Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas.

The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant rs10754558 in the NLRP3 gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in NLRC4 significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their "household contacts" (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed "exhausted" in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.

Relation of right ventricular mechanics to exercise tolerance in children after tetralogy of Fallot repair.

BACKGROUND: Progressive right ventricular (RV) dysfunction and exercise intolerance are common problems after tetralogy of Fallot (TOF) repair. We investigated RV myocardial deformation and dyssynchrony in children after TOF repair and their association with exercise capacity. METHODS: Asymptomatic children after TOF repair were investigated by 2-dimensional speckle tracking echocardiography, magnetic resonance, and metabolic exercise study. Patients with RV outflow obstruction were excluded. Peak RV longitudinal strain and strain rate (SR) and dyssynchrony (RV intraventricular delay) were compared with healthy controls. Associations between RV strain, dyssynchrony, and exercise capacity were analyzed. RESULTS: Thirty-nine (81%) of 48 TOF patients and 40 healthy controls had adequate RV strain imaging. The TOF patients had moderately dilated RVs and normal RV ejection fraction. Right ventricular peak systolic strain (-23.2% ± 5.1% vs -28.5% ± 8.5%, P < .001) and SR (-1.46 ± 0.68 vs -2.1 ± 0.8, P < .001) were reduced in TOF patients compared with controls. Right ventricular intraventricular delay was higher in TOF patients (146.0 ± 159 vs 71.0 ± 92 milliseconds, P = .008). Decreased RV strain and SR were associated with increased RV dyssynchrony (strain parameter estimate [PE] 6.31 [2.30], P = .007; SR [PE] 11.32 [3.84], P = .004). Increased RV-left ventricular delay was associated with prolonged QRS duration (PE 0.13 [0.058], P = .03) and reduced RV ejection fraction (PE -2.95 [1.275], P = .02). Reduced RV peak SR was associated with decreased exercise peak oxygen uptake (PE 0.14 [0.07], P = .04). CONCLUSIONS: After repair of TOF, asymptomatic children have reduced RV deformation in association with RV dyssynchrony and reduced exercise tolerance.

Impaired right and left ventricular diastolic myocardial mechanics and filling in asymptomatic children and adolescents after repair of tetralogy of Fallot.

AIMS: After tetralogy of Fallot (TOF) repair patients have right ventricular (RV) dysfunction and reduced exercise tolerance. Diastolic dysfunction may be important but is as yet poorly characterized. The early diastolic strain rate (SR) is a measure of ventricular relaxation, and may be useful to assess diastolic mechanics in TOF. We hypothesized that children after TOF repair have diastolic dysfunction and dyssynchrony by this measure, and sought to determine their relationship with pulmonary regurgitation (PR), RV enlargement, and aerobic exercise capacity. METHODS AND RESULTS: We prospectively recruited asymptomatic children after TOF repair. RV and PR volumes were measured by magnetic resonance imaging; Doppler and tissue Doppler indices by echocardiography and RV and left ventricular (LV) early diastolic SR by two-dimensional speckle tracking. Exercise peak oxygen consumption (VO(2)) was determined using bicycle ergometry. Results were compared with healthy controls. We studied 53 TOF patients and 49 age-matched controls. TOF patients had significant PR (2.05 ± 1 L/m(2)) with moderate RV dilatation (157 ± 39 mL/m(2)), low-normal RV ejection fraction (49 ± 8.8%), and moderate QRS prolongation (141 ± 23 ms). The RV outflow gradient was 21.7 ± 16.0 mmHg. Patients had RV diastolic dysfunction vs. controls [reduced tricuspid valve (TV) E/A ratio, E' velocity, and longitudinal diastolic SR; increased right atrial volume and TV E/E' ratio]. LV early diastolic radial and circumferential SR were lower in TOF patients in association with more PR [parameter estimate (PE) 0.177 standard error (SE) (0.08) mL/m(2), P = 0.02] and higher RV volumes [(PE) 0.005 (0.002)mL/m(2), P = 0.01]. Diastolic dyssynchrony was not different in TOF patients vs. controls. CONCLUSION: TOF patients have RV and LV diastolic dysfunction associated with RV enlargement and reduced early filling. SR imaging may be useful to quantify early myocardial diastolic dysfunction in these children.

Impaired left ventricular myocardial mechanics and their relation to pulmonary regurgitation, right ventricular enlargement and exercise capacity in asymptomatic children after repair of tetralogy of Fallot.

BACKGROUND: Left ventricular (LV) dysfunction is common in adults late after repair of tetralogy of Fallot (TOF). The early detection of myocardial dysfunction may be important, but LV myocardial strain and dyssynchrony are not well studied in children with TOF. The objective of this study was to investigate LV strain and dyssynchrony in asymptomatic children and adolescents after contemporary repair of TOF. The hypothesis was that impaired LV myocardial mechanics are related to pulmonary regurgitation, right ventricular (RV) enlargement, and exercise capacity. METHODS: Children and adolescents were prospectively studied after TOF repair. LV regional strain and dyssynchrony were assessed using two-dimensional speckle-tracking echocardiography. Ventricular volumes, ejection fraction, and pulmonary regurgitation were assessed using magnetic resonance imaging. Exercise capacity was determined using metabolic exercise testing. RESULTS: One hundred twenty-four subjects (53 patients with TOF and 71 controls) were studied. Regional circumferential (e.g., basal lateral wall, -15.0 ± 7.0% vs -19.0 ± 7.0%, P = .02) and radial (e.g., basal posterior wall, 32.0 ± 18.0% vs 48.0 ± 21.0%, P < .001) LV strain and longitudinal septal strain (-18.5 ± 3.5% vs -20.2 ± 2.8%, P = .01) were significantly reduced in patients with TOF compared with controls. LV mechanical dyssynchrony indices were not significantly different between groups (e.g., standard deviation of time to peak circumferential strain, 52.5 ± 40.4 vs 50.5 ± 27.1 msec, P = .81). Higher pulmonary regurgitation volume and larger RV end-diastolic volume were associated with decreased LV radial strain (P = .09). There was no association between LV longitudinal, radial, or circumferential dyssynchrony and indexed pulmonary regurgitation flow volume, RV end-diastolic volume, or RV ejection fraction. CONCLUSIONS: LV circumferential and radial strain are significantly reduced in children and adolescents after TOF repair and are associated with pulmonary regurgitation and RV dilatation. Resting LV mechanical dyssynchrony does not appear to contribute to early impaired LV strain in this population.

Usefulness of mitral regurgitation as a marker of increased risk for death or cardiac transplantation in idiopathic dilated cardiomyopathy in children.

In adults with idiopathic dilated cardiomyopathy (IDC), mitral regurgitation (MR) is associated with adverse prognosis and is often addressed by surgery or intervention. MR is commonly found in children with IDC, but its prognostic relevance has not been defined, and interventions to reduce MR are not routinely performed in this population. In this study, it was hypothesized that MR is an independent risk factor for death or transplantation. This was a single-center, retrospective study of sequential patients with IDC or familial IDC (left ventricular end-diastolic dimension z score >2 and ejection fraction <50%). Patients with acute myocarditis or previous mitral surgery were excluded. MR severity was graded according to American Society of Echocardiography guidelines as mild, moderate, or severe on the basis of MR jet vena contracta width. Left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were measured by biplane Simpson's method. Forty-two children with IDC were studied. The mean follow-up period was 25 months. At initial assessment, 34 children (82%) were taking angiotensin-converting enzyme inhibitors, 25 (60%) furosemide, 27 (65%) ß blockers, and 7 (17%) intravenous inotropes. The mean indexed end-systolic volume was 91 ± 51 ml/m(2). The mean ejection fraction was 27 ± 16%. MR was mild in 42%, moderate in 19%, severe in 2%, and absent in 35% of patients. MR severity progressed from initial to last evaluation. MR severity was an independent risk factor for lower freedom from death or transplantation. Progression in MR severity increased the annual hazard of death or transplantation by a factor of 2.4 (p = 0.003). In conclusion, MR severity is independently associated with worse clinical status and decreased freedom from death or transplantation in children with IDC.