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Item Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer(American Medical Association, 2016-01) Dang, Chau; Guo, Hao; Najita, Julie; Yardley, Denise; Marcom, Kelly; Albain, Kathy; Rugo, Hope; Miller, Kathy; Ellis, Matthew; Shapira, Iuliana; Wolff, Antonio C.; Carey, Lisa A.; Moy, Beverly; Groarke, John; Moslehi, Javid; Krop, Ian; Burstein, Harold J.; Hudis, Clifford; Winer, Eric P.; Tolaney, Sara M.; Department of Medicine, IU School of MedicineIMPORTANCE: Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. OBJECTIVE: To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. INTERVENTIONS: Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. MAIN OUTCOMES AND MEASURES: Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. RESULTS: Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. CONCLUSIONS AND RELEVANCE: Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.Item Small conductance calcium-activated potassium current is important in transmural repolarization of failing human ventricles(Ovid Technologies Wolters Kluwer - American Heart Association, 2015-06) Yu, Chih-Chieh; Corr, Christopher; Shen, Changyu; Shelton, Richard; Yadava, Mrinal; Rhea, Isaac; Straka, Susan; Fishbein, Michael C.; Chen, Zhenhui; Lin, Shien-Fong; Lopshire, John C.; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBACKGROUND: The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear. METHODS AND RESULTS: We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. CONCLUSIONS: SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.Item Wall motion abnormalities with low-dose dobutamine predict a high risk of cardiac death in medically treated patients with ischemic cardiomyopathy(Wiley, 2009-07) Maskoun, Waddah; Mustafa, Nowwar; Mahenthiran, Jothiharan; Gradus‐Pizlo, Irmina; Kamalesh, Masoor; Feigenbaum, Harvey; Sawada, Stephen G.; Medicine, School of MedicineBACKGROUND: Severe and extensive coronary artery disease is the underlying cause of stress-induced wall motion abnormalities (SWMA) with low-dose (10 microg/kg/min) dobutamine suggesting that these abnormalities may identify those with poor outcome. HYPOTHESIS: We assessed the prognostic value of low-dose SWMA in medically treated patients with ischemic cardiomyopathy. METHODS: Low- and peak-dose dobutamine echocardiography was performed in 235 patients with ischemic cardiomyopathy (ejection fraction 31% +/- 8%) who were treated with medical therapy. The survival of patients with low-dose SWMA (n = 33) was compared with the survival of patients without ischemia (n = 85) and those with peak-dose SWMA (n = 117). RESULTS: There were 123 cardiac deaths (52%) during follow-up of 4.1 +/- 3.3 years. Multivariate predictors of cardiac death were age (p = 0.002, hazard ratio [HR]: 1.03), diabetes (p = 0.028, HR: 1.54), New York Heart Association (NYHA) class III, IV heart failure (p = 0.001, HR: 1.94), the presence of peak dose SWMA (p < 0.001, HR: 2.59), and low-dose SWMA (p = 0.005, HR: 2.28). Survival of patients without ischemia was significantly better than those with peak-dose SWMA (p < 0.0001) and those with low-dose SWMA (p = 0.001). The survival of patients with low-dose SWMA was the same as those with peak-dose SWMA (p = 0.89). CONCLUSIONS: Low-dose SWMA is an independent predictor of cardiac mortality in medically treated patients with ischemic cardiomyopathy. Patients with low-dose SWMA are at equivalent risk to those with peak-dose SWMA.