Circulating miRNA in functional tricuspid regurgitation. Unveiling novel links to heart failure: A pilot study.

AIM: Severe functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, particularly heart failure (HF) and mortality. MicroRNAs (miRNAs) have been recently identified as novel biomarkers in different cardiovascular conditions, but no studies have focused on FTR. We sought to (1) to identify and validate circulating miRNAs as regulators of FTR and (2) to test association of miRNA with heart failure and mortality in FTR. METHODS AND RESULTS: Consecutive patients with isolated severe FTR (n = 100) evaluated in the outpatient Heart Valve Clinic and age- and gender-matched subjects with no TR (controls, n = 50) were prospectively recruited. The experimental design included (1) a screening phase to identify candidate miRNA differentially expressed in FTR (n = 8) compared with controls (n = 8) through miRNA array profiling of 192 miRNAs using quantitative reverse transcription PCR arrays [qRT-PCR]) and (2) a validation phase in which candidate miRNAs identified in the initial screening were selected for further validation by qRT-PCR in a prospectively recruited cohort of FTR (n = 92) and controls (n = 42). Bioinformatics analysis was used to predict their potential target genes and functional pathways elicited. A combined endpoint of hospital admission due to heart failure (HF) and all-cause mortality was defined. Initial screening identified 16 differentially expressed miRNAs in FTR compared with controls, subsequently confirmed in the validation phase (n = 16 were excluded due to significant haemolysis). miR-186-5p, miR-30e-5p, and miR-152-3p identified FTR with high predictive value [AUC of 0.93 (0.88-0.97), 0.83 (0.75-0.91) and 0.84 (0.76-0.92), respectively]. During a median follow-up of 20.4 months (IQR 8-35 months), 32% of FTR patients reached the combined endpoint. Patients with low relative expression of miR-15a-5p, miR-92a-3p, miR101-3p, and miR-363-3p, miR-324-3p, and miR-22-3p showed significantly higher rates of events (log-rank test for all P < 0.01). Both miR-15a-5p [hazard ratio: 0.21 (0.06-0.649, P = 0.007) and miR-92a-3p (0.27 (0.09-0.76), P = 0.01] were associated with outcomes after adjusting for age, gender, and New York Heart Association functional class. CONCLUSIONS: Circulating miRNAs are novel diagnostic and prognostic biomarkers in severe FTR. The quantification of miR-186-5p, miR-30e-5p, and miR-152-3p held strong diagnostic value, and the quantification of miR-15a-5p and miR-92a-3p are independently associated with outcomes. The recognition of specific miRNAs offers a novel perspective for TR evaluation.

STREI: a new index of right heart function in isolated severe tricuspid regurgitation by Speckle tracking Echocardiography.

AIMS: Right ventricular (RV) performance determines clinical management in severe tricuspid regurgitation (TR). Right atrial (RA) function complements RV assessment in TR. This study aimed to design a novel index by Speckle-tracking echocardiography (STREI index) integrating RA and RV strain information and to evaluate the clinical utility of combining RV and RA strain for prediction of cardiovascular (CV) outcomes. METHODS AND RESULTS: Consecutive patients with at least (≥) severe TR evaluated in the Heart Valve Clinic (n = 300) were prospectively included. An additional independent TR cohort was included for external validation (n = 50). STREI index was developed with the formula: [2 * RV-free wall longitudinal strain (RV-FWLS)] + Reservoir RA strain (RASr). The composite endpoint included hospital admission due to HF and all cause-mortality. 176 patients with ≥ severe TR were finally included. STREI index identified a higher percentage of patients with RV dysfunction compared to conventional parameters. After a median follow-up of 2.2 years (IQR: 12-41 months), 38% reached the composite endpoint. STREI values were predictors of outcomes independently of TR severity and RV dimensions. The combination of prognostic cut-off values of RASr (<10%) and RV-FWLS (>-20%) (STREI stratification) stratified 4 different groups of risk independently of TR severity, RV dimensions and clinical status (adj HR per stratum 1.89 (1.4-2.34), p < 0.001). Pre-defined cut-off values achieved similar prognostic performance in the validation cohort (n = 50). CONCLUSION: STREI index is a novel parameter of RV performance that independently predicts CV events. The combination of RA and RV strain stratifies better patients' risk, reflecting a broader effect of TR on right heart chambers.

La clasificación 4A para pacientes con insuficiencia tricuspídea / The 4A classification for patients with tricuspid regurgitation

Introducción y objetivos: La insuficiencia tricuspídea (IT) significativa se asocia con un aumento de la morbimortalidad. La valoración clínica del paciente con IT es un reto. Nuestro objetivo es establecer una nueva clasificación clínica, específica para pacientes con IT, denominada clasificación 4A, y evaluar su impacto pronóstico. Métodos: Se incluyó a pacientes evaluados en la clínica valvular, con IT aislada al menos grave y ausencia de antecedentes de insuficiencia cardiaca (IC). Se recogieron síntomas y signos de astenia, edema en extremidades inferiores, dolor o distensión abdominal y anorexia (asthenia, ankle swelling, abdominal pain or distention and anorexia) y se realizó un seguimiento cada 6 meses. La clasificación 4A abarca desde A0 (ninguna A) a A3 (3 o 4 Aes). Se definió un resultado combinado de ingreso hospitalario debido a IC derecha o muerte de causa cardiovascular. Resultados: Se incluyó a 135 pacientes con IT significativa entre 2016 y 2021 (el 69% mujeres; media de edad, 78±7 años). Durante un seguimiento medio de 26 [intervalo intercuartílico, 10-41] meses, 53 pacientes (39%) alcanzaron el resultado combinado. Ingresaron por IC 46 (34%) y murió un 5% (n=7). Al inicio, el 94% de los pacientes se encontraban en NYHA I o II, mientras que el 24% ya presentaba A2 o A3. La presencia de A2 o A3 se asoció con una alta incidencia de eventos. El cambio en la puntuación de la clasificación 4A fue un marcador independiente de IC y muerte cardiovascular (HR ajustada por unidad de cambio de la clasificación 4A=1,95 [1,37-2,77]; p <0,001). Conclusiones: Se muestra una nueva clasificación clínica específica para pacientes con IT basada en signos y síntomas de IC derecha y predictora de eventos.

Introduction and objectives: Significant tricuspid regurgitation (TR) is associated with increased morbidity and mortality. Clinical evaluation of TR patients is challenging. Our aim was to establish a new clinical classification specific for patients with TR, the 4A classification, and evaluate its prognostic performance. Methods: We included patients with isolated TR that was at least severe and without previous episodes of heart failure (HF) who were assessed in the heart valve clinic. We registered signs and symptoms of asthenia, ankle swelling, abdominal pain or distention and/or anorexia and followed up the patients every 6 months. The 4A classification ranged from A0 (no A) to A3 (3 or 4 As present). We defined a combined endpoint consisting of hospital admission due to right HF or cardiovascular mortality. Results: We included 135 patients with significant TR between 2016 and 2021 (69% females, mean age 78±7 years). During a median follow-up of 26 [IQR, 10-41] months, 39% (n=53) patients had the combined endpoint: 34% (n=46) were admitted for HF and 5% (n=7) died. At baseline, 94% of the patients were in NYHA I or II, while 24% were in classes A2 or A3. The presence of A2 or A3 conferred a high incidence of events. The change in 4A class remained an independent marker of HF and cardiovascular mortality (adjusted HR per unit of change of 4A class, 1.95 [1.37-2.77]; P<.001). Conclusions: This study reports a novel clinical classification specifically for patients with TR that is based on signs and symptoms of right HF and has prognostic value for events.(AU)

Clinical utility and prognostic value of right atrial function in severe tricuspid regurgitation: one more piece of the puzzle.

AIMS: The optimal management of severe tricuspid regurgitation (TR) remains controversial. While right ventricular systolic function is an established prognostic marker of outcomes, the potential role of right atrial (RA) function is unknown. This study aimed to describe RA function by 2D speckle-tracking echocardiography (STE) in at least severe TR and to evaluate its potential association with cardiovascular outcomes. METHODS AND RESULTS: Consecutive patients with at least (≥) severe TR (severe, massive, or torrential TR) evaluated in the Heart Valve Clinic following a comprehensive clinical protocol were included. Consecutive control subjects and patients with permanent isolated atrial fibrillation (AF) were included for comparison (control and AF group, respectively). RA function was measured with 2D-STE and two components of RA function were calculated: reservoir (RASr) and contractile (RASct) strain (AutoStrain, Philips Medical Systems the EPIQ system). A combined endpoint of hospital admission due to heart failure (HF) or all-cause mortality was defined. Patients with ≥ severe TR (n = 140) showed lower RASr compared with controls (n = 20) and with the AF group (n = 20) (P < 0.001). Atrial TR showed lower RASr compared with other aetiologies of TR (P < 0.001). After a median follow-up of 2.2 years (IQR: 12-41 months), RASr remained an independent predictor of mortality and HF. A cut-off value of RASr of <9.4% held the best accuracy to predict outcomes. CONCLUSION: RA function by 2D-STE independently predicts mortality and HF hospitalizations in patients with ≥ severe TR.

The 4A classification for patients with tricuspid regurgitation.

INTRODUCTION AND OBJECTIVES: Significant tricuspid regurgitation (TR) is associated with increased morbidity and mortality. Clinical evaluation of TR patients is challenging. Our aim was to establish a new clinical classification specific for patients with TR, the 4A classification, and evaluate its prognostic performance. METHODS: We included patients with isolated TR that was at least severe and without previous episodes of heart failure (HF) who were assessed in the heart valve clinic. We registered signs and symptoms of asthenia, ankle swelling, abdominal pain or distention and/or anorexia and followed up the patients every 6 months. The 4A classification ranged from A0 (no A) to A3 (3 or 4 As present). We defined a combined endpoint consisting of hospital admission due to right HF or cardiovascular mortality. RESULTS: We included 135 patients with significant TR between 2016 and 2021 (69% females, mean age 78±7 years). During a median follow-up of 26 [IQR, 10-41] months, 39% (n=53) patients had the combined endpoint: 34% (n=46) were admitted for HF and 5% (n=7) died. At baseline, 94% of the patients were in NYHA I or II, while 24% were in classes A2 or A3. The presence of A2 or A3 conferred a high incidence of events. The change in 4A class remained an independent marker of HF and cardiovascular mortality (adjusted HR per unit of change of 4A class, 1.95 [1.37-2.77]; P<.001). CONCLUSIONS: This study reports a novel clinical classification specifically for patients with TR that is based on signs and symptoms of right HF and has prognostic value for events.

Prognostic Impact of Right Ventricular Strain in Isolated Severe Tricuspid Regurgitation.

BACKGROUND: Right ventricular (RV) systolic function is an established marker of outcomes in patients with severe tricuspid regurgitation (TR). Timely detection of RV dysfunction using conventional two-dimensional echocardiography is challenging. RV strain has emerged as an accurate and sensitive tool for the evaluation of RV function, with the capability to detect subclinical RV dysfunction. The aim of this study was to evaluate the prognostic value of RV strain parameters in early stages of severe TR. METHODS: Consecutive patients with at least severe TR (severe, massive, or torrential) and the absence of a formal indication for tricuspid valve intervention in secondary TR evaluated in the Heart Valve Clinic were prospectively included. RV systolic function was measured using conventional echocardiographic indices (RV fractional area change, tricuspid annular plane systolic excursion, and Doppler tissue imaging S wave [S']) and speckle-tracking echocardiography-derived automatic peak global longitudinal strain and free wall longitudinal strain (FWLS) using an automated two-dimensional strain analytic software. A combined end point of hospital admission due to heart failure or all-cause mortality was defined. RESULTS: A total of 266 patients were enrolled in the study, and 151 were ultimately included. Strain parameters detected a higher percentage of abnormal RV values compared with conventional indices. During a median follow-up period of 26 months (interquartile range, 13-42 months), 35% of the patients reached the combined end point. Cumulative event-free survival was significantly worse in patients with impaired RV global longitudinal strain and RV FWLS. Conventional indices of RV systolic function were not associated with outcomes (P > .05 for all). On multivariate analysis, RV FWLS was independently associated with mortality and heart failure (adjusted hazard ratio for abnormal RV FWLS, 5.90; 95% CI, 3.17-10.99; P < .001). CONCLUSION: In early stages of severe TR, RV FWLS is more frequently impaired compared with conventional indices of RV function. Among all parameters, RV FWLS is the strongest predictor of mortality and heart failure, independent of additional prognostic markers.

Invasive management of significant tricuspid regurgitation in clinical practice.

BACKGROUND: Tricuspid regurgitation (TR) is a prevalent condition inside valvular heart disease (VHD) with relevant prognosis implications. However, concordance between real management in clinical practice and invasive treatment recommendations of European Society of Cardiology (ESC) guidelines is unknown. METHODS: A substudy of ESC VHD II survey was performed to evaluate the real treatment of TR compared to the clinical ESC guidelines recommendations published in 2012, 2017 and 2021 was performed. TR cases with surgical indication were divided in 3 groups: 1: severe isolated TR without previous left VHD; 2: moderate/severe TR and concomitant severe left VHD; 3: severe TR plus previous left VHD surgery. RESULTS: Of 902 patients assessed, 123 had significant TR. Fifty (41%) cases demonstrated ESC guidelines 2012-2017 Class I or IIa recommendations for invasive treatment: 9(18%) of group 1, 37(74%) of group 2 and 4(8%) of group 3. Surgery was performed in 24 patients (48%); 1 in group 1(4%), 22 in group 2(92%) and 1 in group 3(4%). Overall concordance was 48% (group 1: 11%; group 2: 59%; group 3: 25%). Regarding the 2021 ESC guidelines only one patient changed groups with an overall concordance of 47% (group 1: 10%; group 2: 59%; group 3: 25%). CONCLUSION: Concordance between 2012, 2017 and 2021 ESC guidelines recommendations and clinical practice for TR surgical intervention is low, especially in those without concomitant severe left VHD. These results suggest the need to improve further guideline implementation and alternative treatments, such as percutaneous, which could resolve potential discrepancies in those clinical scenarios.

Prognostic value of diastolic function parameters in significant aortic regurgitation: the role of the left atrial strain.

BACKGROUND: The management of patients with asymptomatic significant aortic regurgitation (sAR) is often challenging and appropriate timing of aortic valve surgery remains controversial. Prognostic value of diastolic parameters has been demonstrated in several cardiac diseases. The aim of this study was to analyze the prognostic significance of the diastolic function evaluated by echocardiography, in asymptomatic patients with sAR. METHODS: A total of 126 patients with asymptomatic sAR evaluated in the Heart Valve Clinic were retrospective included. Conventional echocardiographic systolic and diastolic function parameters were assessed. Left atrial (LA) auto-strain analysis was performed in a sub-group of 57 patients. A combined end-point of hospital admission due to heart failure, cardiovascular mortality, or aortic valve surgery was defined. RESULTS: During a median follow-up of 34.1 (interquartile range 16.5-48.1) months, 25 (19.8%) patients reached the combined end-point. Univariate analysis showed that LV volumes, LV ejection fraction (LVEF), LV-GLS, E wave, E/e' ratio, LA volume and LA reservoir strain (LASr) were significant predictors of events. Multivariate analysis that tested all classical echocardiographic variables statistically significant in the univariate model showed that LVEDV (HR = 1.02; 95% CI 1.01-1.03; p < 0.001) and E/e' ratio (HR = 1.12; 95% CI 1.03-123; p = 0.01) were significant predictors of events. Kaplan-Meier curve, stratified by median value of LASr, showed that lower LASr values (less than median of 34%) were associated with higher rates of events (p = 0.013). CONCLUSION: In this population of asymptomatic patients with sAR and normal LV systolic function, baseline diastolic parameters were prognostic markers of cardiovascular events; among them, LASr played a significant predictor role.

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

OBJECTIVE: To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV). METHODS: 554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses. RESULTS: Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter. CONCLUSIONS: In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

Prognostic implications of cardiac magnetic resonance feature tracking derived multidirectional strain in patients with chronic aortic regurgitation.

OBJECTIVE: Speckle-tracking echocardiography (STE) deformation parameters detect latent LV dysfunction in chronic aortic regurgitation (AR) and are associated with outcomes. The aim of the study was to evaluate cardiac magnetic resonance (CMR) feature tracking (FT) deformation parameters in asymptomatic patients with AR and implications in outcomes. METHODS: Fifty-five patients with AR and 54 controls were included. Conventional functional CMR parameters, aortic regurgitant volume, and fraction were assessed. CMR-FT analysis was performed with a dedicated software. Clinical data was obtained from hospital records. A combined endpoint included all-cause mortality, cardiovascular mortality, aortic valve surgery, or cardiovascular hospital admission due to heart failure. RESULTS: Left ventricular (LV) mechanics is impaired in patients with significant AR. Significant differences were noted in global longitudinal strain (GLS) between controls and AR patients (- 19.1 ± 2.9% vs - 16.5 ± 3.2%, p < 0.001) and among AR severity groups (- 18.3 ± 3.1% vs - 16.2 ± 1.6% vs - 15 ± 3.5%; p = 0.02 for AR grades I-II, III, and IV). In univariate and multivariate analyses, circumferential strain (GCS) and global radial strain (GRS) but not GLS were associated with and increased risk of the end point with a HR of 1.26 (p = 0.016, 1.04-1.52) per 1% worsening for GCS and 0.90 (p = 0.012, 0.83-0.98) per 1% worsening for GRS. CONCLUSIONS: CMR-FT myocardial deformation parameters are impaired in patients with AR not meeting surgical criteria. GLS decreases early in the course of the disease and is a marker of AR severity while GCS and GRS worsen later but predict a bad prognosis, mainly the need of aortic valve surgery. KEY POINTS: • CMR feature tracking LV mechanic parameters may be reduced in significant chronic AR with normal EF. • LV mechanics, mainly global longitudinal strain, worsens as AR severity increases. • LV mechanics, specially global radial and circumferential strain, is associated with a worse prognosis in AR patients.