Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series.

BACKGROUND: Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. METHODS: Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. RESULTS: Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. CONCLUSION: The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.

Ibrutinib-Associated Atrial Fibrillation.

Ibrutinib, a novel and potent Bruton tyrosine kinase inhibitor, is an effective and well-tolerated treatment for a variety of B-cell lymphomas. However, its use is associated with an increased incidence of atrial fibrillation (AF), ranging from 4% to 16%. We reviewed the original clinical trials that led to the approval of ibrutinib, as well as several other prospective and retrospective studies, to better appreciate the incidence of ibrutinib-associated AF. Based on 16 studies included in our analysis, the incidence of ibrutinib-associated AF was 5.77 per 100 person-years, which is much higher than rates previously reported with ibrutinib and compared with the general adult population. New onset AF in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. In addition, ibrutinib poses unique challenges due to its interactions with many medications that are commonly used to manage AF. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation have to be carefully weighed against this increased risk of bleeding. Ibrutinib's interaction with calcium channel blockers, digoxin, amiodarone, and direct oral anticoagulants can result in either ibrutinib or other drug-related toxicity and careful selection and dose adjustment may be needed. Ibrutinib-associated AF can be a therapy-limiting side effect and physicians should be familiar with the special management considerations imposed by this agent. We review the potential mechanisms and incidence of ibrutinib-associated AF and propose an algorithm for its management.

First spot urine sodium after initial diuretic identifies patients at high risk for adverse outcome after heart failure hospitalization.

BACKGROUND: Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization. METHODS: At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa >60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge. RESULTS: Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa <60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P < .006) than patients with UNa >60. CONCLUSIONS: Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization.

Acute Bilateral Internal Carotid Occlusion from Embolization of Left Atrial Thrombus During Transesophageal Echocardiography: Case Report.

BACKGROUND AND PURPOSE: Transesophageal echocardiography (TEE) is a relatively safe imaging modality used to visualize intracardiac thrombus. SUMMARY OF CASE: We report on a unique, fatal complication during TEE of embolization of a pre-existing "smoking" left atrial thrombus causing acute bilateral internal carotid occlusion, confirmed on angiogram. CONCLUSIONS: Patients with history of lung pathology, such as COPD, who experience retching and cough during transesophageal echocardiography may be more susceptible to embolization of pre-existing thrombi. A need exists to risk stratify such patients.

A C-terminal segment of the V1R vasopressin receptor is unstructured in the crystal structure of its chimera with the maltose-binding protein.

The V1 vascular vasopressin receptor (V1R) is a G-protein-coupled receptor (GPCR) involved in the regulation of body-fluid osmolality, blood volume and blood pressure. Signal transduction is mediated by the third intracellular loop of this seven-transmembrane protein as well as by the C-terminal cytoplasmic segment. A chimera of the maltose-binding protein (MBP) and the C-terminal segment of V1R has been cloned, expressed, purified and crystallized. The crystals belong to space group P2(1), with unit-cell parameters a = 51.10, b = 66.56, c = 115.72 A, beta = 95.99 degrees. The 1.8 A crystal structure reveals the conformation of MBP and part of the linker region of this chimera, with the C-terminal segment being unstructured. This may reflect a conformational plasticity in the C-terminal segment that may be necessary for proper function of V1R.