The Role of Galectin-3 in Heart Failure-The Diagnostic, Prognostic and Therapeutic Potential-Where Do We Stand?

Heart failure (HF) is a clinical syndrome with high morbidity and mortality, and its prevalence is rapidly increasing. Galectin-3 (Gal-3) is an important factor in the pathophysiology of HF, mainly due to its role in cardiac fibrosis, inflammation, and ventricular remodeling. Fibrosis is a hallmark of cardiac remodeling, HF, and atrial fibrillation development. This review aims to explore the involvement of Gal-3 in HF and its role in the pathogenesis and clinical diagnostic and prognostic significance. We report data on Gal-3 structure and molecular mechanisms of biological function crucial for HF development. Over the last decade, numerous studies have shown an association between echocardiographic and CMR biomarkers in HF and Gal-3 serum concentration. We discuss facts and concerns about Gal-3's utility in acute and chronic HF with preserved and reduced ejection fraction for diagnosis, prognosis, and risk stratification. Finally, we present attempts to use Gal-3 as a therapeutic target in HF.

Subclinical Dysfunction of Left Atrial Compliance after Cryoballoon versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation.

It has been suggested that cryoballoon (CB) ablation for paroxysmal atrial fibrillation (PAF) may lead to more extensive left atrial (LA) injury than radiofrequency (RF) ablation; however, results are conflicting. We sought to address this issue using modern echocardiographic techniques estimating the LA function after successful CB and RF ablation for PAF. A total of 90 patients (66% males, mean age 57 ± 10 years) successfully treated (no AF recurrences confirmed in serial 4-7 day ECG Holter monitoring) with RF (51%) or CB (49%) ablation for PAF were retrospectively studied. Echocardiography with speckle tracking (STE) was performed before and 12 months after the procedure. The peak longitudinal LA strain (LAS) and strain rate (LASR) during the reservoir (r), conduit (cd), and contraction (ct) phases were measured in sinus rhythm. Analysis of covariance was applied to compare changes in the echocardiographic parameters over time with the baseline measurements as covariance and the type of ablation as the factor. The parallelism of the slopes of the covariance was tested. The LA diameter decreased (38.3 ± 4.1 mm vs. 36.8 ± 3.6 mm, p < 0.001) in the whole study group at 12 months after ablation. The LASRr and LASRcd increased (1.1 ± 0.3 s-¹ vs. 1.3 ± 0.3 s-¹, p < 0.001 and 1.1 ± 0.3 s-¹ vs. 1.2 ± 0.3 s-¹, p < 0.001, respectively) whereas other LA strain parameters remained unchanged in the whole study group at 12 months after ablation. In the analysis of LA function at 12 months after the procedure regarding the mode of ablation, the worsening of parameters reflecting LA compliance was observed in patients with better pre-served baseline values in the CB ablation subgroup. For baseline LAScd >28%, the difference ΔCB - ΔRF was -7.6 (11.7; -3.4), p < 0.001, and for baseline LAScd >16%, ΔCB - ΔRF was -1.8 (-3.2; -0.4), p = 0.014. The traditional Doppler-derived parameter e' showed the same trend-for baseline e' ≥12 cm/s, ΔCB - ΔRF was -1.7 (-2.8; -0.6), p = 0.003. We conclude that worsening of parameters reflecting LA compliance was observed 12 months after CB ablation compared to RF ablation for PAF in patients who underwent a successful procedure and had better-preserved baseline LA function. This might suggest subclinical dysfunction of LA after the CB ablation procedure. The clinical significance of these findings warrants further investigations.

Prognostic value of galectin-3 and right ventricular function for long-term mortality in heart failure patients treated with cardiac resynchronization therapy.

Recently, associations between the biomarker galectin-3 and numerous pathological processes involved in heart failure (HF) and right ventricular (RV) function have been observed. We aimed to assess the long-term prognostic ability of galectin-3 and RV function parameters for all-cause mortality in HF patients treated with cardiac resynchronization therapy (CRT). We prospectively studied 63 symptomatic HF patients with a left ventricular (LV) ejection fraction (EF) ≤ 35%. The median serum galectin-3 concentration was 13.4 ng/mL (IQR 11.05, 17.15). A detailed assessment of LV and RV geometry and function was performed with echocardiography. CRT defibrillator implantation was achieved in all patients without major complications. The follow-up lasted 5 years. In the multivariable Cox regression model, independent predictors for all-cause mortality were log baseline galectin-3 and baseline RV function expressed as tricuspid annular plane systolic excursion with HR 2.96 (p = 0.037) and HR 0.88 (p = 0.023), respectively. Analysis of subgroups defined by galectin-3 concentration and CRT response showed that patients with high baseline galectin-3 concentrations and a lack of response to CRT had a significantly lower probability of survival. In our patient cohort, the baseline galectin-3 concentration and RV function were independent predictors of long-term all-cause mortality in HFrEF patients following CRT implantation.

Echocardiographic assessment of left atrial function for prediction of efficacy of catheter ablation for atrial fibrillation.

ABSTRACT: Proper selection for catheter ablation (CA) for atrial fibrillation (AF) is still an issue. Echocardiographic assessment of left atrium (LA) is complex and challenging. Speckle tracking echocardiography (STE) with recent standardized LA deformation analysis allows for the quantitative assessment of various LA function parameters. We aimed to assess the value of detailed evaluations of LA function using STE in patients with non-valvular AF without structural heart disease to predict the outcomes after CA for AF. Secondary aim was to analyze the prediction of CA efficacy in patients with normal LA dimension in baseline echocardiography.We studied with transthoracic and transesophageal echocardiography 82 patients (58% males, mean age 57.3 ± 9.5 years) with non-valvular paroxysmal AF without structural heart disease scheduled for CA. Peak longitudinal LA strain (LAS) and strain rate (LASR) during the reservoir (r), conduit (cd) and contraction (ct) phases were measured by STE before the procedure. Patients were followed for 1 year using serial 4 to 7 day Holter ECG monitoring.Complete freedom from any AF recurrence was achieved in 44 (54%) patients. All patients had normal left ventricular systolic and diastolic function and 53 (65%) of them had not enlarged LA. In the multivariable logistic regression analysis, global left atrial reservoir strain (LASr) was identified as an independent predictor of CA efficacy (OR [95% CI]: 1.35 [1.17-1.55], P < .0001). The opportunity of CA success was 135 fold higher for each 1% increase in global LASr.The receiver operating characteristic (ROC) analysis identified global LASr and left atrial conduit strain (LAScd) as the most powerful parameters for predicting of CA outcome with an area under the curve of 0.896 and 0.860, respectively, in the whole study group, and 0.922 and 0.938, respectively, in patients with not enlarged LA.In patients with paroxysmal AF and normal standard echocardiographic assessment, parameters reflecting LA compliance - reservoir and conduit strain, are independent and strong predictors of CA outcome.

Chronotropic Incompetence Limits Aerobic Exercise Capacity in Patients Taking Beta-Blockers: Real-Life Observation of Consecutive Patients.

BACKGROUND: Chronotropic incompetence in patients taking beta-blockers is associated with poor prognosis; however, its impact on exercise capacity (EC) remains unclear. METHODS: We analyzed data from consecutive patients taking beta-blockers referred for cardiopulmonary exercise testing to assess EC. Chronotropic incompetence was defined as chronotropic index (CI) ≤ 62%. RESULTS: Among 140 patients all taking beta-blockers (age 61 ± 9.7 years; 73% males), 64% with heart failure, chronotropic incompetence was present in 80.7%. EC assessed as peak oxygen uptake was lower in the group with chronotropic incompetence, 18.3 ± 5.7 vs. 24.0 ± 5.3 mL/kg/min, p < 0.001. EC correlated positively with CI (ß = 0.14, p < 0.001) and male gender (ß = 5.12, p < 0.001), and negatively with age (ß = -0.17, p < 0.001) and presence of heart failure (ß = -3.35, p < 0.001). Beta-blocker dose was not associated with EC. Partial correlation attributable to CI accounted for more than one-third of the variance in EC explained by the model (adjusted R2 = 59.8%). CONCLUSIONS: In patients taking beta-blockers, presence of chronotropic incompetence was associated with lower EC, regardless of the beta-blocker dose. CI accounted for more than one-third of EC variance explained by our model.

Galectin-3 is related to right ventricular dysfunction in heart failure patients with reduced ejection fraction and may affect exercise capacity.

Galectin-3 is a biomarker of fibrosis, inflammation and oxidative stress, and its role in heart remodelling and exercise intolerance has not been conclusively proven in heart failure (HF) patients with reduced ejection fraction (rEF). We prospectively assessed 67 consecutive patients with symptomatic HF and left ventricular (LV) EF ≤ 35% during optimal medical therapy, with a mean serum galectin-3 concentration of 15.3 ± 6.4 and a median of 13.5 ng/mL. The group with galectin-3 concentrations greater than or equal to the median had significantly worse right ventricular (RV) systolic function parameters (s', TAPSE), higher pulmonary artery systolic pressure, more advanced tricuspid regurgitation and lower RV-to-pulmonary circulation coupling index, while no significant differences were found in LV parameters. Moreover, this group achieved significantly lower parameters in cardiopulmonary exercise testing. Significant negative correlations were found between galectin-3 concentration and RV parameters and exercise capacity parameters and have persisted after adjustment for glomerular filtration rate, but not all of them have persisted after adjustment for NT-proBNP. Multivariate regression analysis revealed that TAPSE (ß coefficient: - 0.605; p < 0.001) and heart rate at peak exercise (ß coefficient: - 0.98; p = 0.009) were independently related to galectin-3 concentration. Elevated galectin-3 concentration in patients with HFrEF might indicate concomitant RV dysfunction and exercise intolerance.

RIVAroxaban TWICE daily for lysis of thrombus in the left atrial appendage in patients with non-valvular atrial fibrillation: the RIVA-TWICE study.

INTRODUCTION: Rivaroxaban is a direct factor Xa inhibitor used once a day for prevention of thrombotic events in patients with atrial fibrillation (AF). However, in a small proportion of subjects thrombus in the left atrial appendage (LAA) is present despite this treatment. The aim of this study was assess the efficacy of increased dose of rivaroxaban (15 mg twice daily) treatment for lysis of thrombus in the LAA. MATERIAL AND METHODS: In the RIVA-TWICE prospective, open label study, with non-blinded patients and blinded outcome assessors, rivaroxaban 15 mg twice daily for 8 weeks was administered in patients with AF who had LAA thrombus despite standard 20 mg once a day therapy. Transesophageal echocardiography was performed at baseline and after 8 weeks. Blood samples were taken to measure the activity of the anti-Xa factor. RESULTS: Fifteen patients (9 males, mean age: 63 ±10 years) were enrolled. Following 8 weeks of rivaroxaban 15 mg twice daily, complete resolution of thrombus in the LAA was observed in 7 (46.7%) patients. The mean activity of anti-Xa factor was significantly higher during rivaroxaban twice daily therapy compared with the standard dose. However, there were no significant differences between effectively and non-effectively treated patients. CONCLUSIONS: Rivaroxaban 15 mg twice daily seems to be safe and may dissolve LAA thrombus when standard rivaroxaban therapy is ineffective. Lower CHA2DS2-VASc and HAS-BLED as well as preserved LAA emptying function identified responders.

Acceleration of sinus rhythm following ablation for atrial fibrillation: a simple parameter predicting ablation efficacy.

BACKGROUND: Pulmonary vein isolation (PVI) is a well­established treatment method in patients with paroxysmal atrial fibrillation (AF). However, the predictors of a successful outcome are less well known. It has been suggested that PVI­induced changes in autonomic control of sinus rate (SR) may correspond to ablation efficacy. AIMS: We aimed to assess whether PVI­induced changes in SR may help identify responders to PVI. METHODS: The study group consisted of 111 consecutive patients (mean [SD] age, 55 [10] years; 81 men) who underwent the first ablation of paroxysmal AF (radiofrequency [RF] ablation, 56 patients; cryoballoon [CB] ablation, 55 patients). The SR was calculated from a standard 12­lead electrocardiogram recorded a day before and 2 days after ablation. Patients were followed for 1 year on an outpatient basis and underwent serial 4- to 7­day Holter electrocardiogram recordings at 3, 6, and 12 months after ablation. RESULTS: Ablation was effective in 74 patients (67%). Univariate and multivariate analyses showed that younger age, faster SR, and a greater increase in SR (ΔSR) after ablation were significantly associated with successful outcome. The results were similar between patients who underwent RF and CB ablation. The sensitivity, specificity, negative predictive value, and positive predictive value of ΔSR higher than 15 bpm for the identification of responders were 53%, 73%, 80%, and 44%, respectively. CONCLUSIONS: Acceleration of SR following ablation for paroxysmal AF may serve as an additional simple clinical parameter that may improve the prediction of outcome after PVI.

Iatrogenic Arteriovenous Fistula and Atrial Septal Defect Following Cryoballoon Ablation for Atrial Fibrillation - Two Correctable Causes of Right Heart Failure.

BACKGROUND Catheter ablation for atrial fibrillation is an important therapeutic intervention. One of the most frequent complications of this procedure is vascular issues including arteriovenous fistula. Iatrogenic atrial septal defect (IASD) has been reported as a complication of transseptal puncture; however, no data are available demonstrating any coexistent of arteriovenous fistula with IASD. CASE REPORT A 61-year-old female patient was admitted to our center for catheter ablation for persistent atrial fibrillation. Her past medical history was significant for cryoballoon ablation for atrial fibrillation in 2015, which was subsequently complicated by hematoma and arteriovenous fistula at puncture site. After general surgery consultation, the patient was qualified for conservative treatment. To exclude left atrial thrombus before redo procedure, transesophageal echocardiography was performed which visualized the presence of 9-mm atrial septal defect with left-to-right shunting, detecting right-to-left shunting using Valsalva maneuver. No significant valvular abnormalities were identified. The next day, pulmonary vein isolation for atrial fibrillation was performed. One month later, a control transthoracic echocardiogram (TTE) revealed hemodynamic significant left-to-right shunting with Qp/Qs 2.0 and high probability of pulmonary hypertension. Vascular surgery for arteriovenous fistula was successfully performed in October 2018. Subsequent TTE, performed a month later, confirmed no left-to-right shunting and no signs of pulmonary hypertension or diminishment of the right atrium. CONCLUSIONS Vascular access during catheter ablation for atrial fibrillation may result in arteriovenous fistula. This condition might affect right atrium pressure leading to increased diameter of previous puncture site at the interatrial septum, causing IASD with significant shunting. In this group of patients, arteriovenous fistula should be treated as soon as possible.

Noninvasive assessment of left atrial fibrosis. Correlation between echocardiography, biomarkers, and electroanatomical mapping.

AIM: Left atrial (LA) fibrosis promotes atrial fibrillation (AF), may predict poor radiofrequency catheter ablation (RFCA) outcome, and may be assessed invasively using electroanatomical mapping (EAM). Speckle tracking echocardiography (STE) enables quantitative assessment of LA function. The aim was to assess the relationship between LA fibrosis derived from EAM and LA echocardiographic parameters as well as biomarkers of fibrosis in patients with AF. METHODS: Sixty-six patients (64% males, mean age 56 ± 10) with nonvalvular AF treated with first RFCA were prospectively studied. Seventy-three percent of patients were in sinus rhythm at the time of examination. LA geometry, systolic, and diastolic function were assessed. In STE global, peak atrial longitudinal (PALS) and contractile (PACS) strain were calculated. LA stiffness index (LAs) - the ratio of E/e' to PALS - was assessed. The EAM of LA was build using Carto System before RFCA. Low amplitude potentials area (LAPA) was quantitatively analyzed and expressed as a percentage of LA surface using the cut-off <0.5 mV to detect potential sites of fibrosis. The serum concentrations of MMP-9, PIIINP, and TGFß1were estimated before RFCA. RESULTS: Pearson correlation analysis showed a significant correlation between LA diastolic function parameters: PALS (-0.54, P < .001), LAs (0.65, P < .001), and LAPA in patients who were in sinus rhythm. Also LA volume significantly correlated with LAPA (0.44, P < .002). None of biomarkers correlated with LAPA. CONCLUSION: Left atrial diastolic parameters derived from STE correlate well with the extent of LA fibrosis. Thus, STE may be useful in the noninvasive assessment of LA fibrosis and selection of candidates for RFCA.

Intracardiac echocardiography for verification for left atrial appendage thrombus presence detected by transesophageal echocardiography: the ActionICE II study.

BACKGROUND: Transesophageal echocardiography (TEE) remains the gold standard for exclusion of left atrial appendage (LAA) thrombus in patients scheduled for direct electrical cardioversion (DEC) or atrial fibrillation (AF) ablation. Recently, intracardiac echocardiography (ICE) of the pulmonary artery (PA) has been shown to provide excellent LAA images and to be useful in verification of equivocal TEE findings. HYPOTHESIS: ICE of the PA may have a role in detecting false-positive TEE results. METHODS: Twenty-one patients (12 male, age 65 ± 8 years, CHADS2VASC2 score [congestive heart failure, hypertension, age ≥ 75, age 65-74, diabetes mellitus, stroke/TIA/thrombo-embolism, vascular disease, sex female] = 2.2; HAS-BLED score [hypertension, abnormal renal and liver function, stroke, bleeding, labile International Normalized Ratio, elderly, drugs or alcohol] = 1.1), in whom a thrombus in the LAA was detected during TEE before DEC or AF ablation, underwent ICE of the PA. RESULTS: On TEE, in 7 (33%) patients, the LAA thrombus was described as "solid" and in the remaining 14 (67%) as "soft." Disagreement between the TEE and ICE (thrombus in TEE and no thrombus in ICE) was found in 9 (43%) patients. In the solid thrombus group, ICE confirmed thrombi existence in 6 and excluded thrombi in 1 patient. In the soft thrombus group, ICE confirmed thrombi in 6 patients and excluded thrombi in the remaining 8 patients. Of the demographic and clinical variables, only the longstanding persistent type of AF was significantly associated with the presence of an LAA thrombus detected both by TEE and ICE. CONCLUSIONS: With TEE, a false positive of an LAA thrombus may be indicated, especially when a thrombus is described as soft rather than solid. Our study suggests that ICE may be a valuable option for verification of a TEE-based diagnosis of a thrombus.

Risk of left atrial appendage thrombus in patients scheduled for ablation for atrial fibrillation: beyond the CHA2DS2VASc score.

INTRODUCTION: Atrial fibrillation (AF) increases the risk of thromboembolic events by promoting clot formation in the left atrial appendage (LAA). Transesophageal echocardiography (TEE) is routinely used to exclude the presence of an LAA thrombus before AF ablation. So far, it has not been established what is the optimal combination of noninvasive parameters for thromboembolic risk stratification in this setting and whether patients at very low risk require TEE. OBJECTIVES: The aim of the study was to assess predisposing factors for an LAA thrombus in patients scheduled for AF ablation and to identify those patients in whom preprocedural TEE is not necessary. PATIENTS AND METHODS: In consecutive 151 patients (107 men; mean age, 57 ±10 years) the type of AF and renal function were assessed in addition to the CHA2DS2VASc score to improve thromboembolic risk stratification. RESULTS: An LAA thrombus or dense echo contrast with a strong suspicion of a probable thrombus was detected in 15 patients (10%). Diabetes, age of 65 years or older, persistent AF, and estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 were predictors of the LAA thrombus. A multivariate logistic regression analysis showed that only persistent AF and an eGFR of less than 60 ml/min/1.73 m2 were independent predictors of the LAA thrombus. The receiver operating characteristic curves showed that the greatest area under the curve (0.845) was achieved for the CHA2DS2VASc-AFR (CHA2DS2VASc plus the type of AF and renal function); the difference was not significant. A CHA2DS2VASc-AFR score of 2 or greater or a CHA2DS2VASc score of 1 or greater identified patients with the LAA thrombus with a sensitivity of 100% (and specificity of 54% and 36%, respectively). CONCLUSIONS: In patients scheduled for AF ablation, an LAA thrombus or dense echo contrast is a relatively common finding despite routine anticoagulant treatment. The addition of AF type and renal function to the CHA2DS2VASc score slightly improves thromboembolic risk stratification and may help identify patients who do not need preprocedural TEE.

Intracardiac echocardiography for detection of thrombus in the left atrial appendage: comparison with transesophageal echocardiography in patients undergoing ablation for atrial fibrillation: the Action-Ice I Study.

BACKGROUND: Transesophageal echocardiography (TEE) is the gold standard for the exclusion of thrombi in the left atrial appendage (LAA) before ablation for atrial fibrillation. Intracardiac echocardiography (ICE) is used to assist atrial fibrillation ablation; however, it can also be used for LAA imaging. The aim of our study was to determine whether ICE could replace TEE and to identify the optimal ICE placement for LAA visualization. METHODS AND RESULTS: Seventy-six consecutive patients (56 men; mean age, 55±9.6 years) scheduled for atrial fibrillation ablation underwent TEE before the procedure and LAA assessment by ICE. An 8F AcuNav probe was introduced into right atrium, pulmonary artery, and coronary sinus. LAA structure was analyzed by the echocardiographer and electrophysiologist who were blinded to the results of TEE. ICE probe was positioned in the right atrium in all patients, in the pulmonary artery in 64 of 74 (86%) patients, and in the coronary sinus in 49 of 74 (66%) patients. The LAA was properly visualized in 56 of 64 (87.5%) patients from the pulmonary artery versus 13 of 49 (26%) patients from the coronary sinus (P<0.001). From the right atrium, the whole LAA cavity could not be seen in any patient. In those patients in whom LAA was visualized properly by ICE, a perfect agreement between ICE and TEE was obtained (both techniques detected LAA thrombus in 2 patients and excluded LAA thrombus in the remaining patients). CONCLUSIONS: ICE can be used safely and effectively for the evaluation of LAA in patients undergoing atrial fibrillation ablation. ICE imaging from pulmonary artery is accurate for LAA visualization. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01371279.