• loop diuretics
• HFrEF
• diastolic function
• B-Lines
• acute heart failure
• volume overload.
• pulmonary congestion
• residual congestion
• right ventricle-arterial coupling
• multiparametric echographic evaluation
• lymphatic congestion

Background. Heart Failure (HF) is a clinical syndrome characterized by symptoms and/or signs attributable to structural and/or functional cardiac abnormalities, resulting in increased intra-cardiac pressures and/or inadequate cardiac output at rest and/or during exercise. In patients with HF, homeostatic derangements promote the activation of baroceptors and neurohumoral systems resulting in renal reabsorption of salt and water with progressive accumulation of interstitial compartment fluids. According to Frank-Starling’s principle, the increased pressure within the interstitium leads to a compensatory expansion of intra-vascular volume. Although renal-induced expansion in body water compartments represents a pivotal mechanism of systemic congestion, redistribution of fluids from peripheral to central vascular bed due to sympathetic-mediated veno-constriction has been demonstrated to play an important role in the pathophysiology of volemic status. The increase in intravascular volume, which is an early compensatory strategy to maintain tissue perfusion, is progressively associated with worsening of volume overload, organ congestion, increased cardiac filling pressures (subclinical congestion phase) and eventually results in the development of signs and symptoms of congestion (clinical congestion phase). Nevertheless, current guidelines only recommend daily assessment of signs and symptoms of congestion to manage diuretic therapy in patients with HF. This approach confines the evaluation only to the tip of the congestion iceberg and overlooks the haemodynamic adaptations lying beneath the overt clinical phase. Accordingly, a significant percentage of patients admitted to hospital departments for acute HF (AHF) presents at discharge residual subclinical congestion, which is associated with increased rehospitalization and mortality in the short and long term. A comprehensive multiparametric approach to pulmonary and systemic congestion could be a useful tool to optimize diuretic and fluid management and avoid potential irreversible expansion of intravascular and interstitial compartments, which may be responsible for the recurrent decompensations characterizing “frequent flyers” patients.
Aims. This single-centre, observational, prospective study, is aimed at investigating the association of clinical and instrumental (old and new) parameters with pulmonary decongestion dynamics and residual congestion, including the pathophysiological link between volume overload and electrolyte composition of plasma and urine samples. Moreover, the prognostic value of the main instrumental parameters has been investigated, taking into account a composite end-point of cardiovascular death, HF rehospitalization, urgent unscheduled visit resulting in changes in diuretic therapy and Kansas City Cardiomyopathy Questionnaire (KCCQ) score <30%.
Methods. We enrolled 42 consecutive patients with acute HF (AHF) with reduced LVEF admitted to the Cardiology Department of Pisa University Hospital from June 2022 to September 2022. Patients aged < 18 or > 95 years and/or patients with cardiogenic shock defined according to the diagnostic criteria proposed by ESC 2021 guidelines and/or patients with severe renal impairment (eGFR < 15 mL/min/1.73m2) or on renal replacement therapy by hemodialysis or peritoneal dialysis have been excluded. All the patients underwent serial multiparametric echographic evaluation including: Trans-Thoracic Echocardiography (TTE), Lung ultrasound (LUS) for the evaluation of B-lines, Internal jugular vein (IJV) evaluation (JV diameter-JVD- and JVD ratio), ultrasound evaluation of cervical thoracic duct diameter (TDd) and assessment of renal congestion. Chest X-ray for the measurement of vascular pedicle diameter (VPd) and serum and urinary biomarkers have also been performed serially. Patients have been evaluated at admission (T0), after 24 – 48h from T0 (T1) and at discharge (T2).
Results. The overall population has been divided into 2 groups according to the decongestion dynamics (number of B-lines at admission – number of B-lines at discharge): ∆B-lines > 15 (12/42) and ∆B-lines ≤ 15 (30/42). Compared to those with ∆B-lines > 15, patients with ∆B-lines ≤ 15 displayed a lower improvement in diastolic function [∆E/e’: 2.3 (0 – 4.3) vs 4.5 (4 – 9.8), p=0.02], pulmonary pressures [∆PAPs: 5 mmHg (-1.3 – 8.5 mmHg) vs 11 mmHg (5.3 – 19.8), p= 0.02], right ventricle-arterial coupling [∆TAPSE/PAPs: 0.10 mm/mmHg (0.05 – 0.15 mm/mmHg) vs 0.16 mm/mmHg (0.12 – 0.28), p=0.01] , lymphatic congestion [∆TDd: 0.6 mm (0.4 – 0.8 mm) vs 0.9 (0.7 – 1 mm), p=0.009] and Chest-Xray-based signs of congestion [∆VPd: 4 mm (3.2 – 6.4 mm) vs 7 (5.2 – 9.8 mm), p=0.009]. Moreover, patients with ∆B-lines ≤ 15 showed a more blunted reduction in urinary chloride (Cl) concentration [∆Clu: 29 mEq/L (-1 – 62 mEq/L) vs 79 mEq/L (34 – 97 mEq/L),p=0.03]. Based on the presence of residual pulmonary congestion at T2, we divided the population into 2 groups: B-linesT2 < 10 (21/42) and B-lines T2 ≥ 10 (21/42). At discharge, compared to those without residual pulmonary congestion, patients with B-lines T2 > 10 displayed a more compromised renal function [eGFR: 42 ml/min (27.5-61 ml/min) vs 62 ml/min (44-81 ml/min), p=0.008], higher values of natriuretic peptides [NT-proBNP: 3733 pg/ml (1368.5-12463 pg/ml) vs 1787 pg/ml (1086-3799 pg/ml), p=0.034], inferior vena cava [ IVC: 19 mm (17-23 mm) vs 16 mm (15.5-17.5 mm), p=0.001] and DT [DTd: 2.0 mm (1.7-2.3 mm) vs 1.7 mm (1.6-1.9 mm), p=0.01] diameters, and worse diastolic function [E/e’: 13 (11.5-16.5) vs 11 (9.3-13), p=0.015]. Moreover, lower values of right ventricle-arterial coupling index [TAPSE/PAPs: 0.54 mm/mmHg (0.41-0.61 mm/mmHg) vs 0.67 mm/mmHg (0.53-0.70 mm/mmHg), p=0.02] along with poor IJV distensibility [JVD ratio: 2.3 (2.0-2.5) vs 2.5 (2.4-2.6), p=0.04] and more pronounced ChestXray-based signs of congestion [VPd: 66 mm (57.5-69 mm) vs 57 mm (52-65 mm), p=0.04] have also been observed in patients with residual pulmonary congestion compared to those with B-linesT2 < 10. Using a univariate linear regression model, a significant association have been observed between decongestion dynamics (∆B-lines) and ∆TDd (r=0.54, p< 0.001), ∆E/e’ (r=0.52, p<0.001), ∆TAPSE/PAPs (r=0.43, p=0.005) and ∆Clu (r=0.43, p=0.009). Moreover, at each time-point, the number of B-lines has proven to be linearly associated with DTd (rT0= 0.54, p< 0.001; rT1=0.62, p< 0.001; rT2=0.72, p< 0.001), TAPSE/PAPs (rT0: 0.38, p=0.013, rT2=0.60, p<0.001), E/e’ (rT0: 0.64, p< 0.001, rT1: 0.66, p<0.001, rT2=0.62, p<0.001). At ROC curve analysis, a value of DTd > 2.4 mm has been demonstrated to predict B-lines > 15 with a sensitivity of 63.8% and a specificity of 94% (AUC: 0.863, p<0.001). After a median follow-up of 40 days (IQR: 32 – 63 days), 10 events occurred. At Kaplan-Meier analysis, the presence of residual congestion (B-linesT2 ≥ 10 vs B-linesT2 < 10; p= 0.013), a poor decongestion dynamic (B-linesT2 ≥ 10 + ∆B-lines ≤ 15 vs B-LinesT2 < 10 + ∆B-lines > 15; p= 0.005), a reduced right ventricle-arterial coupling (TAPSE/PAPs ≤ 0.5 mm/mmHg vs TAPSE/PAPs > 0.5 mm/mmHg; p= 0.03) and persistent lymphatic congestion (DTdT2 >2.4 mm vs DTdT2 ≤ 2.4 mm; p< 0.001) have been demonstrated to confer a worse prognosis. Moreover, the independent prognostic value of extravascular lung water at discharge (B-linesT2) have been assessed in a Cox regression multivariate model including, age, BMI, LVEF, GFR and NT-proBNP [Exp(B): 1.13, IC: 1.02 – 1.25, p=0.015].
Conclusion. In patients with acute HFrEF, during diuretic treatment, both left ventricle filling pressures and right ventricle-arterial coupling influence pulmonary congestion dynamic and the likelihood of persistent pulmonary congestion. Moreover, the effect of loop diuretic on urine concentration of Cl seems to reflect the extent of pulmonary decongestion. Lymphatic congestion is strictly associated with pulmonary congestion and can be easily assessed by the ultrasound-based measurement of the diameter of the cervical tract of TD. Persistent pulmonary congestion, poor decongestion dynamics, right ventricle-arterial uncoupling and lymphatic congestion are associated with a higher rate of adverse events in patients with acute HFrEF, with the most powerful independent prognostic value carried out by the number of B-lines at discharge.