Olivier Hachet

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.

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.

Frequency and Predictors of Stroke After Acute Myocardial Infarction Specific Aspects of In-Hospital and Postdischarge Events

Background and Purpose— Stroke is a serious complication after acute myocardial infarction (AMI) and is closely associated with decreased survival. This study aimed to investigate the frequency, characteristics, and factors associated with in-hospital and postdischarge stroke in patients with AMI. Methods— Eight thousand four hundred eighty-five consecutive patients admitted to a cardiology intensive care unit for AMI, between January 2001 and July 2010. Stroke/transient ischemic attack were collected during 1-year follow-up. Results— One hundred twenty-three in-hospital strokes were recorded: 65 (52.8%) occurred on the first day after admission for AMI, and 108 (87%) within the first 5 days. One hundred six patients (86.2%-incidence rate 1.25%) experienced in-hospital ischemic stroke, and 14 patients (11.4%-incidence rate 0.16%) were diagnosed with an in-hospital hemorrhagic stroke. In-hospital ischemic stroke subtypes according to the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification showed that only 2 types of stroke were identified more frequently. As expected, the leading subtype of in-hospital ischemic stroke was cardioembolic stroke (n=64, 60%), the second was stroke of undetermined pathogenesis (n=38, 36%). After multivariable backward regression analysis, female sex, previous transient ischemic attack (TIA)/stroke, new-onset atrial fibrillation, left ventricular ejection fraction (odds ratio per point of left ventricular ejection fraction), and C-reactive protein were independently associated with in-hospital ischemic stroke. When antiplatelet and anticoagulation therapy within the first 48 hours was introduced into the multivariable model, we found that implementing these treatments (≥1) was an independent protective factor of in-hospital stroke. In-hospital hemorrhagic stroke was dramatically increased (5-fold) when thrombolysis was prescribed as the reperfusion treatment. However, the different parenteral anticoagulants were not predictors of risk in univariable analysis. Finally, only 45 postdischarge strokes were recorded. Postdischarge stroke subtypes showed a more heterogeneous distribution of mechanisms. The annual rate of stroke post-AMI remained stable throughout the 10-year study period. Conclusions— The present study describes specific predictors of in-hospital and postdischarge stroke in patients with AMI. It showed a marked increase in the risk of death, both during hospitalization and in the year after AMI. After hospital discharge, stroke remains a rare event and is mostly associated with high cardiovascular risk.

Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney injury after cardiac bypass surgery

BACKGROUND Pre-operative GDF-15 plasma levels significantly improve the prognostic value of the EuroSCORE for mortality after cardiac surgery. However, despite the strong correlation between GDF-15 and renal function, no data are available regarding the potential interest of pre-operative GDF-15 levels to improve the prediction of acute kidney injury (AKI) after cardiac artery bypass graft (CABG) surgery. METHODS All patients operated on by 2 surgeons for CABG surgery at our university hospital from September 2011 to March 2013 were screened for participation in this prospective, observational study. EXCLUSION CRITERIA age <18years or >80years, previous atrial fibrillation/flutter, previous severe renal failure, previous cardiac surgery, emergency surgery. AKI was defined according to KDIGO criteria. GDF-15 levels in plasma were measured before induction and 12h after surgery. RESULTS 134 patients were included in this study. 42 (31%) developed post-operative AKI. AKI patients had a significantly higher pre-operative log-GDF-15 level (OR=3.64; 95% CI=1.41-9.40, p=0.008), a lower pre-operative eGFR (OR=0.98; 95% CI=0.96-0.99; p=0.026), and most often underwent on-pump surgery (OR=2.60; 95% CI=1.14-5.96, p=0.024). On ROC curves, GDF-15 before induction was found to be the best pre-operative biomarker to predict AKI (AUC=0.83; CI=0.75-0.89), compared with eGFR (AUC=0.67; 95% CI=0.59-0.75), p=0.003 and NT-proBNP (AUC=0.62; CI=0.51-0.72), p<0.001. Pre-operative GDF-15 was also significantly better than the EuroSCORE in predicting AKI (AUC 0.62, 95% CI=0.54-0.70), p<0.001. CONCLUSIONS Pre-operative GDF-15 plasma levels are associated with post-operative AKI in CABG patients. If confirmed in larger cohorts, pre-operative GDF-15 may be of value to improve pre-operative risk stratification among candidates for surgery.

Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice

We aimed to determine whether moderate diet restriction could restore cardiac, oxidative and metabolic alterations induced by postnatal overfeeding (PNOF). Litters of C57BL/6 male mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce PNOF. At 6 months, half of the NL and SL mice were subjected to 20% calorie-restriction (CR: NLCR, SLCR) for one month, while the other half continued to eat ad libitum (AL: NLAL, SLAL). Six-month old SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance, increased cardiac ROS production and decreased left ventricular ejection fraction (LVEF). After CR, SL mice body weight was normalized; however, their fat mass and leptinemia were not decreased, glucose metabolism was improved and LVEF was increased. In SL mice, CR increased the cardiac mitochondrial respiratory rate and decreased cardiac ROS production. Hearts from SLCR mice showed better recovery and smaller postischemic infarct size. Intriguingly, no difference was observed between NLAL and NLCR mice for most of the parameters investigated. Short-term moderate CR not only normalized body weight in SL mice but also improved metabolic programming and reversed oxidative and cardiac dysfunction induced by PNOF.

Observance aux traitements: concepts et déterminants

Resume L’observance aux traitements prescrits pour les maladies chroniques represente un enjeu majeur de sante publique dans le monde. De plus, dans son dernier rapport, l’organisation mondiale de la sante (OMS) soulignait que la mauvaise adherence aux traitements de longue duree est un probleme qui ne fait que croitre ; En effet, un certain nombre d’evaluations rigoureuses, analysees par l’OMS, ont etabli que, dans les pays developpes, la proportion de malades chroniques respectant leur traitement n’etait que de 50 % et tout porte a croire qu’elle est bien plus faible dans les pays en voie de developpement. Pour exemple, en Gambie, en Chine et aux Etats-Unis, seuls, respectivement, 27 %, 43 % et 51 % des patients suivent correctement le schema therapeutique qui leur a ete prescrit pour l’hypertension arterielle. De plus, des tendances similaires pour d’autres pathologies ont ete observees, comme la depression (de 40 a 70 %), l’asthme (43 % pour le traitement d’attaque et 28 % pour le traitement d’entretien) et le VIH/SIDA (de 37 a 83 %). Enfin, la non-observance ne fera que s’amplifier a mesure que la charge mondiale des maladies chroniques va croitre, mais un point fondamental est que l’amelioration de l’observance ne mettra pas en peril les budgets de la sante, bien au contraire. En effet, le respect des traitements prescrits entrainera une baisse significative des depenses, grâce a la diminution du nombre des interventions couteuses, comme les hospitalisations prolongees et frequentes, les soins d’urgence ou les soins intensifs. Parallelement, les professionnels de sante constatent le besoin d’ameliorer l’observance des traitements prescrits, et si le systeme de sante est partiellement responsable de la situation, il est clair que par manque de formation, les equipes de soins n’apportent pas une aide suffisante aux patients. Aussi, une approche multidisciplinaire en vue de l’adhesion est necessaire pour permettre une action coordonnee de tous les professionnels de la sante.

Incremental predictive value of mean platelet volume/platelet count ratio in in-hospital stroke after acute myocardial infarction

Abstract Stroke is a serious complication after acute myocardial infarction (AMI) and is associated with an increased risk of death. Though the pathophysiological mechanisms are not exactly known, increased inflammation and platelet reactivity could play an important role in the occurrence of stroke during AMI. We aimed to investigate the relationship between both mean platelet volume (MPV), a parameter of platelet function, and C-reactive protein (CRP) and the occurrence of in-hospital ischemic stroke (IHS) after AMI. Data were obtained from a French regional survey for AMI that included 5976 patients admitted to an intensive care unit (ICU) between 2001 and 2010. Patients were divided into two groups according to the occurrence of IHS. MPV, platelet count (PC), and CRP were routinely measured at admission to the ICU; 99 (1.6%) IHSs were recorded during hospitalization after admission for AMI. In multivariate analysis, IHS was independently associated with a history of stroke (OR: 1.99%, CI: 1.1–3.49, p = 0.01), impaired left ventricular ejection fraction <40% (OR: 1.88, 95% CI: 1.20–2.94, p = 0.006), impaired renal function (OR: 1.94, 95% CI: 1.27–2.95, p = 0.002), CRP > 10 mg/l (OR: 2.19, 95% CI: 1.44–3.33, p < 0.001), and MPV/PC ratio (OR: 1.04, 95% CI: 1.01–1.08, p = 0.023). Compared with the first to fourth quintiles, the last quintile of the MPV/PC ratio was associated with higher rates of IHS on survival curve analysis (p = 0.014). At hospital admission, a high MPV/PC ratio and a high level of CRP might help to identify patients at increased risk of IHS. Moreover, these results provide new insights into the potential role played by increased inflammation and platelet reactivity in the occurrence of stroke after AMI.

0004 : Overweight in mice induced by perinatal programming exacerbates doxorubicin and trastuzumab cardiotoxicity

Purpose Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.

0132 : Oxidative stress and cardio-metabolic alterations induced by postnatal programming can be reversed in adulthood by a short-term moderate caloric restriction

Postnatal overfeeding (PNOF) in rodents induces early programming of cardio-metabolic risk. Our aim was to determine if a moderate diet restriction could restore cardio-metabolic alterations induced by PNOF. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) to induce PNOF. At weaning, all mice received a standard diet ad libitum (AL). At 6 month of age, half of the NL and SL mice were assigned to a moderate 20% calorie restriction (CR: NLCR, SLCR) for one month, while the other mice continued to eat AL (AL: NLAL, SLAL). Glucose and insulin tolerance tests, cardiac function (echocardiography), body composition (Echo-MRI), cardiac sensitivity to ischemia-reperfusion injury, mitochondrial function, reactive oxygen species (ROS) generation (EPR spectroscopy) and insulin signaling were assessed before and/or after one month of CR. Adult SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance and decreased left ventricular ejection fraction (LVEF). After one month of moderate CR, body weight of SLCR was normalized to this of NLAL however their fat mass and leptinemia were not decreased. Glucose metabolism was improved and LVEF was increased In SLCR. After 30 min of global ischemia, hearts isolated from SLCR mice showed better recovery and smaller infarct size than this of others groups. CR increased the cardiac mitochondrial respiratory rate in SLCR mice whereas cardiac ROS production was significantly decreased in SLCR mice. Insulin signaling in heart was affected neither by PNOF nor by CR. Intriguingly, no difference was observed in NLCR mice for most of the parameters investigated. Our results confirmed the programming of early overfeeding on metabolic and cardiac function. A short-term moderate CR in not only normalized body weight in SL mice but also ameliorate the metabolic programming and reverse the cardiac dysfunction induced by PNOF. The author hereby declares no conflict of interest