Giselle C. Meléndez

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.

Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype

Previously, we have reported sex differences in the cardiac remodeling response to ventricular volume overload whereby male and ovariectomized (OVX) female rats develop eccentric hypertrophy, and intact (Int) female rats develop concentric hypertrophy. In males, this adverse remodeling has been attributed to an initial cascade of events involving myocardial mast cell and matrix metalloproteinase activation and extracellular collagen matrix degradation. The objective of this study was to determine the effect of female hormones on this initial cascade. Accordingly, an aortocaval fistula (Fist) was created in 7-wk-old Int and OVX rats, which, together with sham-operated (sham) controls, were studied at 1, 3, and 5 days postsurgery. In Int-Fist rats, myocardial mast cell density, collagen volume fraction, endothelin (ET)-1, stem cell factor (SCF), and TNF-α remained at control levels or were minimally elevated throughout the study period. This was not the case in the OVX-Fist group, where the initial response included significant increases in mast cell density, collagen degradation, ET-1, SCF, and TNF-α. These events in the OVX-Fist group were abolished by prefistula treatment with a mast cell stabilizer nedocromil. Of note was the observation that ET-1, TNF-α, SCF, and collagen volume fraction values for the OVX-sham group were greater than those of the Int-sham group, suggesting that the reduction of female hormones alone results in major myocardial changes. We concluded that female hormone-related cardioprotection to the volume stressed myocardium is the result of an altered mast cell phenotype and/or the prevention of mast cell activation.

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].

Estrogenic modulation of inflammation-related genes in male rats following volume overload.

Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the β1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes.

Beneficial effects of soy supplementation on postmenopausal atherosclerosis are dependent on pretreatment stage of plaque progression

ObjectiveThe objective of this study was to use a well-established monkey model of atherosclerosis to determine how life stage and preexisting atherosclerosis influence the effectiveness of high-isoflavone soy diet in inhibiting progression of atherosclerosis. MethodsFor 34 months, premenopausal monkeys were fed an atherogenic diet, with protein derived primarily from either animal sources (casein-lactalbumin [CL], n = 37) or high-isoflavone soy beans (Soy, n = 34). Animals were ovariectomized and randomized to groups fed the same diet (CL-CL, n = 20; Soy-Soy, n = 17) or an alternate diet (CL-Soy, n = 17; Soy-CL, n = 17) for an additional 34 months. At ovariectomy, the left common iliac artery was removed to determine the amount of premenopausal atherosclerosis. At necropsy, the right common iliac artery and coronary arteries were collected, and atherosclerosis extent was quantified. CL-CL condition was considered “control.” ResultsModeling Asian women who remain in Asia, monkeys fed soy protein both premenopausally and postmenopausally had a markedly reduced extent of coronary artery atherosclerosis relative to CL controls (P = 0.008). The subset of animals that modeled Asian women who migrate to a Western country (consuming soy premenopausally and CL postmenopausally) had increased progression of postmenopausal iliac artery atherosclerosis (P = 0.003) and was not protected against the development of coronary artery atherosclerosis relative to controls. Relevant to the administration of soy diets to postmenopausal Western women, monkeys fed CL premenopausally and switched to soy postmenopausally derived atheroprotective benefits only if they began the postmenopausal treatment period with relatively small (below the median) plaques. Relative to controls, this group (with small plaques at ovariectomy) had reduced progression of iliac atherosclerosis (P = 0.038) and smaller coronary artery plaques (P = 0.0001) that were less complicated (P = 0.05) relative to controls. ConclusionsThe results suggest that significant atheroprotective benefits of dietary soy are derived from treatment that begins premenopausally and continues postmenopausally or from treatment that is started during early postmenopause (when plaques are still small).

Is Myocardial Fibrosis a New Frontier for Discovery in Cardiotoxicity Related to the Administration of Anthracyclines

The success of therapeutic advancements during the last decade have resulted in an increase in the number of cancer survivors, with now >14.5 million cases in the United States in 2016.1 However, this success has created a paradigm: cardiotoxicity and left ventricular (LV) dysfunction have become the most frequent adverse effects of cancer treatment regimens—especially anthracyclines—offsetting the benefits of these life-saving therapies. Navigating patients through cancer treatment while mitigating the development of LV dysfunction has become increasingly important. See Article by Farhad et al Traditionally, the most widely used strategies to detect cardiotoxicity included monitoring of LV ejection fraction (LVEF) by cardiac imaging or directly visualizing myocellular injury from right heart endomyocardial biopsies.2 Although histopathologic examinations are often revealing, their invasive nature and consequent associated risks favor the development of more suitable alternatives. Notably, the rapid evolution of noninvasive cardiac imaging strategies to monitor cardiac function is providing new opportunities for the early detection of LV dysfunction. Cardiovascular magnetic resonance (CMR) imaging is rapidly becoming a central diagnostic tool in cardiovascular medicine, not only because of its ability to provide accurate volumetric and functional systolic and diastolic function measurements of the ventricles, but also because of its unique ability to characterize myocardial tissue and, thereby, determine the pathogenesis of myocardial dysfunction.3 These features are particularly important in the cardio-oncology arena when trying to determine the pathogenesis of an LVEF decline in a patient treated for cancer that also exhibits several other cardiovascular comorbidities. CMR uses the tissue response of exposure to nonionizing electromagnetic radiation within magnetic fields to generate within the body contrast between different structures and tissues and, thereby, allowing the identification of abnormal pathology.4 Novel mapping techniques capture the evolution of T1 recovery within a single breath-hold, and if measured before and after the …

Relation of Pre-anthracycline Serum Bilirubin Levels to Left Ventricular Ejection Fraction After Chemotherapy.

Myocardial injury because of oxidative stress manifesting through reductions in left ventricular ejection fraction (LVEF) may occur after the administration of anthracycline-based chemotherapy (A-bC). We hypothesized that bilirubin, an effective endogenous antioxidant, may attenuate the reduction in LVEF that sometimes occurs after receipt of A-bC. We identified 751 consecutively treated patients with cancer who underwent a pre-A-bC LVEF measurement, exhibited a serum total bilirubin level <2 mg/dl, and then received a post-A-bC LVEF assessment because of symptomatology associated with heart failure. Analysis of variance, Tukeys Studentized range test, and chi-square tests were used to evaluate an association between bilirubin and LVEF changes. The LVEF decreased by 10.7 ± 13.7%, 8.9 ± 11.8%, and 7.7 ± 11.5% in group 1 (bilirubin at baseline ≤0.5 mg/dl), group 2 (bilirubin 0.6 to 0.8 mg/dl), and group 3 (bilirubin 0.9 to 1.9 mg/dl), respectively. More group 1 patients experienced >15% decrease in LVEF compared with those in group 3 (p = 0.039). After adjusting for age, coronary artery disease/myocardial infarction, diabetes mellitus, hematocrit, and the use of cardioactive medications, higher precancer treatment bilirubin levels and lesser total anthracycline doses were associated with LVEF preservation (p = 0.047 and 0.011, respectively). In patients treated with anthracyclines who subsequently develop symptoms associated with heart failure, pre-anthracycline treatment serum bilirubin levels inversely correlate with subsequent deterioration in post-cancer treatment LVEF. In conclusion, these results suggest that increased levels of circulating serum total bilirubin, an intrinsic antioxidant, may facilitate preservation of LVEF in patients receiving A-bC for cancer.

Left Ventricular Mass Change After Anthracycline Chemotherapy

Background: Myocardial atrophy and left ventricular (LV) mass reductions are associated with fatigue and exercise intolerance. The relationships between the receipt of anthracycline-based chemotherapy (Anth-bC) and changes in LV mass and heart failure (HF) symptomatology are unknown, as is their relationship to LV ejection fraction (LVEF), a widely used measurement performed in surveillance strategies designed to avert symptomatic HF associated with cancer treatment. Methods and Results: We performed blinded, serial assessments of body weight, LVEF and mass, LV-arterial coupling, aortic stiffness, and Minnesota Living with Heart Failure Questionnaire measures before and 6 months after initiating Anth-bC (n=61) and non–Anth-bC (n=15), and in 24 cancer-free controls using paired t and &khgr;2 tests and multivariable linear models. Participants averaged 51±12 years, and 70% were women. Cancer diagnoses included breast cancer (53%), hematologic malignancy (42%), and soft tissue sarcoma (5%). We observed a 5% decline in both LVEF (P<0.0001) and LV mass (P=0.03) in the setting of increased aortic stiffness and disrupted ventricular-arterial coupling in those receiving Anth-bC but not other groups (P=0.11–0.92). A worsening of the Minnesota Living with Heart Failure Questionnaire score in Anth-bC recipients was associated with myocardial mass declines (r=−0.27; P<0.01) but not with LVEF declines (r=0.11; P=0.45). Moreover, this finding was independent of LVEF changes and body weight. Conclusions: Early after Anth-bC, LV mass reductions associate with worsening HF symptomatology independent of LVEF. These data suggest an alternative mechanism whereby anthracyclines may contribute to HF symptomatology and raise the possibility that surveillance strategies during Anth-bC should also assess LV mass.

DECREASES IN LEFT VENTRICULAR MASS AND NOT LEFT VENTRICULAR EJECTION FRACTION ARE ASSOCIATED WITH HEART FAILURE SYMPTOMS IN CANCER PATIENTS SIX MONTHS AFTER POTENTIALLY CARDIOTOXIC CHEMOTHERAPY

Background: Cancer therapy related cardiovascular dysfunction (CTRCD) is a known consequence of modern cancer therapies and is identified through changes in left ventricular ejection fraction (LVEF) and strain by echocardiography or cardiovascular magnetic resonance (CMR) imaging. LV remodeling and