Circulating MicroRNA in patients with repaired tetralogy of Fallot.

BACKGROUND: Emerging data suggest that heart-related microRNAs (miRs) may serve as circulating biomarkers of myocardial injury. We aimed to determine the circulating profile of miRs in patients with volume-overloaded right ventricles after repair of tetralogy (TOF). MATERIALS AND METHODS: A total of 104 TOF patients and 70 controls were recruited. The study was conducted in two phases: (1) determination of circulating heart-related miRs described in left heart diseases (miR-1, miR-133a, miR-208a, miR-208b and miR423-5p) by quantitative real-time PCR in 49 patients and 30 controls and followed by validation in an independent cohort of 55 patients and 40 controls; (2) expression profiling of serum samples from eight patients and eight controls, followed by validation. Alteration in circulating miRNA expression was related to cardiac functional indices as assessed by 2D speckle tracking and 3D echocardiography. RESULTS: No significant differences in serum levels of left heart-associated miRNAs were found between patients and controls. Of the candidate 19 miRNAs identified by profiling, upregulation of miR-99b and down-regulation of miR-766 were validated. However, no correlations were found between miRs levels and echo indices. CONCLUSION: In young adults with repaired TOF and volume-overloaded right ventricles, circulating levels of miR-99b and miR-766, but not left heart-associated miRNAs, were significantly altered.

Circulating microRNA expression profile and systemic right ventricular function in adults after atrial switch operation for complete transposition of the great arteries.

BACKGROUND: Data on the use of circulating microRNAs (miRNAs) as biomarkers of cardiovascular diseases are emerging. Little, however, is known on the expression profile of circulating of microRNAs in congenital heart malformations with a systemic right ventricle that is prone to functional impairment. We aimed to test the hypothesis that circulating miRNA profile is altered in patients late after atrial switch operation for complete transposition of the great arteries (TGA) and further explored possible relationships between alteration of circulating miRNAs and systemic ventricular contractility. METHODS: Circulating miRNA expression profiling of serum samples from 5 patients and 5 healthy controls was performed. The results were validated in 26 patients and 20 controls using real-time quantitative reverse-transcription polymerase chain reaction for candidate miRNAs with fold changes >3 by expression profiling. Systemic ventricular myocardial acceleration during isovolumic contraction (IVA) was determined by colour tissue Doppler echocardiography. RESULTS: Compared with controls, patients had significantly lower systemic ventricular IVA (p = 0.002). Of the 23 upregulated miRNAs identified by profiling, 11 were validated to be increased in patients compared with controls: miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93. Among the validated 11 miRNAs, miR-18a (r = -0.45, p = 0.002) and miR-486-5p (r = -0.35, p = 0.018) correlated negatively with systemic ventricular IVA for the whole cohort. CONCLUSIONS: A distinct serum miRNA expression signature exists in adults with complete TGA after atrial switch operation, with serum miR-18a and miR-486-5p being associated with systemic ventricular contractility.

Circulating levels of biomarkers of collagen synthesis and ventricular function and dyssynchrony in adolescents and young adults after repair of tetralogy of Fallot.

BACKGROUND: Circulating carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) are biomarkers of collagen synthesis. We tested the hypothesis that circulating PICP and PIIINP are altered and may correlate with ventricular volume load and function in patients with repaired tetralogy of Fallot (TOF). METHODS AND RESULTS: Serum PICP and plasma PIIINP levels were determined in 39 patients with repaired TOF aged 17.7 ± 4.1 years and 25 healthy controls and correlated with right ventricular (RV) and left ventricular (LV) volumes, functional indices, and mechanical dyssynchrony as assessed by 3-dimensional and tissue Doppler echocardiography. Compared with controls, patients had significantly higher circulating PICP (P = .016) and PIIINP (P = .008) levels, worse RV function with intra-RV mechanical delay (all P < .001), impaired LV systolic functional indices (all P < .05), and greater LV systolic dyssynchrony index (SDI) (P < .001). For the whole cohort, circulating PICP and PIIINP levels correlated with age (P = .001 and P < .001, respectively), body mass index (P = .033 and P = .012, respectively), LV eccentricity (P = .035 and P = .046, respectively), RV end-diastolic volume (P = .029 and P = .047, respectively), and LV SDI (both P < .001). In addition, PICP levels correlated negatively with RV and LV isovolumic acceleration and RV ejection fraction. Multiple linear regression analysis identified LV SDI as a significant independent correlate of circulating levels of PICP (ß = .31, P = .045) and PIIINP (ß = .37, P = .004). CONCLUSION: Circulating levels of PICP and PIIINP correlate positively with LV mechanical dyssynchrony in patients after TOF repair, implicating a possible role of increased collagen synthesis in its pathogenesis.

Plasma Levels of High Sensitivity Cardiac Troponin T in Adults with Repaired Tetralogy of Fallot.

Detectable low circulating level of cardiac troponin T (cTnT) may reflect subclinical myocardial injury. We tested the hypothesis that circulating levels of hs-cTnT are altered in adults with repaired tetralogy of Fallot (TOF) and associated with ventricular volume load and function. Eighty-eight TOF patients and 48 controls were studied. Plasma hs-cTnT levels were determined using a highly sensitive assay (hs-cTnT). The right (RV) and left ventricular (LV) volumes and ejection fraction (EF) were measured using 3D echocardiography and, in 52 patients, cardiac magnetic resonance (CMR). The median (interquartile range) for male and female patients were 4.87 (3.83-6.62) ng/L and 3.11 (1.00-3.87) ng/L, respectively. Thirty percent of female but none of the male patients had increased hs-cTnT levels. Female patients with elevated hs-cTnT levels, compared to those without, had greater RV end-diastolic and end-systolic volumes and LV systolic dyssynchrony index (all p < 0.05). For patient cohort only, hs-cTnT levels correlated positively with CMR-derived RV end-diastolic volume and negatively with echocardiography-derived LV and RV EF (all p < 0.05). Multiple linear regression identified sex and RV EF as significant correlates of log-transformed hs-cTnT levels. Increased hs-cTnT levels occur in 30% of female patients after TOF repair, and are associated with greater RV volumes and worse RV EF.

Three-dimensional mechanical dyssynchrony and myocardial deformation of the left ventricle in patients with tricuspid atresia after Fontan procedure.

BACKGROUND: The aim of this study was to test the hypothesis that dyssynchronous contraction of functional single ventricles occurs in Fontan patients and is related to indices of myocardial deformation and global ventricular function. METHODS: Twenty patients with tricuspid atresia (mean age, 23.5 ± 7.1 years) were studied 17.8 ± 3.8 years after undergoing the Fontan procedure. Three-dimensional echocardiographic data were acquired for determination of left ventricular (LV) volumes and systolic dyssynchrony indices. LV myocardial deformation was determined using speckle-tracking echocardiography. Calibrated integrated backscatter intensity was measured as an index of myocardial fibrosis. The results were compared with those in 20 controls. RESULTS: Compared with controls, patients had significantly greater systolic dyssynchrony indices (6.13 ± 1.32% vs 4.06 ± 0.84%, P < .001). The prevalence of LV mechanical dyssynchrony (systolic dyssynchrony index > 5.74%) in patients was 55% (95% confidence interval, 32%-77%). LV global systolic longitudinal, radial, and circumferential strain (P < .001 for all), longitudinal systolic (P < .001) and early diastolic (P < .001) strain rate, and circumferential systolic (P < .001) and early diastolic (P = .009) strain rate were significantly lower in patients than in controls, while the average calibrated integrated backscatter was higher (P < .001). Patients with LV dyssynchrony (n = 11) had lower global LV longitudinal strain (P = .02), reduced LV ejection fractions (P = .002), and higher average calibrated integrated backscatter (P = .03) compared with those without LV dyssynchrony (n = 9). CONCLUSIONS: A high proportion of patients with tricuspid atresia after the Fontan operation exhibit LV mechanical dyssynchrony, which may in part be related to myocardial fibrosis and has implications for myocardial deformation and global ventricular function.

Circulating annexin A5 levels after atrial switch for transposition of the great arteries: relationship with ventricular deformation and geometry.

BACKGROUND: Inflammatory cytokines, cardiomyocyte apoptosis, and altered collagen turnover may contribute to unfavourable ventricular remodeling. This unfavourable ventricular remodelling is well documented in patients after atrial switch operation for complete transposition of the great arteries. We therefore tested if levels of circulating markers of inflammation, apoptosis, collagen synthesis, and extracellular matrix degradation are altered in patients after atrial switch operation for transposition of the great arteries. METHODS AND RESULTS: Circulating tumour necrosis factor (TNF)-α, annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in 27 patients aged 25.2±3.1 years and 20 controls. Ventricular myocardial deformation and left ventricular eccentricity index (EI) were determined by speckle tracking and two-dimensional echocardiography, respectively. Compared with controls, patients had significantly higher circulating AnxA5 (p<0.001) and TNF-α (p = 0.018) levels, but similar PICP, PIIINP, MMP-1 and TIMP-1 levels. For the whole cohort, plasma AnxA5 correlated with serum TNF-α (p = 0.002), systemic ventricular global longitudinal strain (GLS) and systolic and early diastolic strain rate (all p<0.001), and subpulmonary ventricular GLS and early diastolic strain rate (both p<0.001). In patients, plasma AnxA5 level correlated positively with subpulmonary ventricular EI (p = 0.027). Multiple linear regression analysis identified systemic ventricular GLS (ß = -0.50, p<0.001) and serum TNF-α (ß = 0.29, p = 0.022) as significant correlates of plasma AnxA5. CONCLUSIONS: Elevated plasma AnxA5 level in patients after atrial switch operation is associated with impaired systemic myocardial deformation, increased subpulmonary ventricular eccentricity, and increased serum TNF-α level.