[Methods of development of recommendations for clinical practice (RCP) and of setting-up of a platform cancer heart vessels (PTF-CHV) in the inter3C Vaucluse-Arles]. / Méthodes d'élaboration des recommandations pour la pratique clinique (RPC) et fonctionnement de la plate forme cœur vaisseaux cancer (PTF-CVC) dans l'inter3C Vaucluse pays d'Arles.

Monitoring and prevention of cardiovascular complications of anti-neoplastic treatment are currently well known for anthracyclines and trastuzumab but remain poorly implemented. The management of cardiac and vascular side effects of targeted therapies is not codified. The purpose of the platform heart-vessel cancer is to optimize the management of such complications within a small area (Vaucluse region of Arles). The platform will offer prescribers an easily accessible database, doctors performing exams standardized monitoring forms and patients a uniform follow-up. We report here the methodology of the elaboration of recommendations for clinical practice and the ways to develop the platform. After a year of active process, an analysis of the will be performed to see opportunities for improvement and dissemination on a larger scale.

C-reactive protein and transesophageal echocardiographic markers of thromboembolism in patients with atrial fibrillation.

BACKGROUND: To determine whether C-reactive protein (CRP) in combination with a stroke risk stratification scheme can help in identifying transesophageal echocardiographic (TEE) markers of thromboembolism such as left atrial (LA)/left atrial appendage (LAA) thrombus, severe LA/LAA spontaneous echocardiographic contrast (SEC), and aortic plaque ≥ 4 mm. METHODS: Transthoracic echocardiography, TEE, and CRP measurement were performed at admission in 178 patients with non-valvular atrial fibrillation not receiving oral anticoagulant therapy. Patients were classified as at low, moderate, or high risk of thromboembolism based on seven clinical risk stratification schemes (SPAF, CHADS(2), Framingham, Birmingham/NICE, ACC/AHA/ESC 2006 guidelines, ACCP 2008, CHA(2)DS(2)VASc). RESULTS: Severe LA/LAA SEC, LA/LAA thrombus, and aortic plaque ≥ 4 mm were present in 6.2%, 6.7%, and 10.1% of patients, respectively. The combination of CRP with a cut-off value of 3.4 mg/L with the Birmingham/Nice or ACC/AHA/ESC 2006 risk score, led to a negative predictive value of 100% in low-risk patients and 91% in moderate-risk patients. For the detection of severe LA/LAA SEC or thrombus, a good discrimination (area under curve ≥ 0.70) using only clinical risk markers was observed for all classifications except for the Framingham and CHADS(2) risk scores. The addition of CRP did not improve the detection of LA/LAA SEC or thrombus, or of severe LA/LAA SEC, thrombus, or aortic plaque. CONCLUSION: The combination of clinical risk markers and CRP can help to exclude the presence of the TEE markers LA/LAA SEC or LA/LAA thrombus, particularly in patients classified at low or moderate risk of stroke.

Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials.

BACKGROUND: Cardiotoxicity of molecular targeted therapies (MTT) is poorly understood and is being investigated among patients with metastatic solid tumours. The frequency of cardiac events among patients receiving MTT has been evaluated in various ways, particularly troponin elevations. PATIENTS AND METHODS: We prospectively evaluated cardiotoxicity among patients included in Phase 1 trials receiving molecular targeted therapies (MTT) for a metastatic solid tumour. At baseline, all patients were examined before the first cycle and monitored including a clinical examination, ECG and troponin I measurement. A trans-thoracic echocardiography was performed at baseline and before each cycle. Patients were enrolled in different trials investigating : an anti-VEGF monoclonal antibody, anti-VEGFR tyrosine kinase inhibitors, and a kinesin inhibitor. RESULTS: Among the 90 patients evaluated, 10 (11%) experienced chest pain and troponin I elevation (n = 2,20%) or asymptomatic troponin I elevation (n = 8, 80%) during follow-up. All patients were re-evaluated at the time of symptoms or troponin I elevation with trans-thoracic echocardiography, cardiac magnetic resonance and coronary angiography. All except one patient, had a normal LVEF during their re-evaluation. One patient exhibited ECG changes (T wave inversion). No QTc interval prolongation was found. On cardiac magnetic resonance, no late gadolinium myocardial enhancement was observed. All coronary angiographies were normal (no occlusion, or coronary stenosis >50%). All patients received beta blockers and aspirin. All Patients were re-challenged with the study drug and no cardiotoxicity was observed during follow up. CONCLUSION: Troponin elevations are frequent among patients receiving molecular targeted therapies. Re-challenging these patients after a careful evaluation and under medical treatment seems to be possible. The mechanism underlying troponin elevations does not seem to be associated with coronary occlusion nor with toxic myocarditis.

Cardiac side effects of molecular targeted therapies: towards a better dialogue between oncologists and cardiologists.

Molecular targeted therapies (MTTs) have become a major component of modern management of various hematological and solid malignancies. However, some MTTs have been associated with cardiotoxicity. MTT-induced cardiovascular side effects include left ventricular systolic dysfunction, heart failure, conduction abnormalities, acute coronary syndrome, and hypertension. One of the most threatening complications of MTT, and notably of angiogenic inhibitors, is QT prolongation with the risk of torsades de pointe and sudden death. The precise incidence of cardiovascular events associated with MTT as well as their reversibility are unknown. Here, we summarize what is known about the cardiotoxicity of MTT, emphasizing MTTs that target tyrosine kinases. We have tried to provide both the basic mechanisms underlying specific cardiotoxicities (such as the interruption of specific signaling pathways leading to cardiomyocyte dysfunction and/or death), and offer guidance regarding the optimal way to detect and treat these cardiotoxicities.

Factors influencing the level of circulating procoagulant microparticles in acute pulmonary embolism.

BACKGROUND: Flow cytometry has shown levels of platelet-derived microparticles (PMPs) and endothelial-derived microparticles (EMPs) to be elevated in deep-vein thrombosis. Cardiovascular risk factors can also contribute to hypercoagulability due to circulating procoagulant microparticles (CPMPs). AIMS: To investigate in a case-control study the respective contribution of pulmonary embolism and cardiovascular risk factors to the level of hypercoagulability due to CPMPs. METHODS: CPMP, PMP and EMP levels were measured in 45 consecutive patients (age 67.9 +/- 11.6 years; 66.7% men) admitted to an intensive care unit for acute pulmonary embolism (APE), 45 healthy control subjects with no history of venous thromboembolism or vascular risk factors (Controls(noCVRFs)), and 45 patients with cardiovascular risk factors (Controls(CVRFs)). APE was diagnosed by spiral computed tomography or scintigraphy. CPMP levels were assessed using a prothrombinase assay on platelet-depleted plasma (results expressed as nmol/L equivalent). RESULTS: CPMP levels were higher in APE patients than in Controls(noCVRFs) (medians 4.7 vs 3.2 nmol/L, interquartile ranges [IQRs] 2.9-11.1 vs 2.3-4.6 nmol/L; p=0.02). Similar results were reported for PMPs (medians 2.2 vs 1.9 nmol/L, IQRs 1.7-5.8 vs 1.4-2.4 nmol/L; p=0.02), whereas EMP levels were not significantly different. However, CPMP procoagulant activity was not significantly different in APE patients and Controls(CVRFs). CONCLUSIONS: CPMPs and PMPs were significantly elevated in APE patients vs Controls(noCVRFs), but this correlation was not significant when APE patients were compared with Controls(CVRFs). Our observations highlight the importance of adjusting for the presence of cardiovascular risk factors in conditions in which microparticle levels are raised.

Should all patients with non-valvular atrial fibrillation be anticoagulated?

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. The prevalence and incidence of AF are rising, as confirmed in several European and American registries. Guidelines published in 2008 from the European Society of Cardiology/American Heart Association and from the American College of Chest Physicians, clarified the strategy of antithrombotic treatment in AF, which is based on the presence of risk factors for thromboembolism. This approach allows physicians to classify patients as at low, moderate or high risk, according to their individual risk characteristics, which are relatively similar in both sets of recommendations. Patients at moderate risk, however, who might justify anticoagulant or antiplatelet treatment, could be better characterized using morphological (echocardiographic) and/or biological factors or risk markers. Recent data have shown that the existence of a thrombogenic milieu in the left atrium (e.g., dilatation of the left atrial appendage and/or thrombus and/or spontaneous echocontrast and/or reduced emptying/filling flow velocity) indicates a higher risk of embolism and mortality. Furthermore, high-sensitivity C-reactive protein and haemostasis markers of coagulation are associated with thromboembolic risk and excess mortality in AF. Although current recommendations for the management of AF are not based on such markers, both could help physicians choose the optimal antithrombotic treatment (either vitamin K antagonists or antiplatelet drugs) according to the patient's specific risk profile. Nowadays, registries confirm under-prescription of vitamin K antagonist treatment in the 'real world,' even in patients at high thromboembolic risk, and over-prescription for at least one-third of low-risk patients. It is crucially important to realize that the risk of bleeding in patients with risk factors (e.g., older age, hypertension) is close to the risk of thromboembolism, which can have devastating outcomes in patients in AF. Alternative and efficient strategies (new oral anticoagulants, non-surgical closure of the left atrial appendage using percutaneous devices) are currently under investigation. Therefore reducing the risk of thromboembolism should be physicians' primary aim, particularly with the advent of alternative treatments and the development of new antithrombotic drugs such as oral thrombin and factor Xa inhibitors, which are currently being evaluated in clinical trials.

Circulating procoagulant microparticles in acute pulmonary embolism: a case-control study.

We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagulability in 45 patients with acute pulmonary embolism (APE) and in 45 controls with and 45 controls without cardiovascular risk factors. Concentrations of CPMPs and platelet-derived microparticles (PMPs) were statistically significantly higher in patients with APE than in controls without cardiovascular risk factors. PMPs appeared to be the main source of procoagulant microparticle release in APE, but this correlation disappeared when APE patients were compared to controls with cardiovascular risk factors. CPMPs may have a role in venous thrombosis as mediators of cardiovascular risk factors.

QT interval prolongation among patients treated with angiogenesis inhibitors.

Among toxicities associated with molecular targeted agents (MTA), cardiovascular toxicities remain largely unknown or underestimated. Their frequency is variable and dependent on the compound. A high incidence of hypertension, symptomatic or asymptomatic left ventricular systolic dysfunction, acute coronary syndrome, arterial and venous thrombosis has been observed in patients receiving MTA. One of the most threatening complications of angiogenic inhibitors (AI) could be QT prolongation with the risk of torsade de pointes (TdP) and sudden death. QT prolongation and torsade de pointes accounted for 29% of cardiac and non-cardiac post-marketing withdrawals. The assessment of the effects of drugs on cardiac repolarization is the subject of recent guidelines and recommendations. Regulatory agencies now require practically every new pharmaceutical compound to undergo a thorough investigation of its propensity to modify cardiac repolarization. To reduce the incidence of QT prolongation and torsade de pointes in patients receiving AI, cancer patients should be closely monitored while receiving AI.

Is the aortic root dilated in obstructive sleep apnoea syndrome?

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) is associated with an increased risk of arterial hypertension (AH), coronary artery disease, atrial arrhythmias, heart failure, stroke and death. Whether OSAS influences aortic root size has not been fully investigated. The aim of our study was to investigate aortic root diameter and aortic stiffness in OSAS. METHODS: Using transthoracic Doppler echocardiography, we evaluated 76 patients with OSAS (mean age 52.7 +/- 9.5 years, 70 men [92%]) with no overt cardiovascular disease. The following parameters were measured offline: aortic diameter at Valsalva sinuses, aortic regurgitation (AR) grade, left ventricular (LV) mass, LV ejection fraction (LVEF, Simpson rule), systolic pulmonary artery pressure (sPAP). Aortic stiffness (carotid-femoral pulse wave velocity, PWV) was measured non-invasively using SphygmoCor technology. RESULTS: Mean duration of OSAS was four years and 84% of patients were being treated with continuous positive airway pressure. AH was documented in 39 (51%) patients. The mean aortic root diameter was 35.3 +/- 3.8 mm (26.9-44.6 mm) and the prevalence of aortic root dilatation was 3.9% (3 of 76 patients). On univariate analysis, age and sex were significant predictors of aortic root dilatation whereas arterial hypertension was not. CONCLUSIONS: The prevalence of aortic root enlargement was not increased in OSAS. Only age and sex and not arterial hypertension, were associated with aortic dilatation.

Triage patients with suspected pulmonary embolism in the emergency department using a portable ultrasound device.

The diagnosis of pulmonary embolism (PE) is difficult, despite validated diagnostic models. We sought to determine the value of a portable ultrasound device for triage of patients with suspected PE referred to the emergency department, using simplified echo criteria. We prospectively studied 103 consecutive patients with suspected PE, referred to our emergency department. After D-dimer screening, 76 patients were prospectively enrolled in this ultrasound study and underwent helical chest tomography, transthoracic echocardiography, and venous ultrasonography. Among patients with PE (n = 31), a right ventricular dilation was detected in 17 patients (55%), a direct visualization of clot in the lower limbs was present in 18 patients (58%), and 8 patients (26%) had both right ventricular dilation and deep venous thrombosis. The sensitivity and specificity of a combined ultrasound strategy using echocardiography and venous ultrasonography were respectively 87% (95% confidence interval 74% to 96%), and 69% (95% confidence interval 53% to 82%). The sensitivity of this combined strategy was significantly improved as compared to venous ultrasonography alone (P = 0.01) or echocardiography alone (P = 0.005). In patients with dyspnea or with high clinical probability of PE, this combined strategy was particularly relevant with high sensitivities (respectively 94% and 100%). Echocardiography combined with venous ultrasonography using a portable ultrasound device is a reliable method for screening patients with suspected PE referred to an emergency department, especially in patients with dyspnea or with high clinical probability.