title: Noninvasive Measures of Ventricular-Arterial Coupling and Circumferential Strain Predict Cancer Therapeutics-Related Cardiac Dysfunction.
abstract: This study sought to determine the relationships between echocardiography-derived measures of myocardial mechanics and cancer therapeutics-related cardiac dysfunction (CTRCD).
  
  
  
  Doxorubicin and trastuzumab are highly effective breast cancer therapies, but have a substantial risk of CTRCD. There is a critical need for the early detection of patients at increased risk of toxicity.
  
  
  
  We performed a prospective, longitudinal cohort study of breast cancer participants undergoing doxorubicin and/or trastuzumab therapy. Echocardiography was performed prior to therapy initiation (baseline) and at standardized follow-up intervals during and after completion of therapy. Ejection fraction (EF), strain, strain rate, and ventricular-arterial coupling (effective arterial elastance [Ea]/end-systolic elastance [Eessb]) were quantitated. CTRCD was defined as a ≥10% reduction in EF from baseline to <50%. Multivariable logistic regression models were used to determine the associations between baseline levels and changes from baseline in echocardiographic measures and CTRCD. Receiver-operating characteristic curves were used to evaluate the predictive ability of these measures.
  
  
  
  In total, 135 participants contributed 517 echocardiograms to the analysis. Over a median follow-up time of 1.9 years (interquartile range: 0.9 to 2.4 years), 21 participants (15%) developed CTRCD. In adjusted models, baseline levels and changes in Ea/Eessb, circumferential strain, and circumferential strain rate were associated with 21% to 38% increased odds of CTRCD (p < 0.001). Changes in longitudinal strain (p = 0.037), radial strain (p = 0.015), and radial strain rate (p = 0.006) were also associated with CTRCD. Ea/Eessb(area under the curve: 0.703; 95% confidence interval: 0.583 to 0.807) and circumferential strain (area under the curve: 0.655; 95% confidence interval: 0.517 to 0.767) demonstrated the greatest predictive utility. Sensitivity analyses using an alternative CTRCD definition did not impact our results.
  
  
  
  Over an extended follow-up time, ventricular-arterial coupling and circumferential strain were strongly predictive of CTRCD. Our findings suggest a noninvasive strategy to identify high-risk patients prior to, during, and after cardiotoxic cancer therapy.
authors.affiliation: Department of Pediatrics, Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Narayan
authors.affiliation: Department of Biostatistics and Epidemiology, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Benjamin
authors.initials: B
authors.lastname: French
authors.affiliation: Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Khan
authors.affiliation: Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Theodore
authors.initials: T
authors.lastname: Plappert
authors.affiliation: Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Hyman
authors.affiliation: Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Akinyemi
authors.initials: A
authors.lastname: Bajulaiye
authors.affiliation: Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan
authors.initials: S
authors.lastname: Domchek
authors.affiliation: Department of Biostatistics and Epidemiology, The University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.affiliation: Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Amy
authors.initials: A
authors.lastname: Clark
authors.affiliation: Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Matro
authors.affiliation: Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Angela
authors.initials: A
authors.lastname: Bradbury
authors.affiliation: Department of Medicine, Division of Oncology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fox
authors.affiliation: Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Carver
authors.affiliation: Department of Biostatistics and Epidemiology, The University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Cardiology, The University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, The University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bonnie.ky@uphs.upenn.edu.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D001696:Biomechanical Phenomena; D001943:Breast Neoplasms / Q000188:drug therapy*; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000009:adverse effects*; D004452:Echocardiography; D004548:Elasticity; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000503:physiopathology; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008137:Longitudinal Studies; D008875:Middle Aged; D015999:Multivariate Analysis; D009200:Myocardial Contraction; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D013314:Stress, Mechanical; D013318:Stroke Volume; D013997:Time Factors; D000068878:Trastuzumab / Q000009:adverse effects*; D016276:Ventricular Function
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab
keywords: cardio-oncology; cardiotoxicity; echocardiography; mechanics