Heloisa Sawaya

Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients treated with Anthracyclines, Taxanes and Trastuzumab

Background—Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results—Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions—In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.

Inflammatory arthritis can be reined in by CpG-induced DC-NK cell cross talk

Unmethylated CpG-oligodeoxynucleotides (ODNs) are generally thought of as potent adjuvants with considerable therapeutic potential to enhance immune responses against microbes and tumors. Surprisingly, certain so-called stimulatory CpG-ODNs strongly inhibited the effector phase of inflammatory arthritis in the K/BxN serum transfer system, either preventively or therapeutically. Also unexpected was that the inhibitory influence did not depend on the adaptive immune system cells mobilized in an immunostimulatory context. Instead, they relied on cells of the innate immune system, specifically on cross talk between CD8α+ dendritic cells and natural killer cells, resulting in suppression of neutrophil recruitment to the joint, orchestrated through interleukin-12 and interferon-γ. These findings highlight potential applications of CpG-ODNs and downstream molecules as antiinflammatory agents.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab

BACKGROUND Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Newest echocardiographic techniques for the detection of cardiotoxicity and heart failure during chemotherapy.

Chemotherapy-induced cardiotoxicity has become a significant public health issue. Left ventricular ejection fraction is routinely used to monitor cardiotoxicity but fails to detect subtle alterations in cardiac function. Improvements in the measurement of left ventricular ejection fraction, physical or pharmacologic stressors, and novel cardiac functional indices may be useful in the detection of cardiotoxicity. The improvements in the detection and therapy of cancer have led to the emergence of chemotherapy-induced cardiotoxicity. New echocardiographic techniques may be useful in the detection of patients undergoing chemotherapy treatments who could benefit from alternative cancer treatments, therefore decreasing the incidence of cardiotoxicity.

Human Resistin in Chemotherapy-Induced Heart Failure in Humanized Male Mice and in Women Treated for Breast Cancer

Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease.

Altered adhesion molecules expression on peripheral blood mononuclear cells from patients with systemic sclerosis and clinical correlations

The aim of the study was to evaluate the expressions of adhesion molecules (AM) on peripheral blood mononuclear cells (PBMNC) from systemic sclerosis (SSc) patients. Thirty-one SSc patients (ACR) and 20 normal subjects were selected for the study. PBMNC were analyzed for LFA-1α, LFA-1β, ICAM-3, ICAM-1, and l-selectin expressions. ICAM-3 expression was decreased while ICAM-1 was increased on SSc PBMNC, compared to controls (p = 0.04 and 0.003, respectively). A positive association was found between LFA-1α (r = 0.37, p = 0.03), LFA-1β (r = 0.38, p = 0.002), ICAM-3 (r = 0.42, p = 0.01), and l-selectin (r = 0.38, p = 0.03) expressions and greater number of immunosuppressive drugs taken by SSc patients. Also, anti-centromeric positive SSc patients had lower expressions of LFA-1α, LFA-1β, ICAM-3, and l-selectin. Lower expression of ICAM-3 and higher expression of ICAM-1 suggest that AMs may be involved in the pathogenesis of scleroderma.

Effects of subacute dietary salt intake and acute volume expansion on diastolic function in young normotensive individuals

AIMS Chronic excess salt intake may have blood pressure-independent adverse effects on the heart such as myocardial hypertrophy and fibrosis. Effects of subacute sodium loading with excess dietary salt on diastolic function in normotensive individuals have been conflicting and the mechanisms are poorly understood. METHODS AND RESULTS Thirteen healthy normotensive subjects (age 24 ± 4 years) entered a 2-week crossover study with 1 week of a low-salt diet <10 mEq/day and 1 week of a high-salt diet >200 mEq/day. At the end of each study week, left ventricular dimensions, systolic, and diastolic function were assessed with echocardiography before and after 2 L of normal saline infusion. One week of high-salt and low-salt diets did not lead to differences in echocardiographic parameters of systolic or diastolic function, even after rapid volume expansion with saline infusion. The peak early diastolic strain rate (SR) increased after volume loading both after completion of low-salt (1.62 ± 0.23/s vs. 1.82 ± 0.14/s, P < 0.05) and high-salt diets (1.67 ± 0.16/s vs. 1.86 ± 0.22/s, P < 0.05). There was a positive correlation between the peak early diastolic SR and the cardiac index (r = 0.52, P = 0.017). CONCLUSION In healthy normotensive individuals, subacute excess dietary sodium intake does not affect diastolic function. The peak early diastolic SR, similar to other mitral Doppler and tissue Doppler parameters of diastolic function, appears to be strongly dependent on pre-load.

LONGITUDINAL CHANGES IN MULTIPLE BIOMARKERS ARE ASSOCIATED WITH CARDIOTOXICITY IN BREAST CANCER PATIENTS TREATED WITH DOXORUBICIN, TAXANES AND TRASTUZUMAB

Anthracyclines and trastuzumab (Herceptin®) have led to significant improvements in breast cancer survival, but are associated with an increased risk of cardiotoxicity. Moreover, biomarker strategies to identify or predict which patients are at risk for cardiotoxicity remain poorly understood. Our