Aurélie Gudjoncik

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.

Outcomes After Acute Myocardial Infarction in HIV-Infected Patients Analysis of Data From a French Nationwide Hospital Medical Information Database

Background— We aimed to assess in-hospital case fatality and 1-year prognosis in HIV-infected patients with acute myocardial infarction. Methods and Results— From the PMSI (Program de Medicalisation des Systemes d’informatique) database, data from 277 303 consecutive acute myocardial infarction patients hospitalized from January 1, 2005, to December 31, 2009, were analyzed. Surviving patients were followed up for 1 year after discharge. HIV-infected patients were compared with uninfected patients. Among the cohort, HIV-infected patients (n=608) accounted for 0.22%. All-cause hospital and 1-year mortality rates were lower in the HIV-infected group than in uninfected patients (3.1% versus 8.1% [ P <0.001] and 1.4% versus 5.5% [ P <0.001], respectively). From the database, we then analyzed a cohort derived from a matching procedure, with 1 HIV patient matched with 2 patients without HIV, based on age and sex (n=1824). Ischemic cardiomyopathy was more frequent in the HIV group (7.6% versus 4.2%, P =0.003). Hospitalization and 1-year mortality rates were similar in the 2 groups (3.1% versus 2.1% [ P =0.168] and 1.4% versus 1.7% [ P =0.642], respectively). However, at 12 months, hospitalizations for episodes of heart failure were significantly more frequent in HIV-infected than in uninfected patients (3.3% versus 1.4%, respectively; P =0.020). HIV infection, diabetes mellitus, history of ischemic cardiomyopathy, and undergoing percutaneous coronary intervention were associated in univariate analysis with occurrence of heart failure. By multivariable analysis, HIV infection (odds ratio 2.82, 95% confidence interval 1.32–6.01), diabetes mellitus, and undergoing percutaneous coronary intervention remained independent predictors of heart failure. Conclusions— The present study demonstrates that after acute myocardial infarction, HIV status influences long-term risk, although the short-term risk in HIV patients is comparable to that in uninfected patients. # Clinical Perspective {#article-title-41}Background— We aimed to assess in-hospital case fatality and 1-year prognosis in HIV-infected patients with acute myocardial infarction. Methods and Results— From the PMSI (Program de Medicalisation des Systèmes d’informatique) database, data from 277 303 consecutive acute myocardial infarction patients hospitalized from January 1, 2005, to December 31, 2009, were analyzed. Surviving patients were followed up for 1 year after discharge. HIV-infected patients were compared with uninfected patients. Among the cohort, HIV-infected patients (n=608) accounted for 0.22%. All-cause hospital and 1-year mortality rates were lower in the HIV-infected group than in uninfected patients (3.1% versus 8.1% [P<0.001] and 1.4% versus 5.5% [P<0.001], respectively). From the database, we then analyzed a cohort derived from a matching procedure, with 1 HIV patient matched with 2 patients without HIV, based on age and sex (n=1824). Ischemic cardiomyopathy was more frequent in the HIV group (7.6% versus 4.2%, P=0.003). Hospitalization and 1-year mortality rates were similar in the 2 groups (3.1% versus 2.1% [P=0.168] and 1.4% versus 1.7% [P=0.642], respectively). However, at 12 months, hospitalizations for episodes of heart failure were significantly more frequent in HIV-infected than in uninfected patients (3.3% versus 1.4%, respectively; P=0.020). HIV infection, diabetes mellitus, history of ischemic cardiomyopathy, and undergoing percutaneous coronary intervention were associated in univariate analysis with occurrence of heart failure. By multivariable analysis, HIV infection (odds ratio 2.82, 95% confidence interval 1.32–6.01), diabetes mellitus, and undergoing percutaneous coronary intervention remained independent predictors of heart failure. Conclusions— The present study demonstrates that after acute myocardial infarction, HIV status influences long-term risk, although the short-term risk in HIV patients is comparable to that in uninfected patients.

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.

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.

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.

Relationship Between Fragmented QRS and No-Reflow, Infarct Size, and Peri-Infarct Zone Assessed Using Cardiac Magnetic Resonance in Patients With Myocardial Infarction

BACKGROUND The relation between fragmented QRS complex (fQRS) and cardiac magnetic resonance parameters is poorly documented in ischemic cardiopathy. METHODS Among 209 consecutive patients, those with fQRS were compared with those without fQRS. Cardiac magnetic resonance studies with late gadolinium-enhanced sequences were done during the week after acute myocardial infarction. RESULTS fQRS was present in 113 (54%) patients, and associated with a significantly lower left ventricular ejection fraction, increased left ventricular volumes, a larger infarct size (IS), and a larger peri-infarct zone. Microvascular obstruction was more frequent in patients with fQRS (62% vs 45%; P = 0.014) and the extent of the microvascular obstruction was significantly larger (1.6% [range, 0.0-4.4] vs 0.0 [range, 0.0-2.1]; P = 0.004). Finally, the transmurality score in the 2 study populations was identical (48% vs 47%; P = 0.895). In multivariate logistic regression analysis, only IS (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09; P < 0.001), systolic blood pressure (OR, 1.02; 95% CI, 1.01-1.04; P < 0.001), and left ventricular end-systolic volume (OR, 1.02; 95% CI, 1.00-1.03; P = 0.013) remained independent predictors of fQRS. CONCLUSIONS This study revealed that fQRS was associated with increased IS, myocardial perfusion abnormalities, decreased left ventricular ejection fraction, and increased left heart volumes. These findings show that fQRS is a reliable marker of infarct size and acute ventricular remodelling.

Prognosis of silent atrial fibrillation after acute myocardial infarction at 1-year follow-up

Background Silent atrial fibrillation (AF), assessed by continuous ECG monitoring (CEM), has recently been shown to be common in acute myocardial infarction (AMI), and associated with higher hospital mortality. However, the long-term prognosis is still unknown. We aimed to assess 1-year prognosis in patients experiencing silent AF in AMI. Methods All consecutive patients with AMI who were prospectively analysed by CEM during the first 48 h after admission and who survived at hospital discharge were included. Silent AF was defined as asymptomatic episodes lasting at least 30 s. Patients were followed up at 1 year for cardiovascular (CV) outcomes. Results Among the 737 patients analysed, 106 (14%) developed silent AF and 32 (4%) symptomatic AF. Compared with the no-AF group, patients with silent AF were markedly older (79 vs 62 years, p<0.001), more frequently hypertensive (71% vs 49%, p<0.001) and less likely to be smokers (23% vs 37%, p<0.001). Also, they were more likely to have impaired LVEF (50% vs 55%, p<0.001). Risk factors in patients with silent AF were similar to those in patients with symptomatic AF. However, a history of stroke or AF was less frequent in silent AF than in symptomatic-AF patients (10% vs 25% and 10% vs 38%, respectively). At 1 year, CV events including hospitalisation for heart failure (HF) and CV mortality were markedly higher in silent-AF patients than in no-AF patients (6.6% vs 1.3% and 5.7% vs 2.0%, p<0.001, respectively). Conclusions Our large prospective study showed for the first time that silent AF is associated with worse 1-year prognosis after AMI. Systematic screening and specific management should be investigated in order to improve outcomes of patients after AMI.

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.

Smokeless tobacco, sport and the heart

Smokeless tobacco (snuff) is a finely ground or shredded tobacco that is sniffed through the nose or placed between the cheek and gum. Chewing tobacco is used by putting a wad of tobacco inside the cheek. Smokeless tobacco is widely used by young athletes to enhance performance because nicotine improves some aspects of physiology. However, smokeless tobacco has harmful health effects, including cardiovascular disorders, linked to nicotine physiological effects, mainly through catecholamine release. Nicotine decreases heart rate variability and the ventricular fibrillation threshold, and promotes the occurrence of various arrhythmias; it also impairs endothelial-dependent vasodilation and could therefore promote premature atherogenesis. At rest, heart rate, blood pressure, inotropism, cardiac output and myocardial oxygen consumption are increased by nicotine, leading to an imbalance between myocardial oxygen demand and supply. The same occurs at submaximal levels of exercise. These increases are accompanied by a rise in systemic resistances. At maximal exercise, heart rate, cardiac output and maximal oxygen uptake (V˙O2max) are unaffected by nicotine. Because endothelial dysfunction is promoted by nicotine, paradoxical coronary vasoconstriction may occur during exercise and recovery. Nicotine induces a decrease in muscular strength and impairs anaerobic performance. However, nicotine is used in sports as it diminishes anxiety, enhances concentration and agility, improves aerobic performance and favours weight control. Importantly, smokeless tobacco, similar to cigarette smoking, leads to nicotine dependence through dopaminergic pathways. Smokeless tobacco has harmful cardiovascular effects and is addictive: it fulfils all the criteria for inclusion in the World Anti-Doping Agency prohibited list as a doping product. Smokeless tobacco use in sporting activities must be discouraged.