for primary open angle glaucoma.

Author

Emmanuel S Buys, Yu-Chieh Ko, Clemens Alt, Sarah R Hayton, Alexander Jones, Laurel T Tainsh, Ruiyi Ren, Andrea Giani, Maeva Clerté, Emma Abernathy, Robert E T Tainsh, Dong-Jin Oh, Rajeev Malhotra, Pankaj Arora, Nadine de Waard, Binglan Yu, Raphael Turcotte, Daniel Nathan, Marielle Scherrer-Crosbie, Stephanie J Loomis, Jae H Kang, Charles P Lin, Haiyan Gong, Douglas J Rhee, Peter Brouckaert, Janey L Wiggs, Meredith S Gregory, Louis R Pasquale, Kenneth D Bloch, and Bruce R Ksander

Subjects
Medicine, Science
Abstract

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1-deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.

Published
2013
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14. Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

Author

Zhen Guo, Carla Valenzuela Ripoll, Antonino Picataggi, David R. Rawnsley, Mualla Ozcan, Julio A. Chirinos, Ezhilarasi Chendamarai, Amanda Girardi, Terrence Riehl, Hosannah Evie, Ahmed Diab, Attila Kovacs, Krzysztof Hyrc, Xiucui Ma, Aarti Asnani, Swapnil V. Shewale, Marielle Scherrer-Crosbie, Lauren Ashley Cowart, John S. Parks, Lei Zhao, David Gordon, Francisco Ramirez-Valle, Kenneth B. Margulies, Thomas P. Cappola, Ankit A. Desai, Lauren N. Pederson, Carmen Bergom, Nathan O. Stitziel, Michael P. Rettig, John F. DiPersio, Stefan Hajny, Christina Christoffersen, Abhinav Diwan, and Ali Javaheri

Subjects
autophagy, TFEB, Apolipoprotein B, biology, Chemistry, Autophagy, anthracycline, Original Research - Preclinical, Cell biology, APOM, Apoptosis, apolipoprotein M, biology.protein, medicine, Doxorubicin, Nuclear protein, Cardiology and Cardiovascular Medicine, cardiomyopathy, Protein kinase B, medicine.drug
Abstract

ObjectivesDetermine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity.BackgroundApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF).MethodsIn the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic (ApomTG), ApoM knockout (ApomKO), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls.ResultsApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients.ApomTGmice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass.ApomTGattenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH.ConclusionsApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy.HighlightsCirculating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathyAnthracycline treatment reduces circulating ApoM in humans and miceIncreasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacyAutophagic impairment is characteristic of human anthracycline cardiomyopathy

Published
2023
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15. Ischemia With Nonobstructive Coronary Arteries

Author

Harmony R. Reynolds, Ariel Diaz, Derek D. Cyr, Leslee J. Shaw, G.B. John Mancini, Jonathon Leipsic, Matthew J. Budoff, James K. Min, Cameron J. Hague, Daniel S. Berman, Bernard R. Chaitman, Michael H. Picard, Sean W. Hayes, Marielle Scherrer-Crosbie, Raymond Y. Kwong, Renato D. Lopes, Roxy Senior, Sudhanshu K. Dwivedi, Todd D. Miller, Benjamin J.W. Chow, Ramesh de Silva, Gregg W. Stone, William E. Boden, Sripal Bangalore, Sean M. O’Brien, Judith S. Hochman, and David J. Maron

Subjects
Radiology, Nuclear Medicine and imaging, Cardiology and Cardiovascular Medicine
Published
2023
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16. Advances in Multimodality Imaging in Cardio-Oncology

Author

Lauren A. Baldassarre, Sarju Ganatra, Juan Lopez-Mattei, Eric H. Yang, Vlad G. Zaha, Timothy C. Wong, Chadi Ayoub, Jeanne M. DeCara, Susan Dent, Anita Deswal, Arjun K. Ghosh, Mariana Henry, Abhishek Khemka, Monika Leja, Lawrence Rudski, Hector R. Villarraga, Jennifer E. Liu, Ana Barac, and Marielle Scherrer-Crosbie

Subjects
Cardiology and Cardiovascular Medicine
Published
2022
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17. Biomedical Imaging in Experimental Models of Cardiovascular Disease

Author

David E. Sosnovik and Marielle Scherrer-Crosbie

Subjects
Mice, Diffusion Tensor Imaging, Cardiovascular Diseases, Physiology, Positron-Emission Tomography, Animals, Models, Theoretical, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, Magnetic Resonance Imaging, Article
Abstract

Major advances in biomedical imaging have occurred over the last 2 decades and now allow many physiological, cellular, and molecular processes to be imaged noninvasively in small animal models of cardiovascular disease. Many of these techniques can be also used in humans, providing pathophysiological context and helping to define the clinical relevance of the model. Ultrasound remains the most widely used approach, and dedicated high-frequency systems can obtain extremely detailed images in mice. Likewise, dedicated small animal tomographic systems have been developed for magnetic resonance, positron emission tomography, fluorescence imaging, and computed tomography in mice. In this article, we review the use of ultrasound and positron emission tomography in small animal models, as well as emerging contrast mechanisms in magnetic resonance such as diffusion tensor imaging, hyperpolarized magnetic resonance, chemical exchange saturation transfer imaging, magnetic resonance elastography and strain, arterial spin labeling, and molecular imaging.

Published
2022
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18. Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice

Author

Jing Liu, Sarah Lane, Rahul Lall, Michele Russo, Laurie Farrell, Melis Debreli Coskun, Casie Curtin, Raquel Araujo-Gutierrez, Marielle Scherrer-Crosbie, Barry H. Trachtenberg, Jonghan Kim, Emanuela Tolosano, Alessandra Ghigo, Robert E. Gerszten, and Aarti Asnani

Subjects
Multidisciplinary
Abstract

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients ( n = 30) and replicated key findings in a second cohort ( n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx −/− mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Published
2022
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19. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author

Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, Mohammed Hussain, Mohammed Saleem, Moisés Blanco-Calvo, Moisés Jiménez-Santos, Mona Bhatia, Monica Rosca, Monika Laukyte, Montserrat Gracida Blanca, Montserrat Vila Perales, Mouaz H Al-Mallah, Moysés de Oliveira Filho, Mpiko Ntsekhe, Muhamed Saric, Mulei Chen, Myriam Brousseau, Myrthes Emy Takiuti, Nada Cemerlic-Adjic, Nadia Asif, Nadia Gakou, Nafisa Hussain, Nana O Katamadze, Nancy L Clapp, Nancy Aedy, Nandita Nataraj, Nanette K Wenger, Naomi Uchida, Nasrul Ismail, Natalia S Oliveira, Natalia de Carvalho Maffei, Natalie Spitzer, Natasha C Putnam, Naved Aslam, Neamat Mowafy, Neeraj Pandit, Neeraj Parakh, Nevena Garcevic, Ngaire Meadows, Nhi N Tran, Nicholas Danchin, Nicki Lakeman, Nicola Johnston, Nicolas W Shammas, Nicole Saint Vrestil, Nicole Deming, Nier Zhong, Niket Patel, Nikola N Boskovic, Nikolaos Karogiannis, Nikos Werner, Nina Johnston, Ning Zhang, Ning Zhou, Niree Hindoyan, Nirmal Kumar, Nitika Chadha, Nitish Naik, Nodira Aripova, Noloyiso Mtana, Nona A Eskelson, Noor Syamira Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, 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Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, Mohammed Hussain, Mohammed Saleem, Moisés Blanco-Calvo, Moisés Jiménez-Santos, Mona Bhatia, Monica Rosca, Monika Laukyte, Montserrat Gracida Blanca, Montserrat Vila Perales, Mouaz H Al-Mallah, Moysés de Oliveira Filho, Mpiko Ntsekhe, Muhamed Saric, Mulei Chen, Myriam Brousseau, Myrthes Emy Takiuti, Nada Cemerlic-Adjic, Nadia Asif, Nadia Gakou, Nafisa Hussain, Nana O Katamadze, Nancy L Clapp, Nancy Aedy, Nandita Nataraj, Nanette K Wenger, Naomi Uchida, Nasrul Ismail, Natalia S Oliveira, Natalia de Carvalho Maffei, Natalie Spitzer, Natasha C Putnam, Naved Aslam, Neamat Mowafy, Neeraj Pandit, Neeraj Parakh, Nevena Garcevic, Ngaire Meadows, Nhi N Tran, Nicholas Danchin, Nicki Lakeman, Nicola Johnston, Nicolas W Shammas, Nicole Saint Vrestil, Nicole Deming, Nier Zhong, Niket Patel, Nikola N Boskovic, Nikolaos Karogiannis, Nikos Werner, Nina Johnston, Ning Zhang, Ning Zhou, Niree Hindoyan, Nirmal Kumar, Nitika Chadha, Nitish Naik, Nodira Aripova, Noloyiso Mtana, Nona A Eskelson, Noor Syamira Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, Raewyn Fisher, Rafael Beyar, Rafael Diaz, Rafael Selgas, Raffaele Bugiardini, Raffaele Fanelli, Raisa Kavalakkat, V S Rajalekshmi, Rajat S Barua, Rajeev Menon, Rajesh Gopalan Nair, Rajesh Francis, Rajiv Narang, Rakesh Yadav, Ralph Alan Huston, T Ramakrishnan, Ramesh de Silva, Rami El Mahmoud, Ramiro Carvalho, Ramon de Jesús-Pérez, Ramona Stevens, Ran Leng, Ranjan Kachru, Ranjit Kumar Nath, Raquel Sanchez, Raven R Dwyer, Raven Lee, Ray Wyman, Raymond C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M Rivest, Sandra S Zier, Sandra Ahoud, Sandy Carr, Sanjay Ganapathi, Sanjay Shetty, Sanjeev Sharma, Santa Jimenez, Santhosh Satheesh, Santiago A Garcia, Sara Fernandez, Sara Karlsson, Sara Salkind, Sara Temiyasathit, Sarah Medina Rodriguez, Sarah Beaudry, Sarah Hadjih, Sarah Williams, Sarah Zahrani, Sarju Ralhan, Sasa Hinic, Sasko Kedev, Satinder Singh, Satoshi Yasuda, Satvic Cholenahally Manjunath, Sau Lee, Scott M Kaczkowski, Scott Kinlay, Sean W Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits

Subjects
Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Published
2020
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20. Women with peripartum cardiomyopathy have normal ejection fraction, but abnormal systolic strain, during pregnancy

Author

Lisa D. Levine, Yu Kang, Jennifer Lewey, Marielle Scherrer-Crosbie, Ruth Tamrat, and Zoltan Arany

Subjects
medicine.medical_specialty, Peripartum cardiomyopathy, Case Report, Heart failure, Case Reports, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Diseases of the circulatory (Cardiovascular) system, Strain echocardiography, 030212 general & internal medicine, Peripartum Period, Pregnancy, Ejection fraction, business.industry, Gestational age, medicine.disease, RC666-701, Cardiology, Gestation, Cardiology and Cardiovascular Medicine, business, Body mass index, Maternal morbidity
Abstract

We report a case series of six women with peripartum cardiomyopathy (PPCM) who incidentally underwent echocardiography prior to the clinical presentation of PPCM. For comparison, we identified controls, matched 2:1 on age, race, body mass index, gestational age, and hypertensive disorder. Among the six cases, all were diagnosed with PPCM during the post‐partum period. Pre‐PPCM echocardiograms were performed between 17.7 weeks of gestation and 13 days post‐partum. Baseline left ventricular ejection fraction and size were normal and similar to the 12 matched controls (60% ± 6.6% vs. 61.4% ± 6.3%, P = 0.63) or left ventricular end‐diastolic dimension (4.6 cm ± 0.2 cm vs. 4.5 cm ± 0.4 cm, P = 0.689). There was a trend towards a less negative (more abnormal) mean global longitudinal strain in cases compared with controls (−14% ± 4% vs. −18.3% ± 4.5%, P = 0.0658). Mean global circumferential strain was significantly less negative (more abnormal) in cases compared with controls (−21.5% ± 5% vs. −29.3% ± 7.6%, P = 0.0329). We conclude that women who develop PPCM have normal left ventricular ejection fraction during gestation preceding PPCM, indicating that the disease develops acutely in the peripartum period. Abnormal strain can be detected, however, suggesting that strain imaging could represent a screening method in populations at high risk for PPCM if confirmed in future studies.

Published
2021

21. List of contributors

Author

Theodore P. Abraham, Luigi P. Badano, Thor Edvardsen, John Gorcsan, Nobuyuki Kagiyama, Allan L. Klein, Wojciech Kosmala, Kenya Kusunose, Thomas H. Marwick, Denisa Muraru, Kazuaki Negishi, Dermot Phelan, Zoran B. Popović, Marielle Scherrer-Crosbie, Partho P. Sengupta, Amil Shah, Sirish Shrestha, Paaladinesh Thavendiranathan, James Thomas, and Jens-Uwe Voigt

Published
2022
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22. Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction

Author

Andrea A. Guerrero, N. Adrian Leu, Carl F Wittig, Mark L. Kahn, Ingrid Marti-Pamies, Marielle Scherrer-Crosbie, T.C. Stevenson Keller, Swapnil V. Shewale, Kendra McDaid, Lillian Lim, Phyllis A. Gimotty, Stephanie Sterling, and Alan T. Tang

Subjects
Cardiac function curve, medicine.medical_specialty, Vascular Endothelial Growth Factor C, Myocardial Infarction, Ventricular Function, Left, Mice, Internal medicine, medicine, Lymphatic vessel, Animals, Humans, Myocardial infarction, Progenitor cell, Lymphangiogenesis, Lymphatic Vessels, Ejection fraction, business.industry, Heart, General Medicine, medicine.disease, Vascular Endothelial Growth Factor Receptor-3, Lymphatic system, medicine.anatomical_structure, Heart failure, Cardiology, Commentary, business, Research Article
Abstract

In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all three genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction two weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by non-lymphangiogenic mechanisms.

Published
2021

23. The role of premorbid transthoracic echocardiogram in identifying adverse clinical outcomes in patients admitted with COVID-19

Author

M Ambrosino, N Patel, L Panepinto, S Denduluri, C Lee, M Byers, Marielle Scherrer-Crosbie, Srinath Adusumalli, and Jordana B. Cohen

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, Atrial fibrillation, medicine.disease, Drug usage, Obstructive sleep apnea, Emergency medicine, medicine, Medical history, In patient, Hemodialysis, Transthoracic echocardiogram, Cardiology and Cardiovascular Medicine, business
Abstract

Background/Introduction The novel coronavirus disease (COVID-19) inpatient mortality rate is approximately 20% in the United States. Reports have described a wide pattern of abnormalities in echocardiograms performed in patients admitted with COVID-19. The role of premorbid transthoracic echocardiogram (TTE) in the prediction of COVID-19 severity and mortality is yet to be fully assessed. Purpose To assess whether a pre-COVID TTE can identify patients at high risk of adverse outcomes who are admitted with COVID-19. Methods All patients who underwent a TTE from one year to one month prior to an index inpatient admission for COVID-19 were retrospectively enrolled across five clinical sites. Demographic information, medical history, and laboratory data were included for analysis. Echocardiograms were analyzed by an observer blinded to clinical data. Linear and logistic regressions were performed to detect the association of variables with death, invasive mechanical ventilation, initiation of dialysis, and a composite of these endpoints during the COVID-19 admission. Outcomes were then adjusted for a risk score using inverse propensity weighting incorporating age, sex, diabetes, hypertension, obstructive sleep apnea, history of atherosclerotic cardiovascular disease, atrial fibrillation, diuretic use, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. Results There were 104 patients (68±15 years old, 49% male, BMI 31.4±9.1kg/m2) who met inclusion criteria (baseline characteristics in Table 1). Mean time from TTE to positive SARS-CoV-2 PCR test was 139±91 days. Twenty-nine (28%) participants died during the index COVID-19 admission. There was no association of pre-COVID echocardiographic measures of systolic ventricular function with any endpoint. Diastolic function, as assessed by LV e', was associated with mortality (Table 2). There were 25 patients (24%) with a normal lateral e' (≥10cm/s); none died. There were 35 (34%) patients with LV e' lateral velocity Conclusion In patients with an echocardiogram prior to COVID-19, impaired diastolic function as represented by an abnormal LV e' lateral velocity was associated with both inpatient COVID-19 mortality and a composite outcome of death, mechanical ventilation, and initiation of dialysis, even after adjustment for multiple co-morbidities and medication use. Knowledge of the pre-COVID TTE results may help clinicians identify patients at higher risk of adverse outcomes during an admission for COVID-19. Funding Acknowledgement Type of funding sources: None.

Published
2021
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24. Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart

Author

Miguel-Angel Perales, Joseph R. Carver, Daniel J. Lenihan, Sarju Ganatra, Thomas J. Ryan, Monika Leja, Negaresh Mousavi, Bonnie Ky, Vlad G. Zaha, Richard M. Steingart, Eric H. Yang, Jae H. Park, Jennifer E. Liu, Ana Barac, Salim S. Hayek, Marielle Scherrer-Crosbie, and Carrie Lenneman

Subjects
Cardiotoxicity, medicine.medical_specialty, Ejection fraction, business.industry, Cardiogenic shock, 030204 cardiovascular system & hematology, Pulmonary edema, medicine.disease, Chimeric antigen receptor, 03 medical and health sciences, Cytokine release syndrome, 0302 clinical medicine, Internal medicine, Cardiology, Medicine, Chimeric Antigen Receptor T-Cell Therapy, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Adverse effect
Abstract

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

Published
2019
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25. Preparing the Cardiovascular Workforce to Care for Oncology Patients

Author

Rupal O'Quinn, Jennifer E. Liu, Negareh Mousavi, Daniel J. Lenihan, Marielle Scherrer-Crosbie, Bonnie Ky, Thomas J. Ryan, Joseph R. Carver, Carrie Lenneman, Sarju Ganatra, Salim S. Hayek, Eric H. Yang, Ana Barac, Anita Arnold, Monika Leja, and Jose Banchs

Subjects
education.field_of_study, medicine.medical_specialty, business.industry, Population, Stakeholder, Cancer, Cardiovascular care, Disease, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Family medicine, Workforce, Epidemiology, medicine, Oncology patients, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, education, business
Abstract

Cardiovascular disease and cancer are the 2 main causes of death in the United States. They intersect on multiple levels, sharing common causal mechanisms and epidemiological risk factors. The growing prevalence and complexity of cardiovascular disease and cancer have resulted in the development of the discipline of cardio-oncology. Preparing the cardiovascular workforce for the care of a growing population of cancer patients is necessary to enhance the delivery of high-quality cardiovascular care for patients with cancer. The goal of this review is to present the dedicated efforts of the cardio-oncology community to meet the growing need for education and training of cardiovascular practitioners providing care to cancer patients and survivors. Integration in general cardiology training programs and the efforts of the stakeholder organizations serve as an example of how a multidimensional, innovative approach can address provider education and training needs in a relatively new discipline.

Published
2019
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26. An Initial Evaluation of Human Plasma cMLC-1 as a Potential Protein Biomarker for Trastuzumab-Induced Cardiotoxicity, Breast Cancer Screening and Progression

Author

Ling Yu, Read Allen, Lin Jia, Ting Sun, Steve J. Isakoff, Marielle Scherrer-Crosbie, Hui Zheng, Charlotte S. Walmsley, Katherine Hesler, Ava N. Varasteh, Christopher J. Pinto, Daniel E. McLoughlin, Wenjin Wu, and Xinhui Wang

Subjects
skin and connective tissue diseases
Abstract

Background Trastuzumab is a targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab-induced cardiotoxicity (TIC) has been reported as a single agent or combined with anthracycline. Methods such as biomarkers for early TIC detection is not available. Blood-based protein biomarker prostate-specific antigen (PSA) for diagnosis, screening, prediction of response to therapy, and disease progression has revolutionized management and outcome of prostate cancer. Nevertheless, no blood biomarkers exist for breast cancer diagnosis or screening. Methods We evaluated for the first time the potentials of cardiac myosin light chain 1(cMLC-1) as a biomarker to predict TIC, screen breast cancer and monitor breast cancer progression. Plasma cMCL-1 was measured quantitatively using enzyme-linked immunosorbent assays (ELISA). Archived paired plasma samples collected before and after trastuzumab treatment from 15 HER2 + patients with or without cardiotoxicity, recently collected unpaired plasma samples from 79 breast cancer patients (40 HER2+, 39 HER2- ) and 46 healthy donors were tested for cMLC-1 levels. Results We found that elevated plasma level of cMLC-1 is associated with cardiotoxicity in 43% of trastuzumab-treated patients. In addition, we demonstrated that elevated plasma cMCL-1 is associated with breast cancer. The cutoff cMLC-1 concentration is estimated to be 44.99 ng/mL with a sensitivity of 59.49% (95%CI: 48.47%-69.63%) and specificity of 71.74% (95%CI: 57.45% -82.68%). We also found that plasma cMCL-1 is more elevated in HER2- than in HER2 + breast cancer patients. As a result, improved sensitivity of 79.49% (95%CI: 64.47%-89.22%) with the specificity of 63.04% (95%CI:48.60%-75.48%) were obtained for cMLC-1 to predict HER2- breast cancer with the cutoff at 37.17 ng/mL. Moreover, we determined that cMLC-1 level was significantly higher in patients with metastatic breast cancer than in patients with non-metastatic breast cancer. Conclusions Here we report the first exploratory human study on the potential of cMLC-1 as a blood protein biomarker for predicting TIC. Additionally, we show our findings which shed light on and filled, to some extent, the gap of knowledge of the potential of cMLC-1 as a blood protein biomarker for screening breast cancer, especially for HER2- breast cancer, and disease progression of breast cancer.

Published
2021
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27. Ultrasound-Enhancing Agents and Associated Adverse Reactions: A Potential Connection to the COVID-19 Vaccines?

Author

Dinesh Jagasia, Michelle McGovern, Srinath Adusumalli, Marielle Scherrer-Crosbie, Richard Weiss, Meshal Soni, Sheldon E. Litwin, and Ron Jacob

Subjects
2019-20 coronavirus outbreak, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), business.industry, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Virology, Article, Connection (mathematics), Medicine, Humans, Radiology, Nuclear Medicine and imaging, Cardiology and Cardiovascular Medicine, business, Ultrasonography
Published
2021

28. Abstract 15488: Epidemiological Profile of Cardiovascular Risk Factors and Outcomes in Patients With Solid Organ and Haematological Malignancies

Author

Prajith Jeyaprakash, Marielle Scherrer-Crosbie, Urmi Jethwani, Gary Gan, Aaia Aladdin, Aditya Bhat, Fiona Kwok, David Chandrakumar, Cindy Li, Amanda Johnston, and Timothy C. Tan

Subjects
medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Cardiovascular risk factors, Physiology (medical), Epidemiology, medicine, In patient, Solid organ, Cardio oncology, Cardiology and Cardiovascular Medicine, Intensive care medicine, business
Abstract

Introduction: Chemotherapy remains the cornerstone in the management of solid organ malignancies (SOM) and hematological malignancies (HM). Although life-prolonging, it is not without cost, with heart failure and arrhythmia becoming increasingly recognised complications of treatment. Although there is significant overlap in the chemotherapeutic management of SOM and HM, epidemiological information on the differential prevalence of baseline cardiovascular risk factors and outcomes in these populations is scarce. Hypothesis: A differential cardiovascular risk profile and clinical course will be appreciated in patients with SOM and HM undergoing chemotherapy. Methods: Retrospective observational study design. Patients admitted to our institution undergoing chemotherapy for SOM (2014-2018) or HM (2012-2015) were reviewed. Baseline demographic and clinical data was collated and patients were followed for up to five years following chemotherapy for occurrence of major adverse cardiac events (MACE) defined as the development of new-onset heart failure or arrhythmia. Results: 545 hematology and 435 oncology patients with malignancy were assessed. Compared to those with HM, those treated for SOM had a poorer cardiovascular risk profile (table 1). At mean follow-up period of 22.8±17.8 months, no significant difference in the incidence of the composite endpoint (9.4% vs 9.0%, p=0.45) or its components was observed. Higher rates of anthracycline therapy was observed in patients with HM (100% vs 17%, p < 0.01), however its use did not have a differential effect on MACE (12% vs 9%, p=0.25). Conclusions: Compared to patients treated for HM, patients with SOM had a greater burden of cardiovascular risk factors and lower use of anthracycline chemotherapy. Despite this, MACE occurred at similar rates in both groups. The use of anthracyclines was not associated with the development of MACE, suggesting alternative pathways contributing to its development.

Published
2020
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29. Abstract 15870: External Validation of a Risk Score for Heart Failure in Acute Myeloid Leukemia

Author

Gregory Cascino, Nausheen Akhter, Yu Kang, Jessica K. Altman, Peter G. Doukas, Borko Jovanovic, and Marielle Scherrer-Crosbie

Subjects
medicine.medical_specialty, Framingham Risk Score, business.industry, External validation, Myeloid leukemia, medicine.disease, Physiology (medical), Heart failure, Internal medicine, medicine, In patient, Cardio oncology, Cardiology and Cardiovascular Medicine, business
Abstract

Introduction: HF is a major cause of morbidity and mortality in AML patients. This study was designed as an external evaluation of a risk score to determine the risk of HF in patients treated with anthracyclines for AML. Methods: A validation cohort was composed of 204 consecutive patients with AML treated with anthracyclines. 2DSTE was performed using TomTec software to obtain baseline GLS values. LVEF was calculated using modified Simpson’s biplane method. HF hospitalizations were defined using standard clinical criteria. The HF risk score included a baseline GLS > - 15% (6 points), baseline LVEF/= 250 mg/m 2 (2 points), and age > 60 years (1 point). Patients were stratified into low (0 to 2 points), medium (3 to 9 points), and high risk (10 to 17 points). Statistical analysis was performed to evaluate event-free survival of the risk categories. Results: The average age of the cohort was 54 with an average risk score of 7 points. 55% of the patients were male. In total, 44 patients (21%) experienced a hospitalization for HF (median time to hospitalization 1 month) within the follow-up period (median 18 months). The observed incidence of HF by risk category was 14% (18 of 130) in the low, 31% (19 of 61) in medium, and 54% (7 of 13) in high risk group. The association between HF and the risk group category was highly significant (p = 0.001). Event-free survival by risk category (Figure 1) was also statistically significant (p = 0.05), with individuals in the high risk category having a reduced event-free survival. Conclusions: This is the first external validation study of a risk score for HF in AML patients. The risk score that we evaluated was successful at identifying patient who were at higher risk of hospitalization for HF. This may be a useful tool in clinical practice to counsel patients regarding the risk of HF after induction chemotherapy with anthracyclines.

Published
2020
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30. Symptomatic Heart Failure in Acute Leukemia Patients Treated With Anthracyclines

Author

Srinivas Denduluri, Selina M. Luger, Joseph R. Carver, Bruna Morhy Borges Leal Assunção, Shannon R. McCurdy, Yu Kang, Marielle Scherrer-Crosbie, and Bénédicte Lefebvre

Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system, medicine.medical_specialty, Anthracycline, cardiotoxicity, heart failure, risk score, anthracycline, lcsh:RC254-282, Article, Internal medicine, Medicine, acute leukemia, Original Research, Cardiotoxicity, Acute leukemia, Framingham Risk Score, business.industry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Oncology, lcsh:RC666-701, Heart failure, Cardiology and Cardiovascular Medicine, business, Editorial Comment, global longitudinal strain
Abstract

Objectives: The purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. Background: Knowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. Methods: Baseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray’s regression analysis, and from this, a 21-point risk score was generated. Results: Forty patients (8.9%) developed HF. The HF risk score included a baseline GLS >−15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction 60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). Conclusions: We developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

Published
2020

31. Strain Imaging in Cardio-Oncology

Author

Paaladinesh Thavendiranathan, Jennifer E. Liu, Ana Barac, and Marielle Scherrer-Crosbie

Subjects
CMRI, cardiac magnetic resonance imaging, medicine.medical_specialty, animal structures, ROI, region of interest, Cancer therapy, cardiotoxicity, left ventricular function, Text mining, ASE, American Society of Echocardiography, Internal medicine, 3D, 3-dimensional, LVEF, left ventricular ejection fraction, Medicine, cancer, echocardiography, Cardio oncology, DICOM, Digital Imaging and Communications in Medicine, AL, amyloid light chains, Cardiotoxicity, Ejection fraction, business.industry, Cancer, Strain imaging, medicine.disease, Primers in Cardio-Oncology, EACVI, European Association of Cardiovascular Imaging, Patient management, LV, left ventricle, Oncology, STE, speckle tracking echocardiography, 2D, 2-dimensional, Cardiology, GLS, global longitudinal strain, ACC, American College of Cardiology, Cardiology and Cardiovascular Medicine, business, CTRCD, cancer treatment–related cardiac dysfunction, global longitudinal strain, VEGF, vascular endothelium growth factor
Abstract

Echocardiographic imaging is crucial for patient management during cardiotoxic cancer therapy. Left ventricular ejection fraction is the most commonly used parameter for identifying left ventricular dysfunction. However, it lacks sensitivity to detect subclinical changes in cardiac function due to cardiotoxic treatment. Global longitudinal strain (GLS) is the best studied strain parameter with established diagnostic and prognostic value. Multiple studies have demonstrated changes in GLS as an early marker of cardiotoxicity. This document serves as a primer to help clinicians in the acquisition and interpretation of strain in cardio-oncology. Cases with embedded videos illustrate a step-by-step approach to obtaining GLS measurements and common pitfalls to avoid. The document includes a concise summary of the indications of GLS in cardio-oncology and its role in guiding oncological therapy. Practical approaches on how to implement strain in the echo laboratory with guidance on training and quality assurance are also discussed., Central Illustration, Highlights • Compared with LVEF, GLS is a more sensitive and reproducible measure of LV systolic function and has emerged as an early marker of cardiotoxicity. • Despite evidence supporting the clinical utility of GLS imaging, familiarity with the practical process of strain imaging among clinicians is lacking. • Although each vendor has its own proprietary software for strain imaging, the basic steps of measuring GLS are similar. • Education is needed to enhance the performance, analysis, and interpretation of GLS for the management of cardio-oncology patients.

Published
2020

32. Left ventricular segmental strain and the prediction of cancer therapy-related cardiac dysfunction

Author

Henry G Cheng, Christos Davatzikos, Biniyam G. Demissei, Yiwen Qian, Natasha A. Vedage, Bonnie Ky, Yong Fan, Kelsey Shimamoto, Amanda M. Smith, Hari K. Narayan, and Marielle Scherrer-Crosbie

Subjects
medicine.medical_specialty, Heart Diseases, Breast Neoplasms, 030204 cardiovascular system & hematology, Ventricular Function, Left, 03 medical and health sciences, Basal (phylogenetics), Ventricular Dysfunction, Left, 0302 clinical medicine, Breast cancer, Internal medicine, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Cardiotoxicity, Ejection fraction, business.industry, Area under the curve, Cancer, Stroke Volume, General Medicine, Original Articles, Middle Aged, Trastuzumab, medicine.disease, Confidence interval, 030220 oncology & carcinogenesis, Heart failure, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Aims We aimed to determine the early changes and predictive value of left ventricular (LV) segmental strain measures in women with breast cancer receiving doxorubicin. Methods and results In a cohort of 237 women with breast cancer receiving doxorubicin with or without trastuzumab, 1151 echocardiograms were prospectively acquired over a median (Q1–Q3) of 7 (2–24) months. LV ejection fraction (LVEF) and 36 segmental strain measures were core lab quantified. A supervised machine learning (ML) model was then developed using random forest regression to identify segmental strain measures predictive of nadir LVEF post-doxorubicin completion. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥10% absolute LVEF decline pre-treatment to a value Conclusion Our findings suggest that segmental strain measures can enhance cardiotoxicity risk prediction in women with breast cancer receiving doxorubicin.

Published
2020

33. State of the Art: Imaging for Myocardial Viability: A Scientific Statement From the American Heart Association

Author

Robert O. Bonow, Parham Eshtehardi, Marielle Scherrer-Crosbie, Ron Blankstein, Mario J. Garcia, John P. Bois, Cynthia C. Taub, Raymond Y. Kwong, and Joao A.C. Lima

Subjects
Adult, Male, medicine.medical_specialty, Clinical Decision-Making, Myocardial Ischemia, Context (language use), Risk Assessment, Sudden cardiac death, Coronary artery disease, Necrosis, Myocardial perfusion imaging, Predictive Value of Tests, Risk Factors, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Myocardial infarction, Intensive care medicine, Aged, Tissue Survival, Myocardial stunning, Ischemic cardiomyopathy, medicine.diagnostic_test, business.industry, Myocardium, Reproducibility of Results, American Heart Association, Prognosis, medicine.disease, Fibrosis, United States, Cardiac Imaging Techniques, Heart failure, Female, Cardiology and Cardiovascular Medicine, business
Abstract

A substantial proportion of patients with acute myocardial infarction develop clinical heart failure, which remains a common and major healthcare burden. It has been shown that in patients with chronic coronary artery disease, ischemic episodes lead to a global pattern of cardiomyocyte remodeling and dedifferentiation, hallmarked by myolysis, glycogen accumulation, and alteration of structural proteins. These changes, in conjunction with an impaired global coronary reserve, may eventually become irreversible and result in ischemic cardiomyopathy. Moreover, noninvasive imaging of myocardial scar and hibernation can inform the risk of sudden cardiac death. Therefore, it would be intuitive that imaging of myocardial viability is an essential tool for the proper use of invasive treatment strategies and patient prognostication. However, this notion has been challenged by large-scale clinical trials demonstrating that, in the modern era of improved guideline-directed medical therapies, imaging of myocardial viability failed to deliver effective guidance of coronary bypass surgery to a reduction of adverse cardiac outcomes. In addition, current available imaging technologies in this regard are numerous, and they target diverse surrogates of structural or tissue substrates of myocardial viability. In this document, we examine these issues in the current clinical context, collect current evidence of imaging technology by modality, and inform future directions.

Published
2020
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34. Deficiency of bone morphogenetic protein-3b induces metabolic syndrome and increases adipogenesis

Author

Alex Caplan, Emmanuel S. Buys, Ingrid Marti-Pamies, Patrick Seale, Alexia Vite, Jesus Tamez, Marielle Scherrer-Crosbie, Lauren Graves, Robrecht Thoonen, Wei Han, and Daniel Bloch

Subjects
Male, medicine.medical_specialty, Heart Diseases, Physiology, Endocrinology, Diabetes and Metabolism, Adipose tissue, Bone Morphogenetic Protein 3, White adipose tissue, Carbohydrate metabolism, Bone morphogenetic protein, Growth Differentiation Factor 10, Mice, Insulin resistance, Physiology (medical), Internal medicine, Glucose Intolerance, medicine, Adipocytes, Animals, Obesity, Dyslipidemias, Metabolic Syndrome, Mice, Knockout, Adipogenesis, Chemistry, Lipid metabolism, medicine.disease, Mice, Inbred C57BL, Endocrinology, Adipose Tissue, Female, Metabolic syndrome, Insulin Resistance, Research Article, Signal Transduction
Abstract

Bone morphogenetic protein (BMP) receptor signaling is critical for the regulation of the endocrine system and cardiovascular structure and function. The objective of this study was to investigate whether Bmp3b, a glycoprotein synthetized and secreted by adipose tissue, is necessary to regulate glucose and lipid metabolism, adipogenesis, and cardiovascular remodeling. Over the course of 4 mo, Bmp3b-knockout ( Bmp3b−/−) mice gained more weight than wild-type (WT) mice. The plasma levels of cholesterol and triglycerides were higher in Bmp3b−/− mice than in WT mice. Bmp3b−/− mice developed insulin resistance and glucose intolerance. The basal heart rate was higher in Bmp3b−/− mice than in WT mice, and echocardiography revealed eccentric remodeling in Bmp3b−/− mice. The expression of adipogenesis-related genes in white adipose tissue was higher in Bmp3b−/− mice than in WT control mice. In vitro studies showed that Bmp3b modulates the activity of the C/ebpα promoter, an effect mediated by Smad2/3. The results of this study suggest that Bmp3b is necessary for the maintenance of homeostasis in terms of age-related weight gain, glucose metabolism, and left ventricular (LV) remodeling and function. Interventions that increase the level or function of BMP3b may decrease cardiovascular risk and pathological cardiac remodeling.

Published
2020

35. Cardiovascular Care of the Oncology Patient During COVID-19: An Expert Consensus Document From the ACC Cardio-Oncology and Imaging Councils

Author

Roohi Ismail-Khan, Ana Barac, Vlad G. Zaha, Lauren A. Baldassarre, Monika Leja, Jordan B. Strom, Bonnie Ky, Richard Cheng, Marielle Scherrer-Crosbie, Eric H. Yang, Lawrence G. Rudski, Carrie Lenneman, Paaladinesh Thavendiranathan, Jeanne M. DeCara, Susan Dent, Hector R. Villarraga, Samer Ellahham, Chiara Bucciarelli-Ducci, Anita Deswal, Anne H. Blaes, and Jennifer E. Liu

Subjects
Diagnostic Imaging, medicine.medical_specialty, Cancer Research, Coronavirus disease 2019 (COVID-19), Population, MEDLINE, Cardiovascular care, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Pandemic, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, education, Expert Testimony, Cardiotoxicity, education.field_of_study, business.industry, SARS-CoV-2, Cancer, COVID-19, medicine.disease, Oncology, Cardiovascular Diseases, Etiology, Commentary, business, AcademicSubjects/MED00010
Abstract

In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients—individuals with an active or prior cancer history and with or at risk of cardiovascular disease—are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic.

Published
2020

36. Cardiovascular manifestations and treatment considerations in COVID-19

Author

Yuchi Han, Yucheng Chen, Marielle Scherrer-Crosbie, David Mui, Victor A. Ferrari, Yu Kang, Tiffany Chen, and Dinesh Jagasia

Subjects
medicine.medical_treatment, Angiotensin-Converting Enzyme Inhibitors, Review, Comorbidity, Disease, Azithromycin, 030204 cardiovascular system & hematology, Severe Acute Respiratory Syndrome, cardiac risk factors and prevention, systemic inflammatory diseases, 0302 clinical medicine, Case fatality rate, 030212 general & internal medicine, Lung, Cardiogenic shock, Chloroquine, Venous Thromboembolism, Troponin, Cardiovascular Diseases, Cardiology, Angiotensin-Converting Enzyme 2, Coronavirus Infections, Cytokine Release Syndrome, Cardiology and Cardiovascular Medicine, Immunosuppressive Agents, Hydroxychloroquine, medicine.medical_specialty, Acute coronary syndrome, Myocarditis, Pneumonia, Viral, Peptidyl-Dipeptidase A, Angiotensin Receptor Antagonists, Betacoronavirus, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, Internal medicine, Diabetes mellitus, Influenza, Human, medicine, Extracorporeal membrane oxygenation, Humans, Pandemics, SARS-CoV-2, business.industry, Myocardium, Anticoagulants, COVID-19, Disseminated Intravascular Coagulation, medicine.disease, Middle East respiratory syndrome, myocarditis, business, Biomarkers
Abstract

Since its recognition in December 2019, covid-19 has rapidly spread globally causing a pandemic. Pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease are associated with a greater severity and higher fatality rate of covid-19. Furthermore, COVID-19 contributes to cardiovascular complications, including acute myocardial injury as a result of acute coronary syndrome, myocarditis, stress-cardiomyopathy, arrhythmias, cardiogenic shock, and cardiac arrest. The cardiovascular interactions of COVID-19 have similarities to that of severe acute respiratory syndrome, Middle East respiratory syndrome and influenza. Specific cardiovascular considerations are also necessary in supportive treatment with anticoagulation, the continued use of renin-angiotensin-aldosterone system inhibitors, arrhythmia monitoring, immunosuppression or modulation, and mechanical circulatory support.

Published
2020
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37. Contemporary Role of Echocardiography for Clinical Decision Making in Patients During and After Cancer Therapy

Author

Jose Banchs, Jennifer E. Liu, Ana Barac, Paaladinesh Thavendiranathan, Juan Carlos Plana, Negareh Mousavi, and Marielle Scherrer-Crosbie

Subjects
medicine.medical_specialty, medicine.medical_treatment, Clinical Decision-Making, Population, Antineoplastic Agents, 030204 cardiovascular system & hematology, Risk Assessment, Asymptomatic, Ventricular Function, Left, Ventricular Dysfunction, Left, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Predictive Value of Tests, Risk Factors, Trastuzumab, Humans, Medicine, Radiology, Nuclear Medicine and imaging, In patient, Intensive care medicine, education, Cardiotoxicity, education.field_of_study, business.industry, Cancer, medicine.disease, Early Diagnosis, Echocardiography, 030220 oncology & carcinogenesis, Cardiac monitoring, medicine.symptom, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Early recognition of cancer therapy-related cardiac dysfunction (CTRCD) provides an opportunity to mitigate cardiac injury and risk of developing late cardiac events. Echocardiography serves as the cornerstone in the detection and surveillance of CTRCD in patients during and after cancer therapy. Guidelines from professional societies and regulatory agencies have been published on approaches to surveillance, diagnosis, and treatment of CTRCD, although adoption as standard of care remains limited given the lack of evidence on the prognostic value of asymptomatic left ventricular (LV) dysfunction in the oncology population. The frequency of cardiac monitoring and the appropriateness of the Food and Drug Administration (FDA)-recommended cardiac monitoring schedule in all patients receiving trastuzumab for breast cancer has been challenged. Interruption versus continuation of oncological therapy in the setting of asymptomatic LV dysfunction remains a clinical conundrum given the uncertain balance of the risk of cardiac dysfunction and benefit of oncology efficacy. Despite their limitations, echocardiographic measures of LV function continue to play a pivotal role in clinical decision making, with global longitudinal strain emerging as a promising tool in informing and facilitating the selection of cancer treatment and optimizing cardiovascular outcomes. This review highlights the key recommendations of the existing guidelines and discusses recent developments in cardio-oncology imaging practices with the aim of providing practical guidance on the role and use of echocardiography in challenging clinical cases in cardio-oncology.

Published
2018
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38. Collaboration during Crisis: A Novel Point-of-Care Ultrasound Alliance among Emergency Medicine, Internal Medicine, and Cardiology in the COVID-19 Era

Author

Cameron Baston, Dinesh Jagasia, Mili Mehta, Marielle Scherrer-Crosbie, Victor A. Ferrari, Srinath Adusumalli, and Nova Panebianco

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Interprofessional Relations, Point-of-Care Systems, Point of care ultrasound, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Cardiology, MEDLINE, COVID-19, medicine.disease, Alliance, Radiology Nuclear Medicine and imaging, Emergency Medicine, Internal Medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Medical emergency, Letters to the Editor, Cardiology and Cardiovascular Medicine, business, Pandemics, Ultrasonography
Published
2021
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39. Guidelines for measuring cardiac physiology in mice

Author

Lisandra E. de Castro Brás, Merry L. Lindsey, Jitka A. I. Virag, Zamaneh Kassiri, and Marielle Scherrer-Crosbie

Subjects
0301 basic medicine, Quality Control, medicine.medical_specialty, Biomedical Research, Consensus, Heart disease, Heart Diseases, Physiology, Cardiology, Hemodynamics, Translational research, Disease, Review, 030204 cardiovascular system & hematology, Ventricular Function, Left, 03 medical and health sciences, Mice, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Animals, Cause of death, Observer Variation, medicine.diagnostic_test, cardiac physiology, business.industry, Reproducibility of Results, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Cardiovascular physiology, Data Accuracy, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Ventricle, Echocardiography, rigor and reproducibility, Periodicals as Topic, Cardiology and Cardiovascular Medicine, business
Abstract

Cardiovascular disease is a leading cause of death, and translational research is needed to understand better mechanisms whereby the left ventricle responds to injury. Mouse models of heart disease have provided valuable insights into mechanisms that occur during cardiac aging and in response to a variety of pathologies. The assessment of cardiovascular physiological responses to injury or insult is an important and necessary component of this research. With increasing consideration for rigor and reproducibility, the goal of this guidelines review is to provide best-practice information regarding how to measure accurately cardiac physiology in animal models. In this article, we define guidelines for the measurement of cardiac physiology in mice, as the most commonly used animal model in cardiovascular research.Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/guidelines-for-measuring-cardiac-physiology-in-mice/ .

Published
2018

40. Abstract 561: Bone Morphogenetic Protein-3b Deficiency Induces Metabolic Syndrome and Modulates Adipogenesis

Author

Daniel Bloch, Wei Han, Ingrid Marti-Pamies, Patrick Seale, Marielle Scherrer-Crosbie, Robrecht Thoonen, Emmanuel S. Buys, and Alex Caplan

Subjects
Cell metabolism, Physiology, Adipogenesis, Chemistry, Cardiac hypertrophy, medicine, Cellular functions, Metabolic syndrome, Cardiology and Cardiovascular Medicine, medicine.disease, Diabetes type ii, Bone morphogenetic protein, Cell biology
Abstract

Introduction: Bone morphogenetic proteins (BMPs) are mediators in a wide range of cellular functions, including the regulation of cell metabolism. The objective of this study was to investigate the effects of BMP-3b, a glycoprotein synthetized and secreted by adipose tissue, on cardiovascular risk factors. Methods: BMP-3b knock-out (KO) and age-matched male and female wild-type (WT) mice were weighed weekly until 6 months of age. At 6 months, fasting levels of total cholesterol, HDL-C and triglycerides were measured and glucose and insulin tolerance tests were performed. Telemetry was used to determine blood pressure and heart rate in anesthetized mice. Echocardiograms were performed under light sedation (isoflurane 1%). Mice were sacrificed and tissues were resected for gene expression analysis by qPCR. Transient transfections were performed in 3T3-L1 cells to study the interactions of BMP-3b and the C/ebp α promoter. Results: BMP3b KO mice gained more weight than WT mice. The plasma levels of total cholesterol, HDL and triglycerides were higher in BMP-3b KO mice than in WT mice. Insulin and glucose tolerant tests reveal insulin resistance and glucose intolerance in BMP-3b KO mice compared to WT mice. The basal heart rate was higher in BMP-3b KO mice than in WT mice, but no differences were observed in blood pressure. Echocardiography revealed a decrease in relative wall thickness (RWT) and left ventricular ejection fraction (LVEF), and an increase in the left ventricle end diastolic volume (LVEDV) in BMP-3b KO mice, demonstrating eccentric remodeling. Expression of genes ( Pparγ and C/ebpα ) involved in adipogenesis in white adipose tissue was higher in BMP-3b KO mice than in WT controls. Finally, transient transfection assays with 3T3-L1 cells showed that BMP-3b modulates C/ebpα promoter activity. Conclusions: The results of this study suggest that BMP-3b has an important role in the regulation of age-related weight gain, glucose metabolism and LV remodeling. Interventions that increase the level or function of BMP-3b may protect the heart from the adverse effects of cardiovascular risk factors and pathological cardiac remodeling.

Published
2019
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41. Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives

Author

Sarju, Ganatra, Joseph R, Carver, Salim S, Hayek, Bonnie, Ky, Monika J, Leja, Daniel J, Lenihan, Carrie, Lenneman, Negaresh, Mousavi, Jae H, Park, Miguel Angel, Perales, Thomas D, Ryan, Marielle, Scherrer-Crosbie, Richard M, Steingart, Eric H, Yang, Vlad, Zaha, Ana, Barac, and Jennifer E, Liu

Subjects
Clinical Trials as Topic, Receptors, Chimeric Antigen, Cardiovascular Diseases, Neoplasms, Humans, Female, Middle Aged, Cytokine Release Syndrome, Immunotherapy, Adoptive, Article
Abstract

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction (LVEF), pulmonary edema and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include wider patient population, careful patient selection, pre-treatment cardiac evaluation and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

Published
2019

42. Brown adipose tissue: The heat is on the heart

Author

Allyson G. Hindle, Marielle Scherrer-Crosbie, and Robrecht Thoonen

Subjects
0301 basic medicine, medicine.medical_specialty, animal structures, Physiology, Cardiovascular health, Reviews, Biology, 03 medical and health sciences, Adipose Tissue, Brown, Risk Factors, Glucose Metabolism Disorder, Physiology (medical), Internal medicine, Diabetes mellitus, Paracrine Communication, Brown adipose tissue, medicine, Animals, Humans, Endocrine system, Obesity, Dyslipidemias, Glucose Metabolism Disorders, Myocardium, Thermogenesis, Lipid metabolism, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Cardiovascular Diseases, Blood Vessels, Cardiology and Cardiovascular Medicine, Signal Transduction
Abstract

The study of brown adipose tissue (BAT) has gained significant scientific interest since the discovery of functional BAT in adult humans. The thermogenic properties of BAT are well recognized; however, data generated in the last decade in both rodents and humans reveal therapeutic potential for BAT against metabolic disorders and obesity. Here we review the current literature in light of a potential role for BAT in beneficially mediating cardiovascular health. We focus mainly on BAT's actions in obesity, vascular tone, and glucose and lipid metabolism. Furthermore, we discuss the recently discovered endocrine factors that have a potential beneficial role in cardiovascular health. These BAT-secreted factors may have a favorable effect against cardiovascular risk either through their metabolic role or by directly affecting the heart.

Published
2016
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43. Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance

Author

Marcello Panagia, David E. Sosnovik, Yin-Ching Iris Chen, Laura Ernande, Kenneth K. Kwong, Chan Chen, Wei Chao, Marielle Scherrer-Crosbie, and Howard H. Chen

Subjects
medicine.medical_specialty, animal structures, Adipose tissue, Blood flow, 030204 cardiovascular system & hematology, Biology, medicine.disease, Thermogenin, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, Insulin resistance, Heart failure, Internal medicine, Lipid droplet, Brown adipose tissue, medicine, Molecular Medicine, Radiology, Nuclear Medicine and imaging, Adrenergic agonist, Spectroscopy
Abstract

Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the β3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 ± 1 mm(3) versus 65 ± 3 mm(3) ; p

Published
2016
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44. Left Ventricular Global Longitudinal Strain in HER-2 + Breast Cancer Patients Treated with Anthracyclines and Trastuzumab Who Develop Cardiotoxicity Is Associated with Subsequent Recovery of Left Ventricular Ejection Fraction

Author

Alphonse G. Taghian, Hong-wen Fei M.D., Elkan F. Halpern, Marielle Scherrer-Crosbie, Lanqi Hua, Laura Salama, Timothy C. Tan, Kai-Hung Cheng, Shannon M. MacDonald, Xin Zeng, and Mohammed T. Ali

Subjects
medicine.medical_specialty, Longitudinal strain, Receptor, ErbB-2, medicine.medical_treatment, Antineoplastic Agents, Breast Neoplasms, 030204 cardiovascular system & hematology, Cardiotoxins, Ventricular Dysfunction, Left, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Trastuzumab, Elastic Modulus, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Anthracyclines, Radiology, Nuclear Medicine and imaging, Ct diagnosis, In patient, Longitudinal Studies, cardiovascular diseases, Cardiotoxicity, Chemotherapy, Ejection fraction, business.industry, Stroke Volume, Recovery of Function, Middle Aged, medicine.disease, Treatment Outcome, Echocardiography, 030220 oncology & carcinogenesis, cardiovascular system, Cardiology, Elasticity Imaging Techniques, Female, Radiology, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Aim The combination of anthracyclines (AC) and trastuzumab (TRZ) is highly effective in patients with aggressive HER-2 + breast cancer, but has a significant risk of cardiotoxicity (CT). Trastuzumab-induced CT may be reversible. The aim of this study was to identify echocardiographic parameters associated with recovery of left ventricular ejection fraction (LVEF) in patients who developed CT after AC and TRZ treatment. Methods and Results Women with newly diagnosed breast cancer treated with AC followed by TRZ and monitored with serial echocardiograms were retrospectively studied. Left ventricular end-diastolic and systolic volumes, LVEF, and global longitudinal strain (GLS) were examined. Development and reversibility of CT were defined based on changes in LVEF according to the 2014 ASE/EACVI recommendations. Cox analysis was used to determine the association of echocardiographic variables with the subsequent development and reversibility of CT. Ninety-five patients underwent 5 echocardiograms or more in a 17-month (13–28 months) follow-up period. Nineteen patients (20%) developed CT. Left ventricular volumes, LVEF, and GLS measured after AC completion identified the subsequent development of CT. Of the 19 patients with CT, the LVEF partially or fully recovered in 13 (68%). GLS at the time of CT diagnosis was associated with subsequent recovery of LVEF (P = 0.004). Conclusion In patients with breast cancer treated with AC and TRZ who develop CT, GLS at the time of CT diagnosis is associated with subsequent recovery of LVEF and may be useful for risk stratification and to guide treatment.

Published
2016
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45. Preparing the Cardiovascular Workforce to Care for Oncology Patients: JACC Review Topic of the Week

Author

Salim S, Hayek, Sarju, Ganatra, Carrie, Lenneman, Marielle, Scherrer-Crosbie, Monika, Leja, Daniel J, Lenihan, Eric, Yang, Thomas D, Ryan, Jennifer, Liu, Joseph, Carver, Negareh, Mousavi, Rupal, O'Quinn, Anita, Arnold, Jose, Banchs, Ana, Barac, and Bonnie, Ky

Subjects
Male, Interprofessional Relations, Cardiology, Comorbidity, Medical Oncology, United States, Article, Cardiovascular Diseases, Neoplasms, Outcome Assessment, Health Care, Workforce, Humans, Female, Program Development, Program Evaluation
Abstract

Cardiovascular disease and cancer are the two main causes of death in the United States. They intersect on multiple levels, sharing common causal mechanisms and epidemiologic risk factors. The growing prevalence and complexity of cardiovascular disease and cancer have resulted in the development of the discipline of cardio-oncology. Preparing the cardiovascular workforce for the care of a growing population of cancer patients is necessary to enhance the delivery of high-quality cardiovascular care for patients with cancer. The goal of this Council Perspective is to present the dedicated efforts of the cardio-oncology community to meet the growing need for education and training of cardiovascular practitioners providing care to cancer patients and survivors. Integration in general cardiology training programs and the efforts of the stakeholder organizations serve as an example of how a multi-dimensional, innovative approach can address provider education and training needs in a relatively new discipline.

Published
2019

46. Abstract 17207: Cardiovascular Risks in Acute Leukemia Patients Treated With Anthracyclines

Author

Yu Kang, Srinivas Denduluri, Bruna M Assuncao, and Marielle Scherrer-Crosbie

Subjects
Physiology (medical), cardiovascular diseases, Cardiology and Cardiovascular Medicine
Abstract

Introduction: The incidence of acute leukemia has been increasing by about 1.6% per year in the last decade. Anthracyclines remain a standard of care for patients with acute leukemia; survival is increasing at about 1.0% per year. However, little is known about the incidence and risk of major adverse cardiovascular events (MACE) in patients with acute leukemia. Hypothesis: To investigate the incidence of MACE and the risk factors for MACE in patients with acute leukemia treated with anthracyclines. Methods: All adult patients with acute leukemia treated with anthracyclines between January 2005 and April 2018 at the hospital of University of Pennsylvania were studied. MACE were defined as cardiovascular death, symptomatic heart failure, non-fatal acute coronary syndrome, non-fatal ventricular arrhythmia and non-fatal ischemic stroke. Differences between patients with or without MACE were compared by Student’s t test or the Wilcoxon rank comparison. Cox proportional hazard analysis was used to determine significant clinical and echocardiographic parameters associated with MACE. Results: Six hundred and seventy-four patients (234 acute lymphoblastic leukemia (ALL), 440 acute myeloid leukemia (AML), age range: 22 to 93 years) were studied. Seventy-one patients (10.5%) experienced MACEs during a median follow-up period of 16 months (4 to 146 months) after the initiation of chemotherapy. The median time to MACE was 13 months (5 to 107 months). In the patients with MACE,59 (8.8%) developed symptomatic heart failure, 7 (1.0%) died of cardiovascular causes, 3 (0.4%) experienced non-fatal acute myocardial syndrome and 2 (0.3%) had an ischemic stroke. The Table summarizes the characteristics of patients with and without MACE. In a multivariable analysis, a previous history of heart failure (HR: 4.632, P=0.000, 95% CI: 2.572-8.341), leukemia type (HR: 3.155, P=0.002, 95% CI: 1.544-6.446) and baseline LVEF (HR: 0.973, P=0.000, 95% CI: 0.955-0.991) remained associated with MACE. Conclusion: Patients with acute leukemia treated with anthracyclines have a high rate of MACE after chemotherapy. A previous history of heart failure, baseline LVEF and type of leukemia may help to stratify acute leukemia patients at highest risk for MACEs after anthracycline therapy.

Published
2018
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48. Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH

Author

Elizabeth T. Petit, Marie B. Demay, Emmanuel S. Buys, Binglan Yu, Eva S. Liu, Marielle Scherrer-Crosbie, and Robrecht Thoonen

Subjects
0301 basic medicine, Fibroblast growth factor 23, Male, medicine.medical_specialty, Cardiomegaly, Left ventricular hypertrophy, urologic and male genital diseases, Muscle hypertrophy, 03 medical and health sciences, Mice, Endocrinology, Internal medicine, medicine, Myocyte, Animals, Research Articles, business.industry, NFAT, medicine.disease, Calcineurin, Fibroblast Growth Factors, stomatognathic diseases, Fibroblast Growth Factor-23, 030104 developmental biology, business, Hypophosphatemia, Kidney disease
Abstract

Serum levels of fibroblast growth factor 23 (FGF23) markedly increase with renal impairment, with FGF23 levels correlating with the presence of left ventricular hypertrophy (LVH) and mortality in patients with chronic kidney disease (CKD). FGF23 activates calcineurin/nuclear factor of activated T cell (NFAT) signaling and induces hypertrophy in murine cardiomyocytes. X-linked hypophosphatemia (XLH) is characterized by high circulating levels of FGF23 but, in contrast to CKD, is associated with hypophosphatemia. The cardiac effects of high circulating levels of FGF23 in XLH are not well defined. Thus, studies were undertaken to define the cardiac phenotype in the mouse model of XLH (Hyp mice). Echocardiographic and histological analyses demonstrated that Hyp left ventricles (LVs) are smaller than those of wild-type mice. Messenger RNA expression of cardiac hypertrophy markers was not altered in the LV or right ventricle of Hyp mice. However, the Hyp LVs had increased expression of the NFAT target genes NFATc1 and RCAN1. To determine whether phosphate alone can induce markers of hypertrophy, differentiated C2C12 myocytes were treated with phosphate. Phosphate treatment increased expression of cardiac hypertrophy markers, supporting a primary role for phosphate in inducing LVH. Although previous studies showed that increased circulating FGF23 and phosphate levels are associated with LVH, our results demonstrated that in XLH, high circulating levels of FGF23 in the setting of hypophosphatemia do not induce cardiac hypertrophy.

Published
2018

49. Supraclavicular Brown Adipose Tissue 18F-FDG Uptake and Cardiovascular Disease

Author

Meghan H. MacNabb, Marielle Scherrer-Crosbie, Richard A.P. Takx, Amorina Ishai, Ahmed Tawakol, and Quynh A. Truong

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, Adipose tissue, Coronary Artery Disease, Disease, 030204 cardiovascular system & hematology, Risk Assessment, Sensitivity and Specificity, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Adipose Tissue, Brown, Fluorodeoxyglucose F18, Risk Factors, Positron Emission Tomography Computed Tomography, Internal medicine, Hounsfield scale, Brown adipose tissue, Prevalence, medicine, Humans, Tissue Distribution, Radiology, Nuclear Medicine and imaging, Coronary atherosclerosis, Aged, medicine.diagnostic_test, business.industry, Reproducibility of Results, Cancer, Middle Aged, medicine.disease, Clavicle, 030104 developmental biology, medicine.anatomical_structure, Positron emission tomography, Cardiology, Radiopharmaceuticals, business, Body mass index, Boston
Abstract

Preclinical data suggest a negative correlation between brown adipose tissue (BAT) and the degree of coronary atherosclerosis. We sought to evaluate the relationship between (18)F-FDG uptake in supraclavicular BAT in relation to arterial inflammation and subsequent cardiovascular disease (CVD) events in humans.Individuals who underwent (18)F-FDG PET/CT for clinical indications but who did not have either cancer or known atherosclerotic disease at the time of imaging were included. A radiologist masked to clinical data measured (18)F-FDG uptake within BAT (in the supraclavicular region) as well as in subcutaneous adipose tissues. Tissue density was evaluated using CT (Hounsfield units). Arterial inflammation was assessed by measuring arterial (18)F-FDG uptake and calculating target-to-background ratio. CVD events were independently adjudicated by masked cardiologists. Thereafter, the relationship between BAT activity and CVD events was evaluated.A total of 443 patients (age, 55 y [44-66 y]; 44% men; body mass index [BMI], 26 [range, 23-31]) were included, and 30 patients experienced a cardiovascular event during a median follow-up of 4 y. BAT activity negatively correlated with arterial inflammation (r = -0.178, P0.01), a relationship that persisted after correcting for age and BMI (r = -0.147, P0.01). When either high sensitivity or high accuracy thresholds (from receiver-operating curve analyses) were used to define elevated BAT, high BAT was associated with a reduced risk of CVD events (P = 0.048), even after correcting for age (P = 0.037).Our results suggest that increased supraclavicular BAT activity is inversely associated with arterial inflammation, independently of age and BMI. Additionally, increased BAT may be associated with fewer cardiovascular events.

Published
2016
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50. Palmitoyl acyltransferase Aph2 in cardiac function and the development of cardiomyopathy

Author

Baojie Li, Peiquan Zhao, Yong Cang, Yi-Han Chen, Hao Jia, Huijuan Liu, Tielin Zhou, Helene Thibault, Jing Li, Lin He, Stephen P. Goff, Deyong Jia, Sharon Boast, Marielle Scherrer-Crosbie, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
medicine.medical_specialty, Lipoylation, [SDV]Life Sciences [q-bio], Cardiomyopathy, Biology, Eye, Mice, 03 medical and health sciences, 0302 clinical medicine, Palmitoylation, Internal medicine, Calcium-binding protein, Chlorocebus aethiops, medicine, Animals, Protein palmitoylation, Phosphorylation, Palmitoyl acyltransferase, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Calcium-Binding Proteins, Protein phosphatase 1, Biological Sciences, medicine.disease, 3. Good health, Phospholamban, Endocrinology, Echocardiography, COS Cells, cardiovascular system, lipids (amino acids, peptides, and proteins), Cardiomyopathies, Carrier Proteins, Acyltransferases, 030217 neurology & neurosurgery
Abstract

International audience; Protein palmitoylation regulates many aspects of cell function and is carried out by acyl transferases that contain zf-DHHC motifs. The in vivo physiological function of protein palmitoylation is largely unknown. Here we generated mice deficient in the acyl transferase Aph2 (Ablphilin 2 or zf-DHHC16) and demonstrated an essential role for Aph2 in embryonic/postnatal survival, eye development, and heart development. Aph2(-/-) embryos and pups showed cardiomyopathy and cardiac defects including bradycardia. We identified phospholamban, a protein often associated with human cardiomyopathy, as an interacting partner and a substrate of Aph2. Aph2-mediated palmitoylation of phospholamban on cysteine 36 differentially alters its interaction with PKA and protein phosphatase 1 alpha, augmenting serine 16 phosphorylation, and regulates phospholamban pentamer formation. Aph2 deficiency results in phospholamban hypophosphorylation, a hyperinhibitory form. Ablation of phospholamban in Aph2(-/-) mice histologically and functionally alleviated the heart defects. These findings establish Aph2 as a critical in vivo regulator of cardiac function and reveal roles for protein palmitoylation in the development of other organs including eyes.

Published
2015
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