Jennifer H. Jordan

Low to Moderate Dose Anthracycline-Based Chemotherapy Is Associated With Early Noninvasive Imaging Evidence of Subclinical Cardiovascular Disease

OBJECTIVES The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. BACKGROUND Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). METHODS In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. RESULTS Participants averaged 50 ± 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m(2) of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 ± 3 ml to 54 ± 3 ml; p = 0.02), left ventricular strain (-17.7 ± 0.4 to -15.1 ± 0.4; p = 0.0003), pulse wave velocity (6.7 ± 0.5 m/s to 10.1 ± 1 m/s; p = 0.0006), and QOL deterioration (15.4 ± 3.3 to 28.5 ± 3.9; p = 0.008) increased, whereas LVEF (58 ± 1% to 53 ± 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. CONCLUSIONS In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events.

Novel Approach to Early Detection of Doxorubicin Cardiotoxicity by Gadolinium-Enhanced Cardiovascular Magnetic Resonance Imaging in an Experimental Model

Background —To determine if cardiovascular magnetic resonance (CMR) measures of gadolinium (Gd) signal intensity (SI) within the left ventricular (LV) myocardium are associated with future changes in LV ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results —Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of: normal saline (NS) (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). MR determinations of LVEF and myocardial Gd-SI were performed before and then at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were sacrificed at different time points so that histopathological assessments of the LV myocardium could be obtained. Within group analyses were performed to examine time-dependent relationships between Gd-SI and primary events (a deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg of DOX and 10/14 animals receiving 2.5 mg/kg of DOX experienced a primary event; no NS animals experienced a primary event. In animals with a primary event, histopathological evidence of myocellular vacuolization occurred (p=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (p<0.0001) and during the measurement period prior to the event (p=0.0001). In all animals (including NS) without an event, measures of Gd-SI did not differ from baseline. Conclusions —After DOX, low serial measures of Gd-SI predict an absence of a LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.Background—We sought to determine whether cardiovascular magnetic resonance measures of gadolinium (Gd) signal intensity (SI) within the left ventricular myocardium are associated with future changes in left ventricular ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results—Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of normal saline (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). Magnetic resonance determinations of LVEF and myocardial Gd-SI were performed before and at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were euthanized at different time points so that histopathologic assessments of the left ventricular myocardium could be obtained. Within-group analyses were performed to examine time-dependent relations between Gd-SI and primary events (deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg DOX and 10 of 14 animals receiving 2.5 mg/kg DOX experienced a primary event; no normal saline animals experienced a primary event. In animals with a primary event, histopathologic evidence of myocellular vacuolization occurred (P=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (P<0.0001) and during the measurement period before the event (P=0.0001). In all animals (including normal saline) without an event, measures of Gd-SI did not differ from baseline. Conclusions—After DOX, low serial measures of Gd-SI predict an absence of an LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.

Longitudinal Assessment of Concurrent Changes in Left Ventricular Ejection Fraction and Left Ventricular Myocardial Tissue Characteristics After Administration of Cardiotoxic Chemotherapies Using T1-Weighted and T2-Weighted Cardiovascular Magnetic Resonance

Background—In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. Methods and Results—In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51±12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57±6% to 54±7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1±5.1 to 15.9±6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). Conclusions—Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Early Detection of Doxorubicin Cardiotoxicity Using Gadolinium Enhanced Cardiovascular Magnetic Resonance Imaging

Background —To determine if cardiovascular magnetic resonance (CMR) measures of gadolinium (Gd) signal intensity (SI) within the left ventricular (LV) myocardium are associated with future changes in LV ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results —Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of: normal saline (NS) (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). MR determinations of LVEF and myocardial Gd-SI were performed before and then at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were sacrificed at different time points so that histopathological assessments of the LV myocardium could be obtained. Within group analyses were performed to examine time-dependent relationships between Gd-SI and primary events (a deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg of DOX and 10/14 animals receiving 2.5 mg/kg of DOX experienced a primary event; no NS animals experienced a primary event. In animals with a primary event, histopathological evidence of myocellular vacuolization occurred (p=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (p<0.0001) and during the measurement period prior to the event (p=0.0001). In all animals (including NS) without an event, measures of Gd-SI did not differ from baseline. Conclusions —After DOX, low serial measures of Gd-SI predict an absence of a LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.Background—We sought to determine whether cardiovascular magnetic resonance measures of gadolinium (Gd) signal intensity (SI) within the left ventricular myocardium are associated with future changes in left ventricular ejection fraction (LVEF) after receipt of doxorubicin (DOX). Methods and Results—Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of normal saline (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). Magnetic resonance determinations of LVEF and myocardial Gd-SI were performed before and at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were euthanized at different time points so that histopathologic assessments of the left ventricular myocardium could be obtained. Within-group analyses were performed to examine time-dependent relations between Gd-SI and primary events (deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg DOX and 10 of 14 animals receiving 2.5 mg/kg DOX experienced a primary event; no normal saline animals experienced a primary event. In animals with a primary event, histopathologic evidence of myocellular vacuolization occurred (P=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (P<0.0001) and during the measurement period before the event (P=0.0001). In all animals (including normal saline) without an event, measures of Gd-SI did not differ from baseline. Conclusions—After DOX, low serial measures of Gd-SI predict an absence of an LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.

Anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors.

Background—Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. Methods and Results—We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64±12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pretreatment cancer (27.8±0.7%; P<0.01) or cancer-free comparators (26.9±0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). Conclusions—Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities, suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen.

Chronic Statin Administration May Attenuate Early Anthracycline-Associated Declines in Left Ventricular Ejection Function

Background Recent studies show an association between statin therapy and a reduced risk of heart failure among breast cancer survivors. Our goal was to evaluate whether statin therapy for prevention of cardiovascular disease (CVD) would ameliorate declines in left ventricular ejection fraction (LVEF) often observed during anthracycline-based chemotherapy (Anth-bC). Methods In 51 participants (33 women and 18 men; aged 48±2 years), we performed CV magnetic resonance (CMR) measurements of LVEF before and 6 months after initiation of Anth-bC for patients with breast cancer, leukemia, or lymphoma. Fourteen individuals received statin therapy, and 37 received no statin. MR image analysts were blinded to participant identifiers. Results Those receiving statins were older and often had diabetes (DM), hypertension (HTN), and hyperlipidemia (HLD). For those receiving statins, LVEF was 56.6±1.4% at baseline and 54.1±1.3% 6 months after initiating anthracycline (p=0.15). For those not receiving a statin, LVEF was 57.5±1.4% at baseline and decreased to 52.4±1.2% over a similar 6 month interval (p=0.0003). In a multivariable model accounting for age, sex, DM, HTN, HLD, and cumulative amount of anthracycline received, LVEF remained unchanged in participants receiving a statin (+ 1.1±2.6%) versus a −6.5±1.5% decline among those not receiving a statin (p=0.03). Conclusion In conclusion, these data highlight that individuals receiving statin therapy for prevention of CVD may experience less deterioration in LVEF upon early receipt of Anth-bC than individuals not receiving a statin. Further studies with large numbers of participants are warranted to determine if statins protect against LVEF decline in patients receiving Anth-bC.

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

Background The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. Methodology/Principal Findings Given the many factors that might influence p53 function, including expression levels, mutations, cofactor proteins and small molecules, we expanded our previously described yeast-based system to provide the opportunity for efficient investigation of their individual and combined impacts in a miniaturized format. The system integrates i) variable expression of p53 proteins under the finely tunable GAL1,10 promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1. Conclusions/Significance We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins.

Early Myocardial Strain Changes During Potentially Cardiotoxic Chemotherapy May Occur as a Result of Reductions in Left Ventricular End-Diastolic Volume

Cardiac dysfunction and myocellular injury from cancer therapeutics are identified by reductions in left ventricular (LV) ejection fraction (LVEF) or >15% deteriorations in myocardial strain.1 Myocardial strain may deteriorate as a result of increases in LV end-systolic volume (LVESV), reductions in LV end-diastolic volume (LVEDV), or both. Decreases in LVEDV caused by hypovolemia from poor oral intake, emesis, or myocardial loss2 occur during cancer treatment. We sought to determine the frequency with which decrements in myocardial strain were mediated by decreases in LVEDV versus increases in LVESV in patients receiving potentially cardiotoxic chemotherapy. The study was approved by the local institutional review board, and participants provided witnessed, written informed consent. Cardiovascular magnetic resonance examinations were performed on a 1.5-T Siemens Avanto scanner <6 hours before chemotherapy administration both before and 3 months after the initiation of cancer treatment. LV volumes, LVEF, LV mass, relative wall thickness, and midwall eulerian circumferential strain (ECC) were calculated from a series of LV short-axis white-blood cine stacks and a midcavity short-axis grid-tagged image.3 In addition, global longitudinal strain (GLS) was assessed from high-temporal-resolution 2- and 4-chamber cine views …

Progressive 3-Month Increase in LV Myocardial ECV After Anthracycline-Based Chemotherapy

Following myocardial injury, the left ventricular (LV) myocardial extracellular matrix (ECM) can undergo abnormal expansion (due to inflammation and interstitial fibrosis) that can be identified with cardiac magnetic resonance (CMR) assessments of extracellular volume fraction (ECV) [(1,2)][1].

Adiposity Is Associated with Gender-Specific Reductions in Left Ventricular Myocardial Perfusion during Dobutamine Stress

Background Obesity and visceral adiposity are increasingly recognized risk factors for cardiovascular disease. Visceral fat may reduce myocardial perfusion by impairing vascular endothelial function. Women experience more anginal symptoms compared to men despite less severe coronary artery stenosis, as assessed by angiography. Women and men have different fat storage patterns which may account for the observed differences in cardiovascular disease. Therefore, our objective was to evaluate the relationship between visceral adipose tissue distributions and myocardial perfusion in men and women. Methods Visceral and subcutaneous fat distributions and myocardial perfusion were measured in 69 men and women without coronary artery disease using magnetic resonance imaging techniques. Myocardial perfusion index was quantified after first-pass perfusion with gadolinium contrast at peak dose dobutamine stress. Results We observed inverse relationships between female gender (r = -0.35, p = 0.003), pericardial fat (r = -0.36, p = 0.03), intraperitoneal fat (r = -0.37, p = 0.001), and retroperitoneal fat (r = -0.36, p = 0.002) and myocardial perfusion index. Visceral fat depots were not associated with reduced myocardial perfusion at peak dose dobutamine in men. However, in women, BMI (r = -0.33, p = 0.04), pericardial fat (r = -0.53, p = 0.02), subcutaneous fat (r = -0.39, p = 0.01) and intraperitoneal fat (r = -0.30, p = 0.05) were associated with reduced myocardial perfusion during dobutamine stress. Conclusions Higher visceral fat volumes are associated with reduced left ventricular myocardial perfusion at peak dose dobutamine stress in women but not in men. These findings suggest that visceral fat may contribute to abnormal microcirculatory coronary artery perfusion syndromes, explaining why some women exhibit more anginal symptoms despite typically lower grade epicardial coronary artery stenoses than men.