Echocardiographic assessment and clinical implication of functional tricuspid regurgitation in heart failure with reduced or preserved ejection fraction (ECLIPSE-HF) : Rationale and design of the study.

PURPOSE: Functional tricuspid regurgitation (FTR) has been shown to be associated with increased morbidity and mortality in several clinical conditions, including heart failure (HF) with reduced left ventricular ejection fraction as well as pulmonary arterial hypertension (PAH). We have designed a study aiming at: characterizing the echocardiographic morphology of the tricuspid valve apparatus and the pathophysiology of FTR in heart failure with reduced, mid-range or preserved left ventricular ejection fraction (HFrEF, HFmrEF, HFpEF) and in PAH patients; correlating the morphologic characteristics of tricuspid valve apparatus with hemodynamic severity of FTR; correlating the severity of FTR with the clinical condition and outcome. METHODS: The study will be a non-interventional, prospective, international, multicenter, longitudinal study (ClinicalTrials.gov Identifier NCT05209919). The minimum number of patients which are expected to be enrolled is 300 HF patients, including HFrEF, HFmrEF and HFpEF patients, whereas 100 PAH patients will serve as control. The patients will be enrolled in 20 centers in Europe, North America and Saudi Arabia. Standard echocardiographic parameters will be analyzed by local investigators; strain measurements will be performed in a single central core-lab. CONCLUSIONS: This study has been designed to improve our understanding of pathophysiological mechanisms and clinical relevance of FTR across all HF phenotypes. The results could potentially allow a more appropriate selection of heart failure patients with FTR for tricuspid valve intervention by percutaneous or surgical repair or replacement.

Assessment of right ventricle in pulmonary arterial hypertension with three-dimensional echocardiography and cardiovascular magnetic resonance.

AIM: To correlate 3-D Echo and CMR RV parameters and to verify whether they are similarly related to the clinical conditions of patients with pulmonary arterial hypertension (PAH), a disease in which the RV plays a crucial prognostic role. METHODS: We enrolled 34 consecutive PAH patients followed by our PAH clinics. All patients underwent a 3-D Echo and CMR assessment of RV volumes and functions in the same day. The presence or absence of correlation between major findings was investigated; functional RV parameters were also analyzed in relation to 6-min walking test (6MWT) results and BNP/Nt-proBNP plasma levels. Twenty-four subjects served as controls. RESULTS: Good agreement was found between 3-D Echo and CMR measures of RV volumes [RV-end-diastolic volume (r = 0.72, P < 0.0001), RV-end-systolic volume (ESV) (r = 0.80, P < 0.0001)] and function [RV-EF (r = 0.73, P < 0.0001), RV-ESV/SV (r = 0.83, P = 0.001)] for all the subjects of the study. These correlations were stronger in PAH patients than in control subjects. Importantly, 3-D Echo and CMR RV-EF and RV to pulmonary arterial coupling (RV-ESV/SV) similarly correlated with BNP/Nt-proBNP levels and with functional capacity measured at 6MWT in the PAH patients group. CONCLUSIONS: 3-D Echo demonstrated a significant agreement with CMR in the assessment of RV volume and function in PAH patients. Both techniques showed a similar correlation with clinical and prognostic parameters. The use of 3-D Echo should be amply boosted in the real-world clinical evaluation of PAH patients.

Prognostic relevance of Doppler echocardiographic re-assessment in HFrEF patients.

BACKGROUND: Current guidelines do not recommend periodically repeating echocardiograms in the follow-up of stable heart failure patients with reduced ejection fraction (HFrEF). The objective of the study was to verify the additional prognostic information provided by a comprehensive re-assessment of their cardiac function and hemodynamic profile at Doppler echocardiography in HFrEF patients. METHODS: Retrospective analysis of 769 stable HFrEF outpatients who underwent two complete echocardiograms, at baseline and at re-assessment. Main candidate predictors of prognosis were: left ventricular (LV) filling pattern, pulmonary artery systolic pressure (PASP) and right ventricular function (TAPSE). Age, LV ejection fraction, mitral regurgitation severity, NYHA class, brain natriuretic peptide plasma levels at baseline, and their changes at 12 months, were used as covariates. Median follow-up was 30 months. All-cause death was the study end-point. RESULTS: At baseline, restrictive filling pattern and low TAPSE were significant predictors of poor prognosis. At re-evaluation, persistently restrictive/worsened filling pattern, persistently-low/worsened TAPSE and worsened PASP, were associated with poorer survival. A significant interaction between changes in TAPSE, PASP and LV filling pattern was observed: in the restrictive pattern subgroup, survival was poorer in worsened/persistently low TAPSE (p < 0.01); in non-restrictive pattern subgroup, survival was poorer in worsened/persistently elevated PASP (p = 0.01). The re-assessment model improved the C-index from 0.69 to 0.74 (P < 0.01) compared to baseline model. CONCLUSIONS: Doppler echocardiographic re-assessment of LV filling pattern, PASP and TAPSE allows a better prognostic stratification of HFrEF outpatients than baseline evaluation and is additional to changes in BNP and NYHA class.

Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension.

BACKGROUND: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores. METHODS: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy. RESULTS: At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7-8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal. CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Echo and BNP serial assessment in ambulatory heart failure care: Data on loop diuretic use and renal function.

We compared the follow-up data on loop diuretic use and renal function, as assessed by serum creatinine levels, and the estimated glomerular filtration rate (eGFR), of two groups of consecutive ambulatory HF patients: 1) the clinically-guided group, in which management was clinically driven based on the institutional protocol of the HF Unit of the Cardiovascular and Thoracic Department of Pisa (standard of care) and 2) the echo and B-type natriuretic peptide (BNP) guided group (patients conforming to the protocol of the Network Labs Ultrasound (NEBULA) in HF Study Group: Pisa, Perugia, Pavia; Verona, Auckland, and Veruno), in which therapy was delivered according to the serial assessment of BNP and echocardiography. Patients whose follow-up was based on standard of care had a significant higher prevalence of worsening renal function, that was likely related to higher diuretic dosages, whilst, a better management of renal function was observed in the echo-BNP-guided group. The data is related to "Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients" (A. Simioniuc, E. Carluccio, S. Ghio, A. Rossi, P. Biagioli, G. Reboldi, G.G. Galeotti, F. Lu, C. Zara, G. Whalley, P.G. Temporelli, F.L. Dini, 2016; K.J. Harjai, H.K. Dinshaw, E. Nunez, M. Shah, H. Thompson, T. Turgut, H.O. Ventura, 1999; A. Ahmed, A. Husain, T.E. Love, G. Gambassi, L.J. Dell׳Italia, G.S. Francis, M. Gheorghiade, R.M. Allman, S. Meleth, R.C. Bourge, 2006) [1], [2], [3].

Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients.

BACKGROUND: B-type natriuretic peptide (BNP) and echocardiography are potentially useful adjunct to guide management of patients with chronic heart failure (HF).Thus, the aim of this retrospective, multicenter study was to compare outcomes and renal function in outpatients with chronic HF with reduced ejection fraction (HFrEF) who underwent an echo and BNP guided or a clinically driven protocol for follow-up. METHODS AND RESULTS: In 1137 consecutive outpatients, management was guided according to echo-Doppler signs of elevated left ventricular filling pressure and BNP levels conforming to the protocol of the Network Labs Ultrasound (NEBULA) in HF Study Group in 570 (mean EF=30%), while management was clinically driven based on the institutional protocol of the HF Unit of the Cardiovascular and Thoracic Department in 567 (mean EF=33%). Propensity score, matching several confounding baseline variables, was used to match pairs based on treatment strategy. The median follow-up was 37.4months. After propensity matching, a lower incidence of death (HR 0.45, 95%CI: 0.30-0.67, p<0.0001), and death or worsening renal function (HR 0.49, 95%CI 0.36-0.67, p<0.0001) was apparent in echo-BNP-guided group compared to clinically-guided group. Worsening of renal function (≥0.3mg/dl increase in serum creatinine) was observed in 9.8% of echo-BNP-guided group and in 21.4% of clinical assessed group (p<0.0001). The daily dose of loop diuretics did not change in echo-BNP-guided group, while it increased in 65% of patients in clinically-guided group (p<0.0001). CONCLUSIONS: Echo and BNP guided management may improve the outcome and reduce worsening of renal function in outpatients with chronic HFrEF.

Tricuspid annular plane systolic excursion and response to cardiac resynchronization therapy: results from the REVERSE trial.

BACKGROUND: The aims of this study were to evaluate tricuspid annular plane systolic excursion (TAPSE) as a predictor of left ventricular (LV) reverse remodeling and clinical benefit of cardiac synchronization therapy (CRT) and to evaluate the effect of CRT on TAPSE in patients with mildly symptomatic systolic heart failure as a substudy of the REsyncronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) trial. METHODS AND RESULTS: Patients (n = 450) were randomized in a 2:1 fashion to CRT ON or CRT OFF and followed for 12 months. End points were reverse LV remodeling defined as a reduction in LV end-systolic volume of ≥20 mL/m(2) by echocardiography and a clinical composite score, defined as freedom from clinical deterioration. TAPSE was an independent predictor of reverse remodeling, OR = 1.08 (95% CI 1.03-1.14) per mm increase and a favorable clinical composite score, OR = 1.08 (95% CI 1.02-1.14). No significant interactions were observed between TAPSE and CRT ON. CRT ON was not associated with a significant effect on TAPSE compared to CRT OFF, -0.8 ± 4.7 vs. 0.3 ± 5 mm, P = .06. CONCLUSION: TAPSE is an independent predictor of clinical response and improved reverse remodeling in patients with mildly symptomatic heart failure. The effect of CRT is not modified by TAPSE in the present population. CRT is not associated with a clinically significant effect on TAPSE.

Echocardiographic dyssynchrony and health status outcomes from cardiac resynchronization therapy: insights from the PROSPECT trial.

OBJECTIVES: This study sought to assess the prognostic utility of echocardiographic dyssynchrony for health status improvement after cardiac resynchronization therapy (CRT). BACKGROUND: Echocardiographic measures of dyssynchrony have been proposed for patient selection for CRT, but prospective validation studies are lacking. METHODS: A prospective cohort of 324 patients from 53 centers with moderate to severe heart failure, left ventricular dysfunction, QRS > or =130 ms, and available echocardiographic and health status information were identified from the PROSPECT (Predictors of Response to Cardiac Re-Synchronization Therapy) trial, which evaluated the prognostic utility of dyssynchrony measures in CRT recipients. The association of 12 echocardiographic dyssynchrony parameters with 6-month improvement in health status, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), was assessed both as a continuous variable and by responder status (DeltaKCCQ > or =+10 points reflecting moderate to large improvement). RESULTS: Of 12 pre-defined dyssynchrony parameters, only 3 were consistently reported: interventricular mechanical delay (IVMD), left ventricular filling time relative to the cardiac cycle (LVFT), and left ventricular pre-ejection interval. After multivariable adjustment, IVMD (+5.18, 95% confidence interval [CI]: +0.76 to +9.60; p = 0.02) and LVFT (+5.19, 95% CI: +0.45 to +0.94; p = 0.03) were independently associated with 6-month improvements in KCCQ. Patients with 6-month improvements in KCCQ had lower subsequent mortality (adjusted hazard ratio [HR] for each 5-point improvement: 0.83; 95% CI: 0.72 to 0.93; p = 0.03). Additionally, IVMD was associated with CRT responder status (for DeltaKCCQ > or =+10 points: odds ratio [OR]: 1.85; 95% CI: 1.12 to 3.05; p = 0.03), whereas LVFT was not (OR: 1.63; 95% CI: 0.85 to 3.11; p = 0.14). Patients classified as health status responders had a 76% lower subsequent risk of all-cause mortality (adjusted HR: 0.24; 95% CI: 0.07 to 0.84; p = 0.03). CONCLUSIONS: The presence of pre-implantation IVMD and LVFT was associated with 6-month health status improvement, and IVMD was associated with a significant CRT response. These echocardiographic factors may help clinicians counsel patients regarding their likelihood of symptomatic improvement with CRT. ( PROSPECT: Predictors of Response to Cardiac Re-Synchronization Therapy; NCT00253357).

Validation of an echo-Doppler decision model to predict left ventricular filling pressure in patients with heart failure independently of ejection fraction.

AIMS: To test a decision model for non-invasive estimation of left ventricular filling pressure (LVFP) in patients with left ventricular (LV) dysfunction and a wide range of ejection fractions (EF). METHODS AND RESULTS: In patients with LV dysfunction (n = 270; EF = 42 +/- 16%), classification and regression tree (CART) analysis was used to generate a model for the prediction of elevated LVFP, defined as pulmonary capillary wedge pressure (PCWP) >15 mmHg, in a derivation cohort (n = 178). At each step of the decision tree, nodes including single or multiple criteria connected by Boolean operators were tested to achieve the best information entropy gain. Averaged mitral-to-myocardial early velocities ratio (E/e') > or =13 OR E-wave deceleration time <150 ms was closely associated with elevated LVFP. Alternatively, prediction of PCWP >15 mmHg needed the following criteria to be satisfied: (i) intermediate E/e' (13 > E/e' > 8); (ii) left atrial volume index >40 mL/m(2) OR ratio of mitral E-wave and colour M-mode propagation velocity >2 OR difference in duration of pulmonary vein and mitral flow at atrial contraction >30 ms; (iii) estimated pulmonary artery systolic pressure >35 mmHg. Patients were correctly allocated according to PCWP with an 87% sensitivity and a 90% specificity. Compared with the best single parameter estimating LVFP, a 17% relative increase in accuracy was achieved in patients with EF >50%. The model was prospectively validated in a testing group (n = 92): 80% sensitivity, 78% specificity. CONCLUSION: This sequential testing is useful to non-invasively predict LVFP in patients with LV dysfunction, especially in those with preserved EF.

Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: In patients with idiopathic pulmonary hypertension (IPAH) progression of the disease and survival are related to the capability of the right ventricle to adapt to the chronically elevated pulmonary artery pressure. Although several echocardiographic variables have been associated with outcome in previous studies, a comparative evaluation of all right ventricular (RV) function indices obtainable at echocardiography has never been performed. METHODS: 59 patients consecutively admitted in a tertiary referral centre because of IPAH (22 males, mean age 46.3+/-16.1 years, 68% in WHO class III/IV at referral) underwent right heart catheterization and echocardiography. During a median follow-up period of 52 months, 21 patients died and 2 underwent lung transplantation in emergency conditions. RESULTS: The following parameters were associated with survival: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, degree of tricuspid regurgitation, inferior vena cava collapsibility, superior vena cava flow velocity pattern, left ventricular diastolic eccentricity index. Patients with TAPSEor=1.7 had the highest event rate (51.7 per 100 person year); patients with TAPSE>15 mm and mild or no tricuspid regurgitation had the lowest event rate (2.6 per 100 person year). CONCLUSIONS: A comprehensive echocardiographic assessment of RV systolic and diastolic function based on TAPSE, left ventricular diastolic eccentricity index and degree of tricuspid regurgitation allows an accurate prognostic stratification of patients with IPAH.