[Prevention of radiotherapy-related cardiotoxicity : benefits of a specialized cardio-oncologic assessment and follow-up]. / Prévention de la cardio-toxicité de la radiothérapie : apport de la prise en charge cardio-oncologique.

To accept the toxic side effects of any treatment, whether medical, surgical or radiotherapeutic, cannot be avoided but implies to evaluate them taking into account the severity and prognosis of the disease that is concerned. Screening, preventing and treatment of these side effects are an integral aspect of the treatment of cancers. We will here review the contribution of the cardio-oncology, a recently emerged medical specialty. Cardiac irradiation cannot be avoided when treating several cancers, most frequently left sided breast cancer. As soon as radiotherapy is considered, it is of prime importance to evaluate each patient's risk factors and to handle them. If technical progresses have led to the complete disappearance of acute side effects of radiotherapy, this is not true for the delayed ones that may occur many years after the irradiation. Hence the need for «red flags¼ and for a systematic follow-up. Cardiac complications of left breast irradiation concern all aspects of cardiology: diseases of cardiac rhythm, valvulopathies, heart failure, coronary and pericardial disorders.

Admettre les effets secondaires d'un traitement, qu'il soit médical, chirurgical ou radiothérapique, est inévitable, mais impose de les évaluer en intégrant la gravité de l'affection pour laquelle ils sont prescrits. Leur dépistage, leur prévention et leur prise en charge font partie intégrante du traitement d'un cancer. Dans cette revue, nous ferons la synthèse de l'apport à cette démarche d'une discipline récente, la cardio-oncologie. L'irradiation cardiaque est incontournable lors du traitement de plusieurs cancers au premier rang desquels le cancer du sein gauche. Dès qu'elle est envisagée, il est essentiel d'évaluer les facteurs de risque de chaque patient et d'organiser leur prise en charge éventuelle. En effet, si les progrès techniques ont permis la disparition des complications cardiaques aiguës de la radiothérapie, ce n'est encore pas le cas des complications différées qui peuvent survenir de nombreuses années après l'irradiation. D'où la nécessité de «drapeaux rouges¼ et d'un suivi régulier systématique. Ces complications, rarement isolées, concernent tous les aspects de la cardiologie : troubles du rythme, valvulopathies, insuffisance cardiaque, maladies coronaires et atteintes péricardiques.

[Secondary prevention of cardiovascular diseases : targeting all the cardiovascular risk factors]. / Prévention secondaire des maladies cardiovasculaires : cibler l'ensemble des facteurs de risque.

This article focuses on the secondary prevention of cardiovascular (CV) diseases, namely the prevention of recurrence in subjects with a personal history of CV event, and the prevention of a first event in patients identified as at very high risk. For all these patients at very high risk, treatment is primarily based on the application of hygienic and dietary measures, including increasing the volume of physical activity, modifying the diet, and obtaining, if necessary, weight loss, as well as stopping smoking. This strategy has proven its benefits in terms of reducing morbidity and mortality. In addition, these patients must receive pharmacological treatment, whose the additional benefits are proven. The article details the pharmacological classes that are currently recommended, as well as the optimal management of CV risk factors and the therapeutic targets to be achieved.

Cet article s'intéresse à la prévention secondaire des maladies cardio-vasculaires (CV), c'est-à-dire la prévention de la récidive chez les sujets ayant une histoire personnelle d'événement CV, et la prévention d'un premier événement chez les patients identifiés comme à très haut risque. Pour tous ces patients à très haut risque, la prise en charge est, avant tout, basée sur l'application de mesures hygiéno-diététiques, incluant l'augmentation du volume d'activité physique, la modification du régime alimentaire et l'obtention si nécessaire d'une perte pondérale, ainsi que l'arrêt du tabac. Cette stratégie a prouvé ses bénéfices en termes de réduction de la morbidité et de la mortalité. En outre, ces patients doivent recevoir un traitement pharmacologique, dont les bénéfices additionnels sont prouvés. L'article détaille les classes pharmacologiques recommandées actuellement, ainsi que la prise en charge optimale des facteurs de risque CV et les cibles thérapeutiques à atteindre.

[Cardio-oncology and cardio-obstetrics : crucial role of a multidisciplinary approach]. / Cardio-oncologie et cardio-obstétrique : importance d'une approche multidisciplinaire.

In this clinical case, we describe the cardio-oncological history and the complexity of the management of a patient presenting a breast cancer diasgnosed during pregnancy followed by a postpartum cardiomyopathy. A multidisciplinary approach is mandatory.

Dans ce cas clinique, nous décrivons l'histoire cardio-oncologique et la complexité de prise en charge d'une patiente présentant un cancer mammaire découvert lors d'une grossesse, puis, une cardiomyopathie du post-partum. Une approche multidisciplinaire s'avère indispensable.

Recurrent cardiac intimal sarcoma misdiagnosed as a myxoma or malignant transformation of a cardiac myxoma?

Cardiac intimal sarcoma is extremely rare and aggressive primary malignant cardiac tumors. Here, we reported the case of a young man initially operated for a tumor of the left atrium, causing a dynamic obstruction of the mitral valve and (mis-)diagnosed as a myxoma at the histopathological analysis. Patient presented a local recurrence at 3 months and was reoperated. Pathology revealed this time the presence of an intimal sarcoma. Patient received adjuvant chemotherapy. Despite a good local control, the 1-year follow-up positron emission tomography scan revealed the presence of a metastasis in the left adrenal gland that was surgically resected. This article aims to highlight the risk of misdiagnosis in case of cardiac tumors, the hypothetical concept of malignant transformation of a cardiac myxoma, the aggressive course of the extremely rare cardiac intimal sarcoma, and the therapeutic modalities available to treat this pathology.

Two-dimensional speckle tracking echocardiography in goats: repeatability, variability, and validation of the technique using an exercise test and an experimentally induced acute ischemic cardiomyopathy.

BACKGROUND: Two-dimensional speckle tracking (2DST) technique has been validated in numerous animal species, but neither studies of repeatability nor measurements after exercise or in animals with cardiac disease have been reported in goats. Goats are an attractive candidate for animal models in human cardiology because they are easy to handle and have a body and heart size comparable to that of humans. Therefore, the aim of this study was to validate this technique in goats for further clinical and experimental applications in this species. RESULTS: This study was divided into several steps. First, a standardized echocardiographic protocol was performed and 5 cineloops of a right parasternal short-axis view at papillary muscles level were recorded three times at one-day intervals in ten healthy adult unsedated Saanen goats to test repeatability and variability of 2DST measurements. Then, the same measurements were performed immediately before and after a standardized exercise on treadmill in seven of the goats, and at 24 h after induction of an experimental ischemic cardiomyopathy in five of the goats, to test the reliability of the technique to assess physiological and pathological changes. Average and regional measurements of radial and circumferential strain and strain rate, radial displacement, rotation and rotation rate were obtained. Comparisons were performed using two-way ANOVA (p < 0.05). Caprine 2DST average measurements have demonstrated a good repeatability with a low to moderate variability for all measurements except for the diastolic peaks of the circumferential strain rate, radial strain rate and rotation rate. Segmental 2DST measurements were less repeatable than average measurements. Time effect of two-way ANOVA was significant for anteroseptal segment diastolic peaks measurements, rotation and rotation rate measurements. Overall variability of segmental measurements was moderate or high. Segmental and average peak values obtained after exercise and after myocardial ischemia were significantly different than curves obtained at baseline. CONCLUSIONS: The results of this study are consistent with those previously described in other animal species and humans. 2DST echocardiography is a valid technique to evaluate physiological and pathological changes in myocardial function in goats, despite the technical limitations observed in this species.

Cardio-Oncology Services: rationale, organization, and implementation.

AIMS: Anticancer therapies have extended the lives of millions of patients with malignancies, but for some this benefit is tempered by adverse cardiovascular (CV) effects. Cardiotoxicity may occur early or late after treatment initiation or termination. The extent of this cardiotoxicity is variable, depending on the type of drug used, combination with other drugs, mediastinal radiotherapy, the presence of CV risk factors, and comorbidities. A recent position paper from the European Society of Cardiology addressed the management of CV monitoring and management of patients treated for cancer. METHODS AND RESULTS: The current document is focused on the basis of the Cardio-Oncology (C-O) Services, presenting their rationale, organization, and implementation. C-O Services address the spectrum of prevention, detection, monitoring, and treatment of cancer patients at risk of cardiotoxicity and/or with concomitant CV diseases. These services require a multidisciplinary approach, with the aims of promoting CV health and facilitating the most effective cancer therapy. CONCLUSION: The expected growing volume of patients with cancer at risk of developing/worsening CV disease, the advent of new technological opportunities to refine diagnosis, and the necessity of early recognition of cancer therapy-related toxicity mandate an integrative multidisciplinary approach and care in a specialized environment. This document from the ESC Cardio-Oncology council proposes the grounds for creating C-O Services in Europe based on expert opinion.

Variations of circulating cardiac biomarkers during and after anthracycline-containing chemotherapy in breast cancer patients.

BACKGROUND: Over time, the chance of cure after the diagnosis of breast cancer has been increasing, as a consequence of earlier diagnosis, improved diagnostic procedures and more effective treatment options. However, oncologists are concerned by the risk of long term treatment side effects, including congestive heart failure (CHF). METHODS: In this study, we evaluated innovative circulating cardiac biomarkers during and after anthracycline-based neoadjuvant chemotherapy (NAC) in breast cancer patients. Levels of cardiac-specific troponins T (cTnT), N-terminal natriuretic peptides (NT-proBNP), soluble ST2 (sST2) and 10 circulating microRNAs (miRNAs) were measured. RESULTS: Under chemotherapy, we observed an elevation of cTnT and NT-proBNP levels, but also the upregulation of sST2 and of 4 CHF-related miRNAs (miR-126-3p, miR-199a-3p, miR-423-5p, miR-34a-5p). The elevations of cTnT, NT-proBNP, sST2 and CHF-related miRNAs were poorly correlated, suggesting that these molecules could provide different information. CONCLUSIONS: Circulating miRNA and sST2 are potential biomarkers of the chemotherapy-related cardiac dysfunction (CRCD). Nevertheless, further studies and long-term follow-up are needed in order to evaluate if these new markers may help to predict CRCD and to identify the patients at risk to later develop CHF.

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity.

Contemporary cancer management has increased the overall number of cancer survivors, but cardiotoxicity remains a subject of concern, which is a major cause of noncancer mortality among survivors. Among the potential cardiovascular complications, left ventricular (LV) systolic dysfunction is a poor prognostic factor. The importance of its early detection is based on the principle that the likelihood of response to heart failure (HF) treatment is temporally related to the initiation of HF treatment. For these reasons, cardiac monitoring is commonly applied in general practice, based on serial measurements of LV ejection fraction (LVEF); transthoracic echocardiography (TTE) is generally used. However, the LVEF, as a diagnostic and predictive parameter, has significant limitations, which calls for more effective multimodality imaging strategies. This approach requires further study, but there is increasing available data in the literature, encouraging the combination of multimodality imaging parameters and techniques for early cancer therapeutic-related cardiac dysfunction (CTRCD) detection.

New biomarkers for primary mitral regurgitation.

BACKGROUND: Mitral regurgitation is a frequent valvular heart disease affecting around 2.5 % of the population with prevalence directly related to aging. Degeneration of mitral valve is broadly considered as a passive ongoing pathophysiological process and little is known about its physiological deregulation. The purpose of this study was to highlight new biomarkers of mitral regurgitation in order to decipher the underlying pathological mechanism as well as to allow the diagnosis and the monitoring of the disease. RESULTS: Modulation of various blood proteins expression was examined in patients suffering from different grades of mitral regurgitation (mild, moderate and severe) compared to healthy controls. To this end, several routine clinical assays and the multi analyte profile technology targeting 184 proteins were used. High-density lipoprotein, apolipoprotein-A1, haptoglobin and haptoglobin-α2 chain levels significantly decreased proportionally to the degree of mitral regurgitation when compared to controls. High-density lipoprotein and apolipoprotein-A1 levels were associated with effective regurgitant orifice area and regurgitant volume. Apolipoprotein-A1 was an independent predictor of severe mitral regurgitation. Moreover, with ordinal logistic regression, apolipoprotein-A1 remained the only independent factor associated with mitral regurgitation. In addition, myxomatous mitral valves were studied by immunocytochemistry. We observed an increase of LC3, the marker of autophagy, in myxomatous mitral valves compared with healthy mitral valves. CONCLUSION: These potential biomarkers of mitral regurgitation highlighted different cellular processes that could be modified in myxomatous degenerescence: reverse cholesterol transport, antioxidant properties and autophagy.

Mild Cardiotoxicity and Continued Trastuzumab Treatment in the Context of HER2-Positive Breast Cancer.

Breast cancer is the leading cause of cancer death in women worldwide. Trastuzumab, the main HER2-targeted treatment, faces limitations due to potential cardiotoxicity. The management of patients with mild cardiotoxicity on trastuzumab remains uncertain, resulting in treatment discontinuation and negative oncological outcomes. This retrospective study analyzed 23 patients who experienced decreased left ventricular function during trastuzumab treatment. During the 18-month follow-up period, two patients (9%) had severe declines in function, leading to treatment cessation, and one patient (4%) developed heart failure symptoms. However, 21 patients showed mild, reversible myocardial dysfunction without significant differences in final ventricular function compared to a control group (58.4% vs. 61.7%, respectively; p = 0.059). The declines in function were most pronounced at nine months but improved at twelve and eighteen months. Various echocardiographic parameters changed significantly over time. As predictors of severe cardiotoxicity, we identified the following: LVEF before initial chemotherapy (p = 0.022), as well as baseline LVEF before treatment with trastuzumab (p = 0.007); initial left ventricular end systolic volume (p = 0.027); and the initial global longitudinal strain (p = 0.021) and initial velocity time integral in the left ventricular outflow track (p = 0.027). In conclusion, the continuation of trastuzumab should be considered for most patients with mild cardiotoxicity, with close cardiac monitoring and cardioprotective measures. However, identifying the patients at risk of developing severe cardiotoxicity is necessary. According to our data, the initial LVEF and GLS levels appear to be reliable predictors.

Left ventricular dyssynchrony: a dynamic condition.

Left ventricular dyssynchrony (LVD) is common in heart failure patients with LV systolic dysfunction. Contrary to what it could be expected, LVD is not a stable phenomenon. Various conditions (inducible ischemia, exercise, drug administration) may significantly alter the presence and the magnitude of LVD, which could per se modulate response to treatment for heart failure. LVD can be evaluated using validated Doppler-echocardiographic techniques as tissue Doppler imaging. Exercise and dobutamine stress echocardiography can be used tests to unmask LVD. Changes in LV synchronicity during stress test occur independently of inducible ischemia and irrespective of QRS width. The degree of LVD varies substantially from patient to patient. The dynamic increase in LVD represents a strong contributor: (1) to exercise-induced changes in mitral regurgitation, (2) to limitation of stroke volume adaptation during exercise, and (3) to exertional dyspnea. Whether dynamic LVD might independently affect the outcome has not yet been demonstrated. In the setting of CRT, the assessment of dynamic LVD might help patient selection, predict the magnitude of response, and optimize pacing delivery during exercise. Further longitudinal studies are required to confirm the value of assessing dynamic LVD.

Animal models of mitral regurgitation induced by mitral valve chordae tendineae rupture.

BACKGROUND AND AIM OF THE STUDY: Mitral regurgitation (MR) is a common valvular disease throughout the world. Various diagnostic techniques have been developed to assess the causes and severity of MR, and the therapeutic approaches to this disease have been widely documented. However, treatments for chronic MR remain controversial, and various animal models of chronic MR (including chordae tendineae rupture, rapid pacing and ischemia) have been developed to study the pathophysiology and therapeutic approaches to this condition. The study aim was to review the animal MR models that have been developed using a mitral valve chordae tendineae rupture technique. METHODS AND RESULTS: Among the animals used for these investigations, dogs and sheep have been most commonly used as models of MR induced by mitral valve chordae tendineae rupture, mainly due to considerations of cardiac size. Chordae tendineae cutting is performed using either closed- or open-chest techniques. In the closed-chest model, long flexible grasping forceps are positioned percutaneously in order to tear the mitral valve chordae. In the open-chest model, cardiopulmonary bypass is performed, and either selected chordae are cut under direct visualization or a non-specified number of chordae are cut, using a metal device inserted through the left ventricular apex. Whichever model is used, MR has been found to become chronic at three to six months after the induction of MR by chordae rupture. The reported mortality and complication rates of these models are high. CONCLUSION: In the long term, the experimental evolution of chronic MR is similar to the evolution occurring naturally in patients suffering from the condition. Hence, these models could be useful in understanding the disease better, and in testing new therapeutic modalities. The present review summarizes the physiological effects of each of these techniques, and compares the advantages and disadvantages of each procedure.

Repeatability, variability and reference values of pulsed wave Doppler echocardiographic measurements in healthy Saanen goats.

BACKGROUND: Pulsed wave (PW) Doppler echocardiography has become a routine non invasive cardiac diagnostic tool in most species. However, evaluation of intracardiac blood flow requires reference values, which are poorly documented in goats. The aim of this study was to test the repeatability, the variability, and to establish the reference values of PW measurements in healthy adult Saanen goats. Using a standardised PW Doppler echocardiographic protocol, 10 healthy adult unsedated female Saanen goats were investigated three times at one day intervals by the same observer. Mitral, tricuspid, aortic and pulmonary flows were measured from a right parasternal view, and mitral and aortic flows were also measured from a left parasternal view. The difference between left and right side measurements and the intra-observer inter-day repeatability were tested and then the reference values of PW Doppler echocardiographic parameters in healthy adult female Saanen goats were established. RESULTS: As documented in other species, all caprine PW Doppler parameters demonstrated a poor inter-day repeatability and a moderate variability. Tricuspid and pulmonary flows were best evaluated on the right side whereas mitral and aortic flows were best obtained on the left side, and reference values are reported for healthy adult Saanen goats. CONCLUSIONS: PW Doppler echocardiography allows the measurement of intracardiac blood flow indices in goats. The reference values establishment will help interpreting these indices of cardiac function in clinical cardiac cases and developing animal models for human cardiology research.

Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency.

BACKGROUND: Valve dysfunction is a common cardiovascular pathology. Despite significant clinical research, there is little formal study of how valve dysfunction affects overall circulatory dynamics. Validated models would offer the ability to better understand these dynamics and thus optimize diagnosis, as well as surgical and other interventions. METHODS: A cardiovascular and circulatory system (CVS) model has already been validated in silico, and in several animal model studies. It accounts for valve dynamics using Heaviside functions to simulate a physiologically accurate "open on pressure, close on flow" law. However, it does not consider real-time valve opening dynamics and therefore does not fully capture valve dysfunction, particularly where the dysfunction involves partial closure. This research describes an updated version of this previous closed-loop CVS model that includes the progressive opening of the mitral valve, and is defined over the full cardiac cycle. RESULTS: Simulations of the cardiovascular system with healthy mitral valve are performed, and, the global hemodynamic behaviour is studied compared with previously validated results. The error between resulting pressure-volume (PV) loops of already validated CVS model and the new CVS model that includes the progressive opening of the mitral valve is assessed and remains within typical measurement error and variability. Simulations of ischemic mitral insufficiency are also performed. Pressure-Volume loops, transmitral flow evolution and mitral valve aperture area evolution follow reported measurements in shape, amplitude and trends. CONCLUSIONS: The resulting cardiovascular system model including mitral valve dynamics provides a foundation for clinical validation and the study of valvular dysfunction in vivo. The overall models and results could readily be generalised to other cardiac valves.

Changes in mitral regurgitation and left ventricular geometry during exercise affect exercise capacity in patients with systolic heart failure.

AIMS: exercise may dramatically change the extent of functional mitral regurgitation (MR) and left ventricular (LV) geometry in patients with chronic heart failure (CHF). We hypothesized that dynamic changes in MR and LV geometry would affect exercise capacity. METHODS AND RESULTS: this study included 30 CHF patients with functional MR who underwent symptom-limited bicycle exercise stress echocardiography and cardiopulmonary exercise testing for quantitative assessment of MR (effective regurgitant orifice; ERO), and pulmonary artery systolic pressure (PASP). LV sphericity index was obtained from real-time three-dimensional echocardiograms. The patients were stratified into exercised-induced MR (EMR; n = 10, an increase in ERO by ≥13 mm(2)) or non-EMR (NEMR; n = 20, an increase in ERO by <13 mm(2)) group. At rest, no differences in LV volume and function, ERO, and PASP were found between the two groups. At peak exercise, PASP and sphericity index were significantly greater (all P < 0.01) in the EMR group. The EMR group revealed lower peak oxygen uptake (peak VO(2); P = 0.018) and greater minute ventilation/carbon dioxide production slope (VE/VCO(2) slope; P = 0.042) than the NEMR group. Peak VO(2) negatively correlated with changes in ERO (r = -0.628) and LV sphericity index (r = -0.437); meanwhile, VE/VCO(2) slope was well correlated with these changes (r = 0.414 and 0.364, respectively). A multivariate analysis identified that the change in ERO was the strongest predictor of peak VO(2) (P = 0.001). CONCLUSION: dynamic changes in MR and LV geometry contributed to the limitation of exercise capacity in patients with CHF.

Impact of global left ventricular afterload on left ventricular function in asymptomatic severe aortic stenosis: a two-dimensional speckle-tracking study.

AIMS: The present study sought to assess the effect of global left ventricular (LV) afterload on LV myocardial systolic function in patients with aortic stenosis (AS) and preserved LV ejection fraction. METHODS AND RESULTS: We prospectively examined the LV myocardial deformation (i.e. longitudinal, radial, and circumferential) by two-dimensional speckle tracking in 173 patients with asymptomatic severe AS. Thirty-eight patients (22%) had low flow as determined by a low stroke volume index (or=5 mmHg mL/m(2)). Systemic arterial compliance (P = 0.001), circumferential myocardial deformation (P = 0.024), and left atrial area index (P = 0.04) were independently associated with increased global LV load in multivariable analysis. Of note, LV ejection fraction was not identified as a determinant of low flow or increased afterload. CONCLUSION: In asymptomatic patients with severe AS, LV ejection fraction markedly underestimates the extent of myocardial systolic impairment. Intrinsic myocardial dysfunction is particularly common in patients with increased global LV afterload, and especially in the subset of patients with low-flow AS.