Follow Up of acuTe Heart failUre: a pRospective Echocardiographic and Clinical Study (FUTURE)

Acute heart failure (AHF), is defined as rapid onset or rapid worsening of typical signs and symptoms of heart failure (HF), according to the 2016 European Society of Cardiology Guidelines. It is a dangerous clinical condition for patient's life and requires urgent assessment and treatment, which typically lead to the patient's hospitalization. AHF is the first cause of hospitalization in people over 65 in Western countries, accounting for more than 1 million hospitalizations per year in the US. The one-year rehospitalization rate is higher among patients with acute onset of HF rather than among the ones with chronic HF (CHF) (30.7 vs 22.7). In cases of AHF, cardiovascular causes are responsible for readmission in 23.8% of the cases, whereas non-cardiovascular cases accounts for 8.3% of the cases. The rate of rehospitalization in de novo patients is lower than the one observed in subjects with known prior heart failure (8.2% vs 21.4%). In outpatients with CHF, the rehospitalization rate is roughly 22.7%, but only 8.8% is due to a new episode of HF. Our knowledge of the epidemiology of AHF is based primarily on various large-scale registries conducted both in the USA and in Europe. This disease has many repercussions not only in terms of mortality and morbidity, but also in terms of resources and infrastructures necessary for these patients' treatment, which constitutes a high economic burden for the national health care system. Even with growing knowledge and means, nowadays, the prognosis of AHF is still poor and there are no proven therapies that lead to long-term benefits in terms of reduced mortality. A better management of the acute phase of decompensation, including the definition of effective diagnostic-therapeutic workup and the use of innovative drugs, could improve the course of the disease, with positive effects on the patient (gain in survival and reduction of admissions), but also on the community (containment of the overall health costs). Several studies have investigated potential prognostic factors that could help evaluating the risk of cardiovascular events in HF patients, but now there is no accurate and complete prognostic score (that includes anamnestic, clinical, laboratory and echocardiographic parameters), particularly for AHF patients after their admission to the hospital. In recent years, numerous scores have been outlined in various AHF settings, considering only a small number of parameters. The role of echocardiography in the prognostic stratification of HF patients has been extensively studied. Several echocardiographic parameters have been evaluated, such as the dimensions of different cardiac chambers, the diastolic function of both the left (LV) and right ventricle (RV), and LV ejection fraction (LVEF). Several prognostic models have been developed, each of which uses a different combination of variables, suggesting how difficult it is to evaluate the AHF patients' prognosis. All this effort towards the development of so numerous prognostic models is justified by the fact that, despite the evolution of treatments, the risk of rehospitalization and of both intra-hospital mortality and after discharge remains high. LVEF is probably the most studied parameter and has been proven to be an important predictor of short-term and long-term mortality in AHF patients. LV compliance and filling pressures have also been extensively studied through traditional echocardiography. However, available data on the E/e' ratio and its prognostic value in patients with AHF is scarce and often conflicting, in fact some studies have shown that its lack of prognostic value, whereas others suggest that it can identify patients at higher risk of death and hospitalization, if combined to LVEF. Another important parameter to take into account is the systolic pulmonary arterial pressure (PAPs) which has been shown to be an important independent predictor of cardiovascular events. Recently, several studies have included new echocardiographic parameters in the evaluation of these patients' prognosis. Speckle Tracking Echocardiography (STE) is a non-invasive method that allows the assessment of the global and regional ventricular function of both the ventricles and the atria, independently of the angle of insonation. STE is based on the observation that the interaction between the ultrasound beam and the myocardium generates acoustic markers, defined speckle, which can be tracked in their displacement during the cardiac cycle, thanks to a dedicated software. The LV longitudinal strain (LS) represents the myocardial shortening along its longitudinal axis and it is identified by negative curves during systole and by positive ones in diastole. The LS is evaluated in 2-, 3- and 4-chamber apical views: global LS (GLS) is represented by the mean value of the deformation peak of the 18 obtained segments. LS of the RV (RVLS) is obtained in 4-chamber apical view and the segments of interest are 6 (3 for the free wall and 3 for the interventricular septum). Restricting the region of interest to the basal, middle and apical segments of RV free wall, it is possible to analyse the LS of this wall, leaving out the interventricular septum. STE has also been applied to the left atrium (LA) in order to assess its function. Two longitudinal strain parameters of the LA are recognized: the peak atrial LS (PALS), measured at the end of the atrial reservoir phase, and the peak atrial contraction strain (PACS), identified just before the start of the active atrial contraction. In recent years, the application of ultrasounds to the lungs has acquired relevance in the acute setting, in particular in determining the presence of congestion by the analysis of the so-called B lines. The latter represents comet artefacts that originate from the pleural line and they extend vertically towards the bottom of the screen, moving synchronously to the sliding of the lung during the breathing acts. Therefore, despite great effort, to date there are no accurate scores or determinants of short- and medium-term prognosis that allow to improve the management of these patients, keeping also in mind that this would allow the optimization of public spending. The FUTURE study population will prospectively recruit patients who will be admitted to a Coronary Intensive Care Unit or a cardiologic ward for AHF (including both acute exacerbation of chronic heart failure and first episode - de novo; the two populations will be also separately analysed). The basic statistical analysis will evaluate the demographic, clinical and echocardiographic parameters of the study population. The investigation will then focus on the identification of the parameters, among those that were collected, that at the end of the follow up period will be able to predict with greater sensitivity and specificity the risk of re-hospitalization and/or cardiovascular death at 3 and 6 months. A specific prognostic score will be then created from the obtained data, and its field of application would be all hospitalized patients for AHF, in order to predict the short- and medium- term outcome. Furthermore, a statistical sub-analysis will be performed to assess whether the selected prognostic parameters are valid even if the population is divided into 3 groups on the basis of LVEF (as indicated by the ESC guidelines, HFpEF, HFmrEF, HFpEF).

LV dimensions will be measured in parasternal long axis view. LV volumes, LA volume and area will be evaluated in 2- and 4- apical chamber view using the Simpson biplane method as indicated in the ASE recommendations. LV mass will be calculated from the 2D images with the trunk ellipsoid technique. The diastolic phase will be assessed through Pulsed-wave Doppler recordings of trans-mitral flow obtained from the apical 4-chamber view, by placing the sample volume at the level of the valve leaflet tips. Pulsed tissue Doppler imaging (TDI) will be used to measure annular velocities by placing the sample volume at the level of the lateral and septal angle of the mitral annulus from the apical 4-chamber view. Subsequently, the systolic (s'), early diastolic (e') and late (a') diastolic velocities will be obtained by averaging the values obtained. The E/e' ratio will be used as an index of the LV filling pressures. Mitral annulus plane systolic excursion will be assessed using Standard M-mode technique with the cursor placed at the lateral angle of the mitral annulus. From 4-chamber apical view, RV area will be measured both at the end of diastole and at the end of systole. The RV Fractional Area Change will be calculated. Mid-cavity RV linear dimension will be measured halfway between the maximal basal diameter and the apex, at the level of papillary muscles at end-diastole. Sphericity index of the RV will be evaluated as the ratio between the RV late-diastolic diameter and the RV longitudinal axis. RV longitudinal function will be assessed in apical 4-chamber view using TDI at the level of the lateral annulus of the tricuspid valve. The systolic peak velocity (s') will be used as an index of RV longitudinal function together with the tricuspid annulus plane systolic excursion evaluated in M-mode by placing the cursor at the lateral angle of the tricuspid annulus. 2D-STE will be performed from 4- and 2-chamber apical views of the conventional 2D gray-scale images, during a brief breath-hold and with a stable electrocardiographic trace. Particular attention should be paid to the acquisition of an adequate image that allows a clear discrimination of myocardial tissues and extra-cardiac structures. Three consecutive cardiac cycles will be recorded. The frame rate will be set between 40-80 frames/sec. The images acquired in this way will be processed using an appropriate software, with a semi-automatic method of analysing the strain based on the spatial motion of the speckles. The assessment of LV GLS, RV free wall LS and PALS will be performed in accordance to the ASE/EAE Consensus.