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Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma.
Cornell RF, Ky B, Weiss BM, Dahm CN, Gupta DK, Du L, Carver JR, Cohen AD, Engelhardt BG, Garfall AL, Goodman SA, Harrell SL, Kassim AA, Jadhav T, Jagasia M, Moslehi J, O'Quinn R, Savona MR, Slosky D, Smith A, Stadtmauer EA, Vogl DT, Waxman A, Lenihan D
(2019) J Clin Oncol 37: 1946-1955
MeSH Terms: Adult, Aged, Aged, 80 and over, Bortezomib, Cardiovascular Diseases, Disease-Free Survival, Electrocardiography, Female, Heart Diseases, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Multiple Myeloma, Natriuretic Peptide, Brain, Neoplasm Recurrence, Local, Oligopeptides, Prospective Studies, Proteasome Inhibitors, Risk Factors, Time-to-Treatment, Treatment Outcome, Troponin I, Troponin T
Show Abstract · Added November 12, 2019
PURPOSE - Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.
PATIENTS AND METHODS - Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
RESULTS - Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CONCLUSION - CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
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1 Members
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25 MeSH Terms
Cancer therapy-induced cardiovascular toxicity: old/new problems and old drugs.
Beyer AM, Bonini MG, Moslehi J
(2019) Am J Physiol Heart Circ Physiol 317: H164-H167
MeSH Terms: Animals, Anthracyclines, Antibiotics, Antineoplastic, Cardiotoxicity, Cardiovascular System, Heart Diseases, Humans, Protective Agents
Show Abstract · Added November 12, 2019
Cardio-oncology has emerged as an exciting new field at the intersection of cardiology and oncology. While improved oncology treatment efficacy has increased survival rates in cancer patients, the long-term cardiovascular consequences of this life-saving treatment have become more clinically relevant. Both traditional and newer (targeted) cancer therapies can have cardiovascular and metabolic sequelae, resulting in heart failure, coronary artery disease, myocarditis, pericardial disease, hypertension, and vascular and metabolic perturbations (Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. 375: 1457-1467, 2016). Both acute and chronic cardiovascular toxicities have proven challenging for clinicians and patients, significantly contributing to morbidity and mortality. Although chronic cardiovascular disease affects a growing number of cancer survivors (~17 million in the United States in 2019), cardiovascular toxicities associated with cancer and cancer therapies are poorly understood mechanistically. To balance potential damage to the cardiovascular system with effective and efficient cancer treatment, novel strategies are sorely needed. This perspective focuses on an assembly of articles that discuss novel means of counteracting adverse cardiovascular events in response to anticancer therapy. In light of new clinical syndromes in cardiology due to cancer therapies, we hope to highlight promising research opportunities offered by cardio-oncology (Bellinger AM, Arteaga CL, Force T, Humphreys BD, Demetri GD, Druker BJ, Moslehi JJ. Cardio-oncology: how new targeted cancer therapies and precision medicine can inform cardiovascular discovery. 132: 2248-2258, 2015.).
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1 Members
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8 MeSH Terms
Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association.
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
(2019) Circulation 139: e56-e528
MeSH Terms: American Heart Association, Cholesterol, Heart Diseases, Humans, Hypertension, Metabolic Diseases, Nutritional Status, Obesity, Quality of Health Care, Risk Factors, Smoking, Stroke, United States, Venous Thromboembolism
Added April 2, 2019
0 Communities
2 Members
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14 MeSH Terms
Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
(2018) Elife 7:
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Beclin-1, Cell Respiration, Fibrosis, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Heart Diseases, Heart Ventricles, Humans, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proton-Translocating ATPases, Mutation, Myeloid Progenitor Cells, Myocardial Infarction, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Reactive Oxygen Species, Reproducibility of Results, Up-Regulation
Show Abstract · Added December 11, 2018
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
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4 Members
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26 MeSH Terms
Immune checkpoint inhibitors and cardiovascular toxicity.
Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J
(2018) Lancet Oncol 19: e447-e458
MeSH Terms: Antineoplastic Agents, Immunological, Cardiotoxicity, Heart, Heart Diseases, Humans, Neoplasms, Risk Assessment, Risk Factors, Treatment Outcome
Show Abstract · Added October 1, 2018
Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults.
Kresge HA, Khan OA, Wagener MA, Liu D, Terry JG, Nair S, Cambronero FE, Gifford KA, Osborn KE, Hohman TJ, Pechman KR, Bell SP, Wang TJ, Carr JJ, Jefferson AL
(2018) J Am Heart Assoc 7:
MeSH Terms: Age Factors, Aged, Aged, 80 and over, Asymptomatic Diseases, Biomechanical Phenomena, Cognition, Cognition Disorders, Cross-Sectional Studies, Female, Heart Diseases, Humans, Language, Magnetic Resonance Imaging, Cine, Male, Memory, Episodic, Middle Aged, Myocardial Contraction, Neuropsychological Tests, Risk Assessment, Risk Factors, Stress, Mechanical, Stroke Volume, Ventricular Function, Left
Show Abstract · Added March 16, 2018
BACKGROUND - Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults.
METHODS AND RESULTS - Vanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73±7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and *ε4 status. Models were repeated with a cardiac×cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (β=-0.07, =0.04), visuospatial immediate recall (β=-0.83, =0.03), visuospatial delayed recall (β=-0.22, =0.03), and verbal delayed recall (β=-0.11, =0.007). LVEF did not relate to worse performance on any measure (>0.18). No diagnostic interactions were observed.
CONCLUSIONS - Our study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function.
© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
0 Communities
5 Members
0 Resources
23 MeSH Terms
Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association.
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
(2018) Circulation 137: e67-e492
MeSH Terms: American Heart Association, Comorbidity, Data Interpretation, Statistical, Health Status, Heart Diseases, Humans, Life Style, Prognosis, Risk Assessment, Risk Factors, Stroke, United States
Added April 2, 2019
0 Communities
2 Members
0 Resources
12 MeSH Terms
Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.
Fradley MG, Groarke JD, Laubach J, Alsina M, Lenihan DJ, Cornell RF, Maglio M, Shain KH, Richardson PG, Moslehi J
(2018) Br J Haematol 180: 271-275
MeSH Terms: Adult, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Cardiotoxicity, Electrocardiography, Female, Heart Diseases, Humans, Magnetic Resonance Imaging, Multiple Myeloma, Proteasome Inhibitors
Show Abstract · Added December 2, 2017
Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.
© 2017 John Wiley & Sons Ltd.
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1 Members
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11 MeSH Terms
Thermodilution vs Estimated Fick Cardiac Output Measurement in Clinical Practice: An Analysis of Mortality From the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) Program and Vanderbilt University.
Opotowsky AR, Hess E, Maron BA, Brittain EL, Barón AE, Maddox TM, Alshawabkeh LI, Wertheim BM, Xu M, Assad TR, Rich JD, Choudhary G, Tedford RJ
(2017) JAMA Cardiol 2: 1090-1099
MeSH Terms: Aged, Cardiac Catheterization, Cardiac Output, Diabetes Mellitus, Female, Follow-Up Studies, Heart Diseases, Humans, Hypertension, Kaplan-Meier Estimate, Male, Pulmonary Disease, Chronic Obstructive, Renal Insufficiency, Chronic, Retrospective Studies, Tennessee, Thermodilution, Treatment Outcome
Show Abstract · Added June 7, 2018
Importance - Thermodilution (Td) and estimated oxygen uptake Fick (eFick) methods are widely used to measure cardiac output (CO). They are often used interchangeably to make critical clinical decisions, yet few studies have compared these approaches as applied in medical practice.
Objectives - To assess agreement between Td and eFick CO and to compare how well these methods predict mortality.
Design, Setting, and Participants - This investigation was a retrospective cohort study with up to 1 year of follow-up. The study used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) program. The findings were corroborated in a cohort of patients cared for at Vanderbilt University, an academic referral center. Participants were more than 15 000 adults who underwent right heart catheterization, including 12 232 in the Veterans Affairs cohort between October 1, 2007, and September 30, 2013, and 3391 in the Vanderbilt cohort between January 1, 1998, and December 31, 2014.
Exposures - A single cardiac catheterization was performed on each patient with CO estimated by both Td and eFick methods. Cardiac output was indexed to body surface area (cardiac index [CI]) for all analyses.
Main Outcomes and Measures - All-cause mortality over 90 days and 1 year after catheterization.
Results - Among 12 232 VA patients (mean [SD] age, 66.4 [9.9] years; 3.3% female) who underwent right heart catheterization in this cohort study, Td and eFick CI estimates correlated modestly (r = 0.65). There was minimal mean difference (eFick minus Td = -0.02 L/min/m2, or -0.4%) but wide 95% limits of agreement between methods (-1.3 to 1.3 L/min/m2, or -50.1% to 49.4%). Estimates differed by greater than 20% for 38.1% of patients. Low Td CI (<2.2 L/min/m2 compared with normal CI of 2.2-4.0 L/min/m2) more strongly predicted mortality than low eFick CI at 90 days (Td hazard ratio [HR], 1.71; 95% CI, 1.47-1.99; χ2 = 49.5 vs eFick HR, 1.42; 95% CI, 1.22-1.64; χ2 = 20.7) and 1 year (Td HR, 1.53; 95% CI, 1.39-1.69; χ2 = 71.5 vs eFick HR, 1.35; 1.22-1.49; χ2 = 35.2). Patients with a normal CI by both methods had 12.3% 1-year mortality. There was no significant additional risk for patients with a normal Td CI but a low eFick CI (12.9%, P = .51), whereas a low Td CI but normal eFick CI was associated with higher mortality (15.4%, P = .001). The results from the Vanderbilt cohort were similar in the context of a more balanced sex distribution (46.6% female).
Conclusions and Relevance - There is only modest agreement between Td and eFick CI estimates. Thermodilution CI better predicts mortality and should be favored over eFick in clinical practice.
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1 Members
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17 MeSH Terms
Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline.
Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, Dent S, Douglas PS, Durand JB, Ewer M, Fabian C, Hudson M, Jessup M, Jones LW, Ky B, Mayer EL, Moslehi J, Oeffinger K, Ray K, Ruddy K, Lenihan D
(2017) J Clin Oncol 35: 893-911
MeSH Terms: Adult, Heart, Heart Diseases, Humans, Neoplasms, Survivors
Show Abstract · Added March 26, 2017
Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.
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6 MeSH Terms