CA125: a new biomarker in patients with Fontan circulation.

INTRODUCTION AND OBJECTIVES: Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers. METHODS: Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves. RESULTS: We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated. CONCLUSIONS: CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC.

Spatiotemporal Complexity of Vena Contracta and Mitral Regurgitation Grading Using Three-Dimensional Echocardiographic Analysis.

BACKGROUND: Spatiotemporal complexity of the color Doppler vena contracta challenging the assumption of a circular and constant orifice may lead to mitral regurgitation (MR) grading inconsistencies. Using 3D transesophageal echocardiography, we characterized spatiotemporal vena contracta complexity and its impact on MR severity grading. METHODS: In 192 patients with suspected moderate or severe MR (100 primary MR [PMR]; 92 secondary MR [SMR]), we performed three-dimensional vena contracta area (VCA) quantification using single-frame (midsystolic or VCAmid, maximum or VCAmax) and multiframe (VCAmean) methods, as well as measures of orifice shape (shape index) and systolic variation of VCA. Vena contracta complexity and intermethod discrepancies were analyzed and correlated with functional class and pulmonary vein flow (PVF) patterns and with cardiac magnetic resonance (CMR) in a subset of cases (n = 20). RESULTS: The vena contracta was noncircular (shape index > 1.5) in 90% of patients. Severe noncircularity (shape index > 3) was more prevalent in SMR than in PMR (32.4% vs 14.6%). Variations of the VCA were more prominent in SMR than in PMR. VCAmid showed a low grading agreement with VCAmax (62%) and high grading agreement with VCAmean (83.3%). Pulmonary vein flow systolic reversal was associated with MR severity by VCA in SMR but not in PMR. VCAmid and VCAmean showed a stronger association with systolic flow reversal than VCAmax (area under the curve, 0.88, 0.86, and 0.79, respectively). In the subset of patients with CMR quantification, severe MR by VCAmax was graded as nonsevere by CMR more frequently compared with VCAmid and VCAmean. CONCLUSIONS: Highly prevalent spatiotemporal vena contracta complexity features in MR challenge the assumption of a circular and constant orifice. VCAmid seems the best single-frame approximation to multiframe quantification, and VCAmax may lead to severity overestimation.

Changes in echocardiographic parameters over time in paradoxical low-flow low-gradient aortic stenosis.

AIMS: To assess the progression of the disease and evolution of the main echocardiographic variables for quantifying AS in patients with severe low-flow low-gradient (LFLG) AS compared to other severe AS subtypes. METHODS AND RESULTS: Longitudinal, observational, multicenter study including consecutive asymptomatic patients with severe AS (aortic valve area, AVA < 1.0 cm²) and normal left ventricle ejection fraction (LVEF ≥ 50%). Patients were classified according to baseline echocardiography into: HG (high gradient; mean gradient ≥ 40 mmHg), NFLG (normal-flow low-gradient; mean gradient < 40 mmHg, indexed systolic volume (SVi) > 35mL/m2), or LFLG (mean gradient < 40 mmHg, SVi ≤ 35 mL/m²). AS progression was analyzed by comparing patients' baseline measurements and their last follow-up measurements or those taken prior to aortic valve replacement (AVR). Of the 903 included patients, 401 (44.4%) were HG, 405 (44.9%) NFLG, and 97 (10.7%) LFLG. Progression of the mean gradient in a linear mixed regression model was greater in low-gradient groups: LFLG vs. HG (regression coefficient 0.124, P = 0.005) and NFLG vs. HG (regression coefficient 0.068, P = 0.018). No differences were observed between the LFLG and NFLG groups (regression coefficient 0.056, P = 0.195). However, AVA reduction was slower in the LFLG group compared to the NFLG (P < 0.001). During follow-up, in conservatively-managed patients, 19.1% (n = 9) of LFLG patients evolved to having NFLG AS and 44.7% (n = 21) to having HG AS. In patients undergoing AVR, 58.0% (n = 29) of LFLG baseline patients received AVR with a HG AS. CONCLUSION: LFLG AS shows an intermediate AVA and gradient progression compared to NFLG and HG AS. The majority of patients initially classified as having LFLG AS changed over time to having other severe forms of AS, and most of them received AVR with a HG AS.

Plasma Levels of SERCA2a as a Noninvasive Biomarker of Primary Graft Dysfunction After Heart Transplantation.

BACKGROUND: Noninvasive detection of primary graft dysfunction (PGD) remains a major challenge. SERCA2a plays an important role in cardiac homeostasis and its dysregulation has been associated with ventricular dysfunction and rejection. This study aimed to determine the potential utility of plasma levels of SERCA2a as a biomarker of PGD. METHODS: One hundred thirty-five plasma samples were collected from adult recipients 2-6 hours before heart transplantation (HT). Plasma concentrations of SERCA2a were determined using a specific sandwich ELISA. Variables related to the recipient, the donor, and the periprocedural were collected to determine a multivariate predictive model of PGD. RESULTS: Levels of SERCA2a were decreased in patients who developed PGD (median 0.430 ng/mL [interquartile range, 0.260-0.945] versus 0.830 ng/mL [interquartile range, 0.582-1.052]; P = 0.001). Receiver operating characteristic curve analysis revealed that SERCA2a discriminated between patients with and without PGD (AUC = 0.682; P = 0.001), and a cutoff point ≥ 0.60 ng/mL was a protective independent predictor of PGD (odds ratio 0.215 [P = 0.004]). Three independent predictors of PGD in this study were reduced levels of pre-HT SERCA2a, increased bilirubin levels, and short-term mechanical circulatory support bridge to transplantation. The analysis of the receiver operating characteristic curve of the model obtained a significant AUC 0.788, P = 0.0001. CONCLUSIONS: Our findings suggest that assessment of SERCA2a plasma levels may improve risk prediction for the occurrence of PGD and could be considered as a novel noninvasive biomarker in patients undergoing HT.

Value of SERCA2a as a Biomarker for the Identification of Patients with Heart Failure Requiring Circulatory Support.

BACKGROUND: Heart failure (HF) alters the nucleo-cytoplasmic transport of cardiomyocytes and reduces SERCA2a levels, essential for intracellular calcium homeostasis. We consider in this study whether the molecules involved in these processes can differentiate those patients with advanced HF and the need for mechanical circulatory support (MCS) as a bridge to recovery or urgent heart transplantation from those who are clinically stable and who are transplanted in an elective code. MATERIAL AND METHOD: Blood samples from 29 patients with advanced HF were analysed by ELISA, and the plasma levels of Importin5, Nucleoporin153 kDa, RanGTPase-Activating Protein 1 and sarcoplasmic reticulum Ca2+ ATPase were compared between patients requiring MCS and those patients without a MCS need prior to heart transplantation. RESULTS: SERCA2a showed significantly lower levels in patients who had MCS compared to those who did not require it (0.501 ± 0.530 ng/mL vs. 1.123 ± 0.661 ng/mL; p = 0.01). A SERCA2a cut-off point of 0.84 ng/mL (AUC 0.812 ± 0.085, 95% CI: 0.646-0.979; p = 0.004) provided a 92% sensitivity, 62% specificity, 91% negative predictive value and 67% positive predictive value. CONCLUSIONS: In this cohort, patients with advanced HF and a need for MCS have shown significantly lower levels of SERCA2a as compared to stable patients without a need for MCS prior to heart transplantation. This is a small study with preliminary findings, and larger-powered dedicated studies are required to confirm and validate these results.

Glycemic variability in type 2 diabetes mellitus and acute coronary syndrome: liraglutide compared with insulin glargine: a pilot study.

OBJECTIVE: To explore the glucagon-like peptide-1 analogue liraglutide in the hospital setting in patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome and to evaluate the safety and efficacy and its impact on hospitalization and short-term glycemic variability (GV). METHODS: A 12-week, open-label, prospective, randomized pilot clinical study with parallel groups that compared liraglutide (group 1) with glargine (group 2) and its impact on glycemic control and GV. RESULTS: Thirteen patients were included. During hospitalization, mean glucose was 164.75 mg/dL (standard deviation [SD] 19.94) in group 1 and 166.69 mg/dL (38.22) in group 2. GV determined by CV and SD was 20.98 (7.68) vs. 25.48 (7.19) and 34.37 (13.05) vs. 43.56 (19.53) in groups 1 and 2, respectively. Group 1 prandial insulin requirements during hospitalization were lower compared with group 2. Follow-up A1c in group 1 was 6.9% (-1.51%) and 6.5% in group 2 (-1.27). GV after discharge and hypoglycemia were lower in group 1 compared with group 2. CONCLUSIONS: Liraglutide seems to reduce GV in the acute phase of acute coronary syndrome, and patients achieved optimal control with a low incidence of hypoglycemia. These results support the need to explore liraglutide in a larger multicenter trial. Trial registration: The study was approved by the National Medical Ethics Committee of Spain. The study was registered at European Clinical Trials Database (EudraCT): 2014003298-40.

Fontan Circulation in Adult Patients: Acoustic Radiation Force Impulse Elastography as a Useful Tool for Liver Assessment.

OBJECTIVE: The development of liver fibrosis and cirrhosis due to long-standing liver congestion is known to occur in adult patients with Fontan circulation. Hepatic elastography has shown to be a useful tool for the noninvasive assessment and staging of liver fibrosis in chronic liver diseases, although the utility of this technique in Fontan patients remains to be adequately studied. METHODS: Twenty-one patients with Fontan circulation underwent an abdominal ultrasound and an acoustic radiation force impulse (ARFI) elastography. In order to compare the results from this group, a cohort of 14 healthy controls and another group containing 17 patients with cirrhosis were included. The association between the velocity values measured with elastography and clinical and analytical parameters were also studied. RESULTS: Mean shear waves propagation velocity in liver tissue in the Fontan group was 1.86 ± 0.5 m/s, with 76% of patients over the cirrhosis threshold (1.55 m/s). The control group had a mean velocity of 1.09 ± 0.06 m/s, while the cirrhotic group obtained 2.71 ± 0.51 m/s. Seven patients with Fontan circulation had increased liver enzymes. Liver ultrasound showed evidence of chronic liver disease in six patients. Velocity values obtained in the presence or absence of analytical or liver ultrasound abnormalities showed significant differences in the univariate analysis (P = .04 and P = .03 respectively). CONCLUSION: In conclusion, ARFI elastography showed increased wave propagation velocity values in the Fontan population suggesting increased liver stiffness which could be related to advanced fibrosis. A statistically significant association between ARFI values and the presence of analytical and ultrasound abnormalities has been demonstrated.