Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans

Abstract

A reasonably sensitive and specific noninvasive test for doxorubicin cardiotoxicity is needed. In addition, few data exist on the short- and long-term effects of doxorubicin on diastolic filling. To determine if pulsed Doppler indexes of diastolic filling could predict doxorubicin-induced systolic dysfunction, 26 patients (mean age 48 +/- 12 years) were prospectively studied before receiving chemotherapy (control) and 3 weeks after obtaining cumulative doses of doxorubicin. In nine patients developing doxorubicin-induced systolic dysfunction (that is, a decrease in ejection fraction by greater than or equal to 10 ejection fraction units to less than 55%), the isovolumetric relaxation time was prolonged (from 66 +/- 18 to 84 +/- 24 ms, p less than 0.05) after a cumulative doxorubicin dose of 100 to 120 mg/m2. This prolongation preceded a significant decrease in ejection fraction. Other Doppler indexes of filling were impaired after doxorubicin therapy but occurred simultaneously with the decrease in ejection fraction. A greater than 37% increase in isovolumetric relaxation time was 78% (7 of 9) sensitive and 88% (15 of 17) specific for predicting the ultimate development of doxorubicin-induced systolic dysfunction. In 15 patients studied 1 h after the first treatment, doxorubicin enhanced Doppler indexes of filling and shortened isovolumetric relaxation time. In 22 patients, indexes of filling remained impaired and isovolumetric relaxation time was prolonged 3 months after the last doxorubicin dose. In conclusion, doxorubicin-induced systolic dysfunction is reliably predicted by prolongation of Doppler-derived isovolumetric relaxation time. Early after administration, doxorubicin enhances filling and isovolumetric relaxation time. The adverse effects of doxorubicin on both variables persist at least 3 months after cessation of treatment.

Traditional and novel methods to assess and prevent chemotherapy-related cardiac dysfunction noninvasively

“…Greater than 37% increase in IVRT was 78% sensitive and 88% specific for predicting the ultimate development of doxorubicin-induced systolic dysfunction. 41 In a study of 20 patients receiving a mean cumulative dose of doxorubicin of 211 ± 82 mg/m 2 , pulsed tissue Doppler Imaging was reported to show mitral annulus IVRT \ 80 ms in 4 patients who had LVEF \ 50% appeared to outperform both standard Doppler IVRT and basal segment measurements, a finding the authors reported could be of interest to predict later impairment of LV function. 42 However, the published assessment of the MD Anderson Cancer Center has been that echo diastolic measures are more complex than systolic to obtain and interpret, reproducibility of echocardiographic measures of diastolic function has been problematic, and multiple diastolic measurements have had varying levels of success in identifying early cardiac toxicity.…”

“…Echocardiographic evidence that LV diastolic dysfunction precedes resting systolic dysfunction has been reported, but does not appear to correlate with doxorubicin dosage or enhance prediction of CHF. [40][41][42] These parameters include prolonged isovolumetric relaxation period, reduction in peak flow velocity, and the ratio of early peak flow velocity/atrial peak flow velocity, as well as reduction in the deceleration rate of the early peak flow velocity. Stoddard et al 41 reported prolongation of isovolumetric relaxation time (IVRT) by Doppler echocardiography to predict doxorubicin-induced systolic dysfunction in a study of 26 patients.…”

Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors

“…Stoddard et al [12], in a study with 26 patients, found that early changes in a diastolic function parameter (i.e., a prolongation of isovolumetric relaxation time) following anthracycline therapy appeared before changes in systolic dysfunction parameters were identified. Additional studies have found changes in tissue Doppler parameters.…”

“…Some studies have examined the usefulness of several echocardiographic diastolic parameters in detecting anthracyclinerelated cardiac injury [12,13]. However, there is limited information from longitudinal studies about the incidence and evolution of diastolic dysfunction in a large and homogeneous cohort of patients treated with anthracyclines or anthracyclines plus trastuzumab.…”

Early Detection of Doxorubicin Cardiomyopathy Using Two-Dimensional Strain Echocardiography

“…However, it has been demonstrated that left ventricular ejection fraction and fractional shortening are insensitive to detection of doxorubicin cardiomyopathy (McKillop, Bristow 1983, Tjeerdsma, Meinardi 1999. Other measures were found useful in earlier detection of doxorubicin cardiomyopathy such as indices of diastolic dysfunction (Marchandise, Schroeder 1989, Stoddard, Seeger 1992, but considerable individual variability limits practical applicability in the clinical setting (Bu'Lock, Mott 1999) 2-dimensional strain echocardiography is a rapid, easy and objective way of measuring myocardial function. Strain is a measure of myocardial deformation, which is an intrinsic mechanical property.…”