Charles Guenancia

Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms

Anticancer drugs continue to cause significant reductions in left ventricular ejection fraction resulting in congestive heart failure. The best-known cardiotoxic agents are anthracyclines (ANTHs) such as doxorubicin (DOX). For several decades cardiotoxicity was almost exclusively associated with ANTHs, for which cumulative dose-related cardiac damage was the use-limiting step. Human epidermal growth factor (EGF) receptor 2 (HER2; ErbB2) has been identified as an important target for breast cancer. Trastuzumab (TRZ), a humanized anti-HER2 monoclonal antibody, is currently recommended as first-line treatment for patients with metastatic HER2(+) tumors. The use of TRZ may be limited by the development of drug intolerance, such as cardiac dysfunction. Cardiotoxicity has been attributed to free-iron-based, radical-induced oxidative stress. Many approaches have been promoted to minimize these serious side effects, but they are still clinically problematic. A new approach to personalized medicine for cancer that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging.

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

PURPOSE Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer. METHODS We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab. RESULTS Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis. CONCLUSION Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.

Incidence and Predictors of New-Onset Atrial Fibrillation in Septic Shock Patients in a Medical ICU: Data from 7-Day Holter ECG Monitoring

Purpose We investigated incidence, risk factors for new-onset atrial fibrillation (NAF), and prognostic impact during septic shock in medical Intensive Care Unit (ICU) patients. Methods Prospective, observational study in a university hospital. Consecutive patients from 03/2011 to 05/2013 with septic shock were eligible. Exclusion criteria were age <18 years, history of AF, transfer with prior septic shock. Included patients were equipped with long-duration (7 days) Holter ECG monitoring. NAF was defined as an AF episode lasting >30 seconds. Patient characteristics, infection criteria, cardiovascular parameters, severity of illness, support therapies were recorded. Results Among 66 patients, 29(44%) developed NAF; 10 (34%) would not have been diagnosed without Holter ECG monitoring. NAF patients were older, with more markers of heart failure (troponin and NT-pro-BNP), lower left ventricular ejection fraction (LVEF), longer QRS duration and more nonsustained supra ventricular arrhythmias (<30s) on day 1 than patients who maintained sinus rhythm. By multivariate analysis, age (OR: 1.06; p = 0.01) and LVEF<45% (OR: 13.01, p = 0.03) were associated with NAF. NAF did not predict 28 or 90 day mortality. Conclusions NAF is common, especially in older patients, and is associated with low ejection fraction. We did not find NAF to be independently associated with higher mortality.

The iron-regulatory hormone hepcidin: a possible therapeutic target?

The maintenance of stable extracellular and intracellular iron concentrations requires the coordinated regulation of iron transport into plasma. Iron is a fundamental cofactor for several enzymes involved in oxidation-reduction reactions. The redox ability of iron can lead to the production of oxygen free radicals, which can damage various cellular components. Therefore, the appropriate regulation of systemic iron homeostasis is decisive in vital processes. Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. It is synthesized in hepatocytes and in other cells and released into the circulation. It inhibits the release of iron from enterocytes of the duodenum and from macrophages by binding to the iron exporter protein, ferroportin (FPN). FPN is a transmembrane protein responsible for iron export from cells into the plasma. Hepcidin is internalized with FPN and both are degraded in lysosomes. The hepcidin-FPN axis is the principal regulator of extracellular iron homeostasis in health and disease. Its manipulation via agonists and antagonists is an attractive and novel therapeutic strategy. Hepcidin agonists include compounds that mimic the activity of hepcidin and agents that increase the production of hepcidin by targeting hepcidin-regulatory molecules. The inhibition of hepcidin could be a potentially attractive therapeutic strategy in patients suffering from anaemia or chronic inflammation. In this review, we will summarize the role of hepcidin in iron homeostasis and its contribution to the pathophysiology of inflammation and iron disorders. We will examine emerging new strategies that modulate hepcidin metabolism.

Postnatal Overfeeding Causes Early Shifts in Gene Expression in the Heart and Long-Term Alterations in Cardiometabolic and Oxidative Parameters

Background Postnatal overfeeding (OF) in rodents induces a permanent moderate increase in body weight in adulthood. However, the repercussions of postnatal OF on cardiac gene expression, cardiac metabolism and nitro-oxidative stress are less well known. Methodology/Principal Findings Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet. The cardiac gene expression profile was determined at weaning and cardiac metabolism and oxidative stress were assessed at 7 months. The cardiac expression of several genes, including members of the extracellular matrix and apelin pathway, was modified in juvenile OF mice. In adult mice, OF led to an increase in body weight (+30%) and to significant increases in plasma cholesterol, insulin and leptin levels. Myocardial oxidative stress, SOD and catalase activity and mRNA expression were increased in OF mice. In vivo, diastolic and systolic blood pressures were significantly higher and LV shortening and ejection fraction were decreased in OF mice. Ex vivo, after 30 min of ischemia, hearts isolated from OF mice showed lower functional recovery and larger infarct size (31% vs. 54%, p<0.05). Increases in collagen deposition and expression/activity of matrix-metalloproteinase-2 were observed in adult OF mouse hearts. Moreover, an increase in the expression of SOCS-3 and a decrease in STAT-3 phosphorylation were observed in ventricular tissues from OF mice. Conclusions/Significance Our study emphasizes that over-nutrition during the immediate postnatal period in mice leads to early changes in cardiac gene expression, which may permanently modify the heart’s structural organization and metabolism and could contribute to a greater susceptibility to myocardial ischemia-reperfusion injury.

Iron, oxidative stress, and redox signaling in the cardiovascular system

The redox state of the cell is predominantly dependent on an iron redox couple and is maintained within strict physiological limits. Iron is an essential metal for hemoglobin synthesis in erythrocytes, for oxidation-reduction reactions, and for cellular proliferation. The maintenance of stable iron concentrations requires the coordinated regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages, and from storage in hepatocytes. The absorption of dietary iron, which is present in heme or nonheme form, is carried out by mature villus enterocytes of the duodenum and proximal jejunum. Multiple physiological processes are involved in maintaining iron homeostasis. These include its storage at the intracellular and extracellular level. Control of iron balance in the whole organism requires communication between sites of uptake, utilization, and storage. Key protein transporters and the molecules that regulate their activities have been identified. In this field, ferritins and hepcidin are the major regulator proteins. A variety of transcription factors may be activated depending on the level of oxidative stress, leading to the expression of different genes. Major preclinical and clinical trials have shown advances in iron-chelation therapy for the treatment of iron-overload disease as well as cardiovascular and chronic inflammatory diseases.

Growth Differentiation Factor-15 (GDF-15) Levels Are Associated with Cardiac and Renal Injury in Patients Undergoing Coronary Artery Bypass Grafting with Cardiopulmonary Bypass

Objective Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB). Methods Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured. Results Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels. Conclusions During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.

Incidence and prognostic significance of silent atrial fibrillation in acute myocardial infarction

BACKGROUND Silent atrial fibrillation (AF) has been suggested to be frequent after acute myocardial infarction (MI). Continuous ECG monitoring (CEM) has been shown to improve AF screening in patients at risk of stroke. OBJECTIVES We aimed to assess the incidence and prognosis of silent AF in patients with acute MI. METHODS All the consecutive patients with acute MI were prospectively analyzed by CEM ≥ 48 h after admission. Silent AF was defined as asymptomatic episodes lasting at least 30s. The population was divided into three groups: no-AF, silent AF and symptomatic AF. RESULTS Among the 849 patients, 135 (16%) developed silent AF and 45 (5%) symptomatic AF. Compared with the no-AF group, patients with silent AF were markedly older (80 vs. 62 y, p<0.001), more frequently women (43% vs. 30%, p=0.006) and less likely to be smokers (20% vs. 36%, p<0.001). They had impaired left ventricular ejection fraction (LVEF) and left atrial (LA) enlargement. By multivariate analysis, age, history of AF, indexed LA area and LVEF were identified as independent predictors of silent AF. In-hospital heart failure and death rates were markedly higher in silent AF group when compared with no-AF patients (41.8% vs 21.0% and 10.4% vs. 1.3%, respectively). CONCLUSION Our large prospective study showed for the first time that silent AF is more frequent than symptomatic AF after MI. Our work suggests that indexed LA area could help to predict the risk of developing silent AF. Moreover, the onset of silent AF is associated with worse hospital prognosis.

Prognostic value of fragmented QRS on a 12-lead ECG in patients with acute myocardial infarction

OBJECTIVE To investigate the determinants and the prognostic value of fragmented QRS (fQRS) after AMI. PATIENTS AND METHODS Prospective cohort of 307 consecutive patients with AMI. MAIN OUTCOMES MEASURED MACE (death plus non-fatal recurrent MI), hospitalization for an episode of heart failure, ventricular arrhythmia (VT or VF) at two years follow-up. RESULTS On the serial 12-lead ECG recorded during the in-hospital stay, 162 (53%) had no fQRS (no fQRS group). 145 (47%) presented an fQRS, which was persistent in 108 (34%) patients (persistent fQRS group) and transient in 37 (12%) patients (transient fQRS group). Patients with a fragmented QRS (transient or persistent) were older, more likely to be hypertensive and less likely to be smokers than were patients without fQRS. By multivariate logistic regression analysis, only hypertension (OR (95% CI): 1.66 (1.00-2.74); p = 0.047) was associated with an fQRS. During a mean follow-up of 846 ± 297 days, there were 82 MACE recorded: 17 patients died from a CV cause (10% event rate) among patients without fQRS, 22 (20% event rate) among patients with persistent fQRS and 3 (8% event rate) among patients with transient fQRS. Similarly, non-fatal recurrent MI occurred more frequently in patients with fQRS (18 (16%) and 10 (27%)) for persistent and transient fQRS, respectively, vs. 16 (10%) in the no fQRS group (p = 0.019). However, the occurrence of heart failure symptoms and ventricular arrhythmia was not significantly different (p = 0.162 and p = 0.242, respectively). Survival analysis by the Kaplan-Meier method showed a significant difference (log rank p = 0.026) between groups, and only persistent fQRS was associated with decreased survival. In multivariate cox regression analysis, the GRACE score, blood glucose on admission, and B-blockers in the acute phase were independent predictors of MACE at two years. fQRS was not a significant independent predictor of MACE (HR (95% CI): 1.57 (0.95-2.60); p = 0.08). Moreover, fQRS was not a predictor of heart failure or ventricular arrhythmia in univariate analysis. CONCLUSIONS Persistent fQRS on a 12-lead ECG is a marker of decreased survival after AMI, whereas transient fQRS correlates with recurrent MI.

Atrial Fibrillation Is Associated with a Marker of Endothelial Function and Oxidative Stress in Patients with Acute Myocardial Infarction

Background Atrial fibrillation (AF), whether silent or symptomatic, is a frequent and severe complication of acute myocardial infarction (AMI). Asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor, is a risk factor for endothelial dysfunction. We addressed the relationship between ADMA plasma levels and AF occurrence in AMI. Methods 273 patients hospitalized for AMI were included. Continuous electrocardiographic monitoring (CEM) ≥48 hours was recorded and ADMA was measured by High Performance Liquid Chromatography on admission blood sample. Results The incidence of silent and symptomatic AF was 39(14%) and 29 (11%), respectively. AF patients were markedly older than patients without AF (≈ 20 y). There was a trend towards higher ADMA levels in patients with symptomatic AF than in patients with silent AF or no AF (0.53 vs 0.49 and 0.49 μmol/L, respectively, p = 0.18,). After matching on age, we found that patients with symptomatic AF had a higher heart rate on admission and a higher rate of patients with LV dysfunction (28% vs. 3%, p = 0.025). Patients who developed symptomatic AF had a higher ADMA level than patients without AF (0.53 vs. 0.43 μmol/L; p = 0.001). Multivariate logistic regression analysis to estimate symptomatic AF occurrence showed that ADMA was independently associated with symptomatic AF (OR: 2.46 [1.21–5.00], p = 0.013) beyond history of AF, LVEF<40% and elevated HR. Conclusion We show that high ADMA level is associated with the occurrence of AF. Although no causative role can be concluded from our observational study, our work further supports the hypothesis that endothelial dysfunction is involved in the pathogenesis of AF in AMI.