Search

Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Diastolic dysfunction (DD) is common in severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF≥50%)., Aim: To determine the impact of American Society of Echocardiography/European Association of Cardiovascular Imaging-recommended DD grading and left atrial strain on mortality in a cohort of patients with severe AS and preserved LVEF., Methods: We studied patients with severe AS (aortic valve area indexed<0.6 cm 2 /m 2 and/or aortic valve area<1cm 2 ), LVEF≥50% and no or mild AS-related symptoms. The endpoint was all-cause mortality., Results: A total of 387 patients (median age 76years; 53% women) were studied. During a median follow-up of 57 (interquartile range 37; 83) months, 158 patients died. After adjustment for prognostic factors, patients with grade II or III DD had an increased mortality risk versus patients with grade I DD (adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.11-2.38; P=0.013; aHR 4.73, 95% CI 2.49-8.99; P<0.001; respectively). Adding peak atrial longitudinal strain (PALS)≤14% to a multivariable model including DD grade improved predictive performance, with better global model fit, reclassification and discrimination. Patients with grade III DD or grade II DD+PALS≤14% displayed an increased mortality risk versus patients with grade I DD+PALS>14% (aHR 4.17, 95% CI 2.46-7.06; P<0.0001). Those with grade I DD+PALS≤14% or grade II DD+PALS>14% were at intermediate risk (aHR 1.63, 95% CI 1.07-2.49; P=0.024)., Conclusions: Our results demonstrate the strong relationship between DD and mortality in patients with severe AS and preserved LVEF. Patients with grade III or grade II DD and impaired PALS are at very high risk. These data demonstrate the importance of a comprehensive assessment of diastolic function in patients with severe AS., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background The ratio of acceleration time/ejection time (AT/ET) is a simple and reproducible echocardiographic parameter that integrates aortic stenosis severity and its consequences on the left ventricle. No study has specifically assessed the prognostic impact of AT/ET on outcome in patients with high-gradient severe aortic stenosis (SAS) and no or mild symptoms. We sought to evaluate the relationship between AT/ET and mortality and determine the best predictive AT/ET cutoff value in these patients. Methods and Results A total of 353 patients (median age, 79 years; 46% women) with high-gradient (mean pressure gradient ≥40 mm Hg and/or aortic peak jet velocity ≥4 m/s) SAS, left ventricular ejection fraction ≥50%, and no or mild symptoms were studied. The impact of AT/ET ≤0.35 or >0.35 on all-cause mortality was retrospectively studied. During a median follow-up of 39 (25th-75th percentile, 23-62) months, 70 patients died. AT/ET >0.35 was associated with a considerable increased mortality risk after adjustment for established prognostic factors in SAS under medical and/or surgical management (adjusted hazard ratio [HR], 2.54; 95% CI, 1.47-4.37; P <0.001) or conservative management (adjusted HR, 3.29; 95% CI, 1.70-6.39; P <0.001). Moreover, AT/ET >0.35 improved the predictive performance of models including established risk factors in SAS with better global model fit, reclassification, and discrimination. After propensity matching, increased mortality risk persisted when AT/ET >0.35 (adjusted HR, 2.10; 95% CI, 1.12-3.90; P <0.001). Conclusions AT/ET >0.35 is a strong predictor of outcome in patients with SAS and no or only mild symptoms and identifies a subgroup of patients at higher risk of death who may derive benefit from earlier aortic valve replacement.

Background: The relationship between myocardial work assessment using pressure-strain loops by echocardiography before cardiac resynchronization therapy (CRT) and response to CRT has been recently revealed. Among myocardial work parameters, the impact of left ventricular myocardial global wasted work (GWW) on response to CRT and outcome following CRT has been seldom studied. Hence, the authors evaluated the relationship between preprocedural GWW and outcome in a large prospective cohort of patients with heart failure (HF) and reduced ejection fraction receiving CRT., Methods: The study included 249 patients with HF. Myocardial work indices including GWW were calculated using speckle-tracking strain two-dimensional echocardiography using pressure-strain loops. End points of the study were (1) response to CRT, defined as left ventricular reverse remodeling and/or absence of hospitalization for HF, and (2) all-cause death during follow-up., Results: Median follow-up duration was 48 months (interquartile range, 43-54 months). Median preoperative GWW was 281 mm Hg% (interquartile range, 184-388 mm Hg%). Preoperative GWW was associated with CRT response (area under the curve, 0.74; P < .0001), and a 200 mm Hg% threshold discriminated CRT nonresponders from responders with 85% specificity and 50% sensitivity, even after adjustment for known predictors of CRT response (adjusted odds ratio, 4.03; 95% CI, 1.91-8.68; P < .001). After adjustment for established predictors of outcome in patients with HF with reduced ejection fraction receiving CRT, GWW < 200 mm Hg% remained associated with a relative increased risk for all-cause death compared with GWW ≥ 200 mm Hg% (adjusted hazard ratio, 2.0; 95% CI, 1.1-3.9; P = .0245). Adding GWW to a baseline model including known predictors of outcome in CRT resulted in an improvement of this model (χ 2 to improve 4.85, P = .028). The relationship between GWW and CRT response and outcome was stronger in terms of size effect and statistical significance than for other myocardial work indices., Conclusions: Low preoperative GWW (<200 mm Hg%) is associated with absence of CRT response in CRT candidates and with a relative increased risk for all-cause death. GWW appears to be a promising parameter to improve selection for CRT of patients with HF with reduced ejection fraction., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesized that preoperative electromechanical dyssynchrony amenable to cardiac resynchronization therapy (CRT) and QRS narrowing immediately after CRT are both correlated and have a cumulative impact on response and outcome after CRT., Methods: A total of 233 CRT candidates (heart failure New York Heart Association classes II-IV, ejection fraction < 35%, QRS ≥ 120 milliseconds, 44% women, 71 ± 11 years old) were prospectively included. Preoperative electromechanical dyssynchrony amenable to CRT was assessed by septal deformation patterns using speckle tracking echocardiography. QRS narrowing was calculated from 12-lead electrocardiograms before and immediately after CRT implantation. The primary endpoint was overall mortality during long-term follow-up. The NTC clinical trial number is NCT02986633., Results: Eighty-seven percent of patients with preoperative electromechanical dyssynchrony experienced QRS narrowing after CRT (118/136), whereas 69% of patients without preoperative electromechanical dyssynchrony (67/97) experienced QRS narrowing after CRT (P < 0.001). By Cox multivariate analysis, both preoperative electromechanical dyssynchrony and lack of postoperative QRS narrowing were independently associated with an increased risk of mortality during follow-up (adjusted hazards ratio [HR] 2.24, 95% confidence interval [CI] 1.43-3.50 and HR 1.90, 95% CI 1.06-3.38, respectively). Compared with patients with preoperative electromechanical dyssynchrony, patients without both electromechanical dyssynchrony and postoperative QRS narrowing experienced a considerable increased risk of mortality during follow-up (adjusted HR 3.70, 95% CI 1.96-6.97)., Conclusions: Lack of postoperative QRS narrowing after CRT is associated with preoperative electromechanical dyssynchrony. Both preoperative electromechanical dyssynchrony and postoperative QRS narrowing have a favourable cumulative impact on outcome after CRT., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Quantitative assessment of primary mitral regurgitation (MR) using left ventricular (LV) volumes obtained with three-dimensional transthoracic echocardiography (3D TTE) recently showed encouraging results. Nevertheless, 3D TTE is not incorporated into everyday practice, as current LV chamber quantification software products are time consuming., Aims: To investigate the accuracy and reproducibility of new automated fast 3D TTE software (HeartModel A.I. ; Philips Healthcare, Andover, MA, USA) for the quantification of LV volumes and MR severity in patients with isolated degenerative primary MR; and to compare regurgitant volume (RV) obtained with 3D TTE with a cardiac magnetic resonance (CMR) reference., Methods: Fifty-three patients (37 men; mean age 64±12 years) with at least mild primary isolated MR, and having comprehensive 3D TTE and CMR studies within 24h, were eligible for inclusion. MR RV was calculated using the proximal isovelocity surface area (PISA) method and the volumetric method (total LV stroke volume minus aortic stroke volume) with either CMR or 3D TTE., Results: Inter- and intraobserver reproducibility of 3D TTE was excellent (coefficient of variation≤10%) for LV volumes. MR RV was similar using CMR and 3D TTE (57±23mL vs 56±28mL; P=0.22), but was significantly higher using the PISA method (69±30mL; P<0.05 compared with CMR and 3D TTE). The PISA method consistently overestimated MR RV compared with CMR (bias 12±21mL), while no significant bias was found between 3D TTE and CMR (bias 2±14mL). Concordance between echocardiography and CMR was higher using 3D TTE MR grading (intraclass correlation coefficient [ICC]=0.89) than with PISA MR grading (ICC=0.78). Complete agreement with CMR grading was more frequent with 3D TTE than with the PISA method (76% vs 63%)., Conclusion: 3D TTE RV assessment using the new generation of automated software correlates well with CMR in patients with isolated degenerative primary MR., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The frequency of paradoxical low-gradient severe aortic stenosis (AS) varies widely across studies. The impact of misalignment of aortic flow and pressure recovery phenomenon on the frequency of low-gradient severe AS with preserved left ventricular ejection fraction (LVEF) has not been evaluated in prospective studies., Aims: To investigate prospectively the impact of aortic flow misalignment by Doppler and lack of pressure recovery phenomenon correction on the frequency of low-gradient (LG) severe aortic stenosis (AS) with preserved LVEF., Methods: Aortic jet velocities and mean pressure gradient (MPG) were obtained by interrogating all windows in 68 consecutive patients with normal LVEF and severe AS (aortic valve area [AVA] ≤1cm 2 ) on the basis of the apical imaging window alone (two-dimensional [2D] apical approach). Patients were classified as having LG or high-gradient (HG) AS according to MPG <40mmHg or ≥40mmHg, and normal flow (NF) or low flow (LF) according to stroke volume index >35mL/m 2 or ≤35mL/m 2 , on the basis of the 2D apical approach, the multiview approach (multiple windows evaluation) and AVA corrected for pressure recovery., Results: The proportion of LG severe AS was 57% using the 2D apical approach alone. After the multiview approach and correction for pressure recovery, the proportion of LG severe AS decreased from 57% to 13% (LF-LG severe AS decreased from 23% to 3%; NF-LG severe AS decreased from 34% to 10%). As a result, 25% of patients were reclassified as having HG severe AS (AVA ≤1cm 2 and MPG ≥40mmHg) and 19% as having moderate AS. Hence, 77% of patients initially diagnosed with LG severe AS did not have "true" LG severe AS when the multiview approach and the pressure recovery phenomenon correction were used., Conclusions: Aortic flow misevaluation, resulting from lack of use of multiple windows evaluation and pressure recovery phenomenon correction, accounts for a large proportion of incorrectly graded AS and considerable overestimation of the frequency of LG severe AS with preserved LVEF., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Whether echocardiography platform and analysis software impact left ventricular (LV) volumes, ejection fraction (EF), and stroke volume (SV) by transthoracic tridimensional echocardiography (3DE) has not yet been assessed. Hence, our aim was to compare 3DE LV end-diastolic and end-systolic volumes (EDV and ESV), LVEF, and SV obtained with echocardiography platform from 2 different manufacturers., Methods: 3DE was performed in 84 patients (65% of screened consecutive patients), with equipment from 2 different manufacturers, with subsequent off-line postprocessing to obtain parameters of LV function and size (Philips QLAB 3DQ and General Electric EchoPAC 4D autoLVQ). Twenty-five patients with clinical indication for cardiac magnetic resonance imaging served as a validation subgroup., Results: LVEDV and LVESV from 2 vendors were highly correlated (r = 0.93), but compared with 4D autoLVQ, the use of Qlab 3DQ resulted in lower LVEDV and LVESV (bias: 11 mL, limits of agreement: -25 to +47 and bias: 6 mL, limits of agreement: -22 to +34, respectively). The agreement between LVEF values of each software was poor (intraclass correlation coefficient 0.62) despite no or minimal bias. SVs were also lower with Qlab 3DQ advanced compared with 4D autoLVQ, and both were poorly correlated (r = 0.66). Consistently, the underestimation of LVEDV, LVESV, and SV by 3DE compared with cardiac magnetic resonance imaging was more pronounced with Philips QLAB 3DQ advanced than with 4D autoLVQ., Conclusions: The echocardiography platform and analysis software significantly affect the values of LV parameters obtained by 3DE. Intervendor standardization and improvements in 3DE modalities are needed to broaden the use of LV parameters obtained by 3DE in clinical practice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ejection dynamics parameters are useful in assessing prosthetic valve obstruction, but very limited data are available in the setting of native aortic stenosis (AS). The aim of this study was to evaluate and compare the prognostic value of acceleration time (AT) and the ratio of AT to ejection time (ET) in patients with AS., Methods: AT and AT/ET were prospectively measured in 456 patients with AS (aortic valve area < 1.3 cm 2 ; mean aortic valve area, 0.85 ± 0.24 cm 2 ). The relationships between AT/ET, AT, and mortality during follow-up were studied., Results: During a median follow-up period of 35 months (interquartile range, 33-37 months), 124 patients died. After adjustment for variables of prognostic importance, including mean pressure gradient, stroke volume index, and aortic valve replacement as a time-dependent covariate, patients in the highest tertiles of both AT/ET (>0.36) and AT (>112 msec) were at high risk for overall mortality (adjusted hazard ratios, 2.44 [95% CI, 1.46-4.08; P = .001] and 1.78 [95% CI, 1.06-2.98; P = .029], respectively) compared with those in the lowest tertiles of AT/ET and AT, while survival was similar for the other tertiles (P = NS for all). Compared with patients with AT/ET ≤ 0.36, an increased risk for overall mortality was observed in patients with AT/ET > 0.36 (adjusted hazard ratio, 2.51; 95% CI, 1.66-3.78; P < .0001), while the risk for mortality was not significantly increased in patients with AT > 112 msec compared with those with AT ≤ 112 msec. Adding AT/ET > 0.36 to a multivariate model including classical variables of prognostic importance, including mean pressure gradient and stroke volume index, improved predictive performance in terms of overall mortality, with improved global model fit, reclassification, and better discrimination., Conclusions: Among ejection dynamics parameters in patients with AS, AT/ET is strongly associated with excess risk for death during follow-up. AT/ET should be considered in the multiparametric echocardiographic prognostic assessment of patients with AS in clinical practice., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of secondary mitral regurgitation (MR) at baseline versus immediately after and several months after cardiac resynchronization therapy (CRT), beyond left ventricular (LV) reverse remodelling, has yet to be investigated., Aim: To evaluate the clinical significance of secondary MR before and at two timepoints after CRT in a large cohort of consecutive patients with heart failure (HF) and reduced LV ejection fraction., Methods: A total of 198 patients were recruited prospectively into a registry, and underwent echocardiography at baseline and immediately after CRT (on the day of hospital discharge). Echocardiography was also performed 9 months after CRT in 172 patients. The impact of significant secondary MR (≥moderate) on all-cause death, cardiovascular death and hospitalization for HF was studied at each stage., Results: The frequency of significant secondary MR decreased from 23% (n=45) to 8% (n=16) immediately after CRT. Among the 172 patients who underwent echocardiography 9 months after CRT, 17 (10%) had significant secondary MR. During a median follow-up of 48 months, 49 patients died and 36 were hospitalized for HF. Patients with significant secondary MR immediately after or 9 months after CRT had an increased risk of all-cause death, cardiovascular death and hospitalization for HF during follow-up (P<0.05 for all endpoints). After adjustment for LV reverse remodelling, significant secondary MR 9 months after CRT remained associated with an increased risk of all-cause death (adjusted hazard ratio [HR] 3.77; P=0.014), cardiovascular death (adjusted HR 5.36; P=0.037), and hospitalization for HF (adjusted HR 7.33; P=0.001)., Conclusions: Significant secondary MR despite CRT provides important prognostic information beyond LV reverse remodelling. Further studies are needed to evaluate the potential role of new percutaneous procedures for mitral valve repair in improving outcome in these very high-risk patients., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Aims: Specific septal motion related to dyssynchrony is strongly linked to reverse remodelling, in patients with systolic heart failure (HF) receiving cardiac resynchronization therapy (CRT). We aimed to investigate the relationship between septal deformation patterns studied by longitudinal speckle tracking and clinical outcome following CRT., Methods and Results: A total of 284 CRT candidates from two centres (HF NYHA classes II-IV, ejection fraction < 35%, QRS ≥ 120 ms) were prospectively included. Longitudinal strain of the septum in the apical four-chamber view determined three patterns of septal contraction. The endpoints were overall mortality, cardiovascular mortality, and hospitalization for HF. Compared with patterns 1 or 2, pattern 3 was associated with an increased risk for both overall and cardiovascular mortality [hazard ratio (HR) = 3.78, 95% confidence interval (CI): 1.85-7.75, P < 0.001 and HR = 3.84, 95% CI: 1.45-10.16, P = 0.007, respectively] and HF hospitalization (HR = 4.41, 95% CI: 2.18-8.90, P < 0.001). Addition of septal patterns to multivariable models, including baseline QRS width and presence of left bundle branch block, improved risk prediction, and discrimination. In patients with intermediate QRS duration (120-150 ms), pattern 3 remained associated with a worse outcome than pattern 1 or 2 (P < 0.05 for all endpoints)., Conclusion: The identification of septal deformation patterns provides important prognostic information in CRT candidates in addition to ordinary clinical, electrocardiographic, and echocardiographic predictors of outcome in HF patients. This parameter may be particularly useful in patients with intermediate QRS duration in whom the benefit of CRT remains uncertain., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Aims: Patients with significant (3+/4+) aortic regurgitation (AR) require careful monitoring or valve surgery. We sought to evaluate the diagnostic performance of aortic and pulmonary flow comparison in identifying patients with significant AR, by echocardiography., Method: Two hundred forty-six patients with more than trivial AR were prospectively enrolled from three centers. Aortic regurgitation (AR) severity was assessed by an expert using the currently recommended integrative approach. Aortic and pulmonary flows were independently assessed by another investigator to calculate the regurgitant fraction (RF), the aortic to pulmonary flow ratio (Qao/Qp) and the aortic to pulmonary velocity-time integral (VTIao/VTIp) ratio. The control group consisted of 195 patients without AR., Results: A significant correlation was observed between AR grading and RF (r = .82, P < .0001) and Qao/Qp (r = .81, P < .0001), but the correlation was modest for VTIao/VTIp ratio (r = .63; P < .0001). The accuracy of RF and Qao/Qp ratio to identify patients with significant AR was excellent (0.96 and 0.95, respectively), but was significantly lower for VTIao/VTIp ratio at 0.82. A RF > 40% indicated grade 3 or 4 AR with a sensitivity of 83% and a specificity of 93%. A Qao/Qp ratio > 1.6 indicated grade 3 or 4 AR with a sensitivity of 88% and a specificity of 89%. The VTIao/VTIp ratio was not helpful in identifying patients with significant AR, as a wide overlap was found between 1+/2+ and 3+/4+ patients., Conclusion: Regurgitant fraction (RF) and Qao/Qp are helpful in identifying significant AR. The assessment of Doppler aortic/pulmonary flow should be incorporated in the comprehensive evaluation of AR., (© 2017, Wiley Periodicals, Inc.)

Background and Aims: We hypothesized that large exercise-induced increases in aortic mean pressure gradient can predict haemodynamic progression during follow-up in asymptomatic patients with aortic stenosis., Methods: We retrospectively identified patients with asymptomatic moderate or severe aortic stenosis (aortic valve area<1.5cm 2 or<1cm 2 ) and normal ejection fraction, who underwent an exercise stress echocardiography at baseline with a normal exercise test and a resting echocardiography during follow-up. The relationship between exercise-induced increase in aortic mean pressure gradient and annualised changes in resting mean pressure gradient during follow-up was investigated., Results: Fifty-five patients (mean age 66±15 years; 45% severe aortic stenosis) were included. Aortic mean pressure gradient significantly increased from rest to peak exercise (P<0.001). During a median follow-up of 1.6 [1.1-3.2] years, resting mean pressure gradient increased from 35±13mmHg to 48±16mmHg, P<0.0001. Median annualised change in resting mean pressure gradient during follow-up was 5 [2-11] mmHg. Exercise-induced increase in aortic mean pressure gradient did correlate with annualised changes in mean pressure gradient during follow-up (r=0.35, P=0.01). Hemodynamic progression of aortic stenosis was faster in patients with large exercise-induced increase in aortic mean pressure gradient (≥20mmHg) as compared to those with exercise-induced increase in aortic mean pressure gradient<20mmHg (median annualised increase in mean pressure gradient 19 [6-28] vs. 4 [2-10] mmHg/y respectively, P=0.002). Similar results were found in the subgroup of 30 patients with moderate aortic stenosis., Conclusion: Large exercise-induced increases in aortic mean pressure gradient correlate with haemodynamic progression of stenosis during follow-up in patients with asymptomatic aortic stenosis. Further studies are needed to fully establish the role of ESE in the decision-making process in comparison to other prognostic markers in asymptomatic patients with aortic stenosis., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Landmark reports have suggested that patients with QRS widening immediately after cardiac resynchronization therapy (CRT) experienced less frequently reverse left ventricular remodeling during follow-up., Objective: We sought to investigate the relationship between postoperative QRS widening relative to baseline and mortality in a prospective cohort of heart failure patients receiving CRT., Methods: A 12-lead electrocardiogram was recorded for 237 heart failure patients (New York Heart Association class II to IV, left ventricular ejection fraction ≤35%, and QRS width ≥120 ms) before and immediately after CRT device implantation. The relationships between QRS widening, all-cause and cardiovascular mortality, and echocardiographic response to CRT were studied., Results: During a median follow-up of 24 months, 39 patients died. Fifty patients (21%) experienced QRS widening after CRT [QRS(+) group]. During follow-up, all-cause mortality was higher in QRS(+) patients than in QRS(-) patients (36-month survival free from death 81% ± 7% vs 64% ± 16%; log rank, P = .029). After adjustment for important prognostic confounders, QRS(+) patients remained associated with an excess overall mortality (adjusted hazard ratio [HR] 2.67; 95% confidence interval 1.07-6.65; P = .035) and cardiovascular mortality (adjusted hazard ratio 3.63; 95% confidence interval 1.13-11.65; P = .03). QRS(+) patients were less frequent responders to CRT than were QRS(-) patients (20 [47%] vs 136 [83%]; P < .0001)., Conclusion: Postoperative QRS widening relative to baseline after CRT is associated with a considerable increased mortality risk during follow-up. Whether QRS narrowing should be achieved to optimize CRT placement, and thereby increase the rate of CRT responders and improve outcome, deserves further research., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Typically disease-causing CAG/CTG repeats expand, but rare affected families can display high levels of contraction of the expanded repeat amongst offspring. Understanding instability is important since arresting expansions or enhancing contractions could be clinically beneficial. The MutSβ mismatch repair complex is required for CAG/CTG expansions in mice and patients. Oddly, by unknown mechanisms MutSβ-deficient mice incur contractions instead of expansions. Replication using CTG or CAG as the lagging strand template is known to cause contractions or expansions respectively; however, the interplay between replication and repair leading to this instability remains unclear. Towards understanding how repeat contractions may arise, we performed in vitro SV40-mediated replication of repeat-containing plasmids in the presence or absence of mismatch repair. Specifically, we separated repair from replication: Replication mediated by MutSβ- and MutSα-deficient human cells or cell extracts produced slipped-DNA heteroduplexes in the contraction- but not expansion-biased replication direction. Replication in the presence of MutSβ disfavoured the retention of replication products harbouring slipped-DNA heteroduplexes. Post-replication repair of slipped-DNAs by MutSβ-proficient extracts eliminated slipped-DNAs. Thus, a MutSβ-deficiency likely enhances repeat contractions because MutSβ protects against contractions by repairing template strand slip-outs. Replication deficient in LigaseI or PCNA-interaction mutant LigaseI revealed slipped-DNA formation at lagging strands. Our results reveal that distinct mechanisms lead to expansions or contractions and support inhibition of MutSβ as a therapeutic strategy to enhance the contraction of expanded repeats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The present study was designed to evaluate the respective value of left ventricular (LV) reverse remodeling (changes in LV end-systolic volume relative to baseline (ΔLVESV)) or LV performance improvement (ΔLV ejection fraction (ΔLVEF) or ΔGlobal longitudinal strain (GLS)) to predict long-term outcome in a prospective cohort of consecutive patients receiving routine cardiac resynchronization therapy (CRT)., Methods: One hundred and seventy heart failure patients (NYHA classes II-IV, LVEF ≤ 35%, QRS width ≥ 120 ms) underwent echocardiography before and 9 months after CRT. The relationships between ΔLVESV, ΔLVEF, ΔGLS and outcome (all-cause mortality and/or CHF hospitalization, overall mortality, cardiovascular mortality, CHF hospitalization) were investigated., Results: During a median follow-up of 32 months, 20 patients died and 27 were hospitalized for heart failure. ΔLVESV, ΔLVEF or ΔGLS were significantly associated with all-cause mortality or CHF hospitalization (adjusted hazard's ratio (HR) per standard deviation 0.58 (0.43-0.77), 0.39 (0.27-0.57) or 0.55 (0.37-0.83) respectively, all p < 0.01) and all other endpoints (all p < 0.01). Patients with ΔLVESV≥15%, ΔLVEF ≥ 10% and ΔGLS ≥ 1% had a reduced risk of mortality or CHF hospitalization (adjusted HR=0.25 (0.12-0.51), p < 0.001, adjusted HR = 0.26 (0.13-0.54), p < 0.001 and adjusted HR 0.38 (0.19-0.75), p = 0.006 respectively). Overall performance of multivariate models was better using ΔLVESV or ΔLVEF compared with ΔGLS. Interobserver agreement was excellent for ΔLVESV (Intraclass correlation coefficient - ICC-0.91) and ΔGLS (ICC 0.90) but modest for ΔLVEF (ICC 0.76) in a sample of 20 patients from the study population., Conclusions: LV reverse remodeling assessed by ΔLVESV is a strong and reproducible predictor of outcome following CRT. Compared with ΔLVESV, ΔLVEF and ΔGLS have important shortcomings: poorer reproducibility or lower predictive value., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Speckle tracking can be used to measure left ventricular global longitudinal strain (GLS)., Aims: To study the effect of speckle tracking software product upgrades on GLS values and intervendor consistency., Methods: Subjects (patients or healthy volunteers) underwent systematic echocardiography with equipment from Philips and GE, without a change in their position. Off-line post-processing for GLS assessment was performed with the former and most recent upgrades from these two vendors (Philips QLAB 9.0 and 10.2; GE EchoPAC 12.1 and 13.1.1). GLS was obtained in three myocardial layers with EchoPAC 13.1.1. Intersoftware and intervendor consistency was assessed. Interobserver variability was tested in a subset of patients., Results: Among 73 subjects (65 patients and 8 healthy volunteers), absolute values of GLS were higher with QLAB 10.2 compared with 9.0 (intraclass correlation coefficient [ICC]: 0.88; bias: 2.2%). Agreement between EchoPAC 13.1.1 and 12.1 varied by myocardial layer (13.1.1 only): midwall (ICC: 0.95; bias: -1.1%), endocardium (ICC: 0.93; bias: 1.6%) and epicardial (ICC: 0.80; bias: -3.3%). Although GLS was comparable for QLAB 9.0 versus EchoPAC 12.1 (ICC: 0.95; bias: 0.5%), the agreement was lower between QLAB 10.2 and EchoPAC 13.1.1 endocardial (ICC: 0.91; bias: 1.1%), midwall (ICC: 0.73; bias: 3.9%) and epicardial (ICC: 0.54; bias: 6.0%). Interobserver variability of all software products in a subset of 20 patients was excellent (ICC: 0.97-0.99; bias: -0.8 to 1.0%)., Conclusion: Upgrades of speckle tracking software may be associated with significant changes in GLS values, which could affect intersoftware and intervendor consistency. This finding has important clinical implications for the longitudinal follow-up of patients with speckle tracking echocardiography., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The present prospective study was designed to evaluate the accuracy of quantitative assessment of mitral regurgitant fraction (MRF) by echocardiography and cardiac magnetic resonance imaging (cMRI) in the modern era using as reference method the blinded multiparametric integrative assessment of mitral regurgitation (MR) severity. 2-Dimensional (2D) and 3-dimensional (3D) MRF by echocardiography (2D echo MRF and 3D echo MRF) were obtained by measuring the difference in left ventricular (LV) total stroke volume (obtained from either 2D or 3D acquisition) and aortic forward stroke volume normalized to LV total stroke volume. MRF was calculated by cMRI using either (1) (LV stroke volume - systolic aortic outflow volume by phase contrast)/LV stroke volume (cMRI MRF [volumetric]) or (2) (mitral inflow volume - systolic aortic outflow volume)/mitral inflow volume (cMRI MRF [phase contrast]). Six patients had 1 + MR, 6 patients had 2 + MR, 12 patients had 3 + MR, and 10 had 4 + MR. A significant correlation was observed between MR grading and 2D echo MRF (r = 0.60, p <0.0001) and 3D echo MRF (r = 0.79, p <0.0001), cMRI MRF (volumetric) (r = 0.87, p <0.0001), and cMRI MRF (phase contrast r = 0.72, p <0.001). The accuracy of MRF for the diagnosis of MR ≥3+ or 4+ was the highest with cMRI MRF (volumetric) (area under the receiver-operating characteristic curve [AUC] = 0.98), followed by 3D echo MRF (AUC = 0.96), 2D echo MRF (AUC = 0.90), and cMRI MRF (phase contrast; AUC = 0.83). In conclusion, MRF by cMRI (volumetric method) and 3D echo MRF had the highest diagnostic value to detect significant MR, whereas the diagnostic value of 2D echo MRF and cMRI MRF (phase contrast) was lower. Hence, the present study suggests that both cMRI (volumetric method) and 3D echo represent best approaches for calculating MRF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Severe low-gradient, low-flow (LG/LF) aortic stenosis with preserved left ventricular ejection fraction (EF) has been described as a more advanced form of aortic stenosis. However, the natural history and need for surgery in patients with LG/LF aortic stenosis remain subjects of intense debate., Objectives: We sought to investigate the outcome of LG/LF aortic stenosis in comparison with moderate aortic stenosis and with high-gradient (HG) aortic stenosis in a real-world study, in the context of routine practice., Methods: This analysis included 809 patients (ages 75 ± 12 years) diagnosed with aortic stenosis and preserved EF (≥50%). Patients were divided into 4 groups: mild-to-moderate aortic stenosis; HG aortic stenosis; LG/LF aortic stenosis; and low-gradient, normal-flow (LG/NF) aortic stenosis., Results: Compared with mild-to-moderate aortic stenosis patients, LG/LF aortic stenosis patients had smaller valve areas and stroke volumes, higher mean gradients, and comparable degrees of ventricular hypertrophy. Under medical management (22.8 months; range 7 to 53 months), compared with mild-to-moderate aortic stenosis patients, HG aortic stenosis patients were at higher risk of death (adjusted hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.03 to 2.07), whereas LG/LF aortic stenosis patients did not have an excess mortality risk (adjusted HR: 0.88; 95% CI: 0.53 to 1.48). During the entire (39.0 months; range 11 to 69 months) follow-up (with medical and surgical management), the mortality risk associated with LG/LF aortic stenosis was close to that of mild-to-moderate aortic stenosis (adjusted HR: 0.96; 95% CI: 0.58 to 1.53), whereas the excess risk of death associated with HG aortic stenosis was confirmed (adjusted HR: 1.74; 95% CI: 1.27 to 2.39). The benefit associated with aortic valve replacement was confined to the HG aortic stenosis group (adjusted HR: 0.29; 95% CI: 0.18 to 0.46) and was not observed for LG/LF aortic stenosis (adjusted HR: 0.75; 95% CI: 0.14 to 4.05)., Conclusions: In this study, the outcome of severe LG/LF aortic stenosis with preserved EF was similar to that of mild-to-moderate aortic stenosis and was not favorably influenced by aortic surgery. Further research is needed to better understand the natural history and the progression of LG/LF aortic stenosis., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have found a high frequency of mechanical dyssynchrony in patients with heart failure (HF) with preserved ejection fraction (HFpEF), hence suggesting that cardiac resynchronization therapy (CRT) may be considered in HFpEF. The present study was designed to compare the amount of mechanical dyssynchrony between HFpEF patients and (1) HF with reduced EF (HFrEF) patients with an indication for CRT (HFrEF-CRT(+)) group, (2) HFrEF patients with QRS duration < 120 ms (HFrEF-QRS < 120 ms) group, and (3) hypertensive controls (HTN)., Methods: Electrical (ECG) and mechanical dyssynchrony (atrio-ventricular dyssynchrony, interventricular dyssynchrony, intraventricular dyssynchrony) were assessed using conventional, tissue Doppler, and Speckle Tracking strain echocardiography in 40 HFpEF patients, 40 age- and sex-matched HTN controls, 40 HFrEF-QRS < 120 ms patients, and 40 HFrEF-CRT(+) patients., Results: The frequency of left bundle branch block was low in HFpEF patients (5%) and similar to HTN controls (5%, P = 0.85). Indices of dyssynchrony were similar between HFpEF and HTN patients or HFrEF-QRS < 120 ms patients. In contrast, most indices of dyssynchrony differed between HFpEF and HFrEF-CRT(+) patients. The principal components analysis on the entire cohort of 160 patients yielded 2 homogeneous groups of patients in terms of dyssynchrony, the first comprising HFrEF-CRT(+) patients and the second comprising HTN, HFrEF-QRS < 120 ms and HFpEF patients., Conclusions: Mechanical dyssynchrony in HFpEF does not differ from that of patients with HTN or patients with HFrEF and a narrow QRS. This data raises concerns regarding the role of dyssynchrony in the pathophysiology of HFpEF and thereby the potential usage of CRT in HFpEF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: To investigate the value of assessment of mitral regurgitant fraction (RF) using left ventricular (LV) volumes obtained by three-dimensional echocardiography (3DE) to quantify primary mitral regurgitation (MR)., Methods and Results: Sixty patients with primary MR in sinus rhythm were prospectively enrolled. RF was calculated using either 2DE or 3DE LV volumes obtained as follows: (LV total stroke volume - LV forward stroke volume by Doppler)/LV total stroke volume. Severity of MR was graded independently by two cardiologists blinded to LV volumetric data using an integrative approach, as recommended by current guidelines. Sixty patients with LV ejection fraction >50% and no MR were also studied. In patients without MR, 3D total LV stroke volume was more strongly correlated with LV forward stroke volume than 2D total LV stroke volume (r = 0.75, P < 0.0001 vs. r = 0.62, P < 0.0001, respectively). The 3D method had a feasibility of 90% in patients with MR. Inter-reader concordance for MR grading (four grades) was excellent with a Kappa-value of 0.90, P < 0.0001. A significant correlation was observed between grade of MR severity and 3D RF (r = 0.83, P < 0.0001) and 2D RF (r = 0.74, P < 0.0001). Comparisons between individual grades for 3D RF were significant (P < 0.05) except for 3+ vs. 4+ MR (P = 0.213). All patients with 3D RF ≥40% had ≥3+ or 4+ MR and those with 3D RF ≤30% had 1+ or 2+ MR with a 'grey' overlap zone between 30 and 40%., Conclusions: RF can be routinely determined using 3D LV volumes with a high feasibility in patients with primary MR and is reliable for identification of Grade 3+ or Grade 4+ MR. The incorporation of this parameter into the currently recommended multiparametric integrative approach might be helpful to discriminate significant MR., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Speckle tracking is a relatively new, largely angle-independent technique used for the evaluation of myocardial longitudinal strain (LS). However, significant differences have been reported between LS values obtained by speckle tracking with the first generation of software products., Aims: To compare LS values obtained with the most recently released equipment from two manufacturers., Methods: Systematic scanning with head-to-head acquisition with no modification of the patient's position was performed in 64 patients with equipment from two different manufacturers, with subsequent off-line post-processing for speckle tracking LS assessment (Philips QLAB 9.0 and General Electric [GE] EchoPAC BT12). The interobserver variability of each software product was tested on a randomly selected set of 20 echocardiograms from the study population., Results: GE and Philips interobserver coefficients of variation (CVs) for global LS (GLS) were 6.63% and 5.87%, respectively, indicating good reproducibility. Reproducibility was very variable for regional and segmental LS values, with CVs ranging from 7.58% to 49.21% with both software products. The concordance correlation coefficient (CCC) between GLS values was high at 0.95, indicating substantial agreement between the two methods. While good agreement was observed between midwall and apical regional strains with the two software products, basal regional strains were poorly correlated. The agreement between the two software products at a segmental level was very variable; the highest correlation was obtained for the apical cap (CCC 0.90) and the poorest for basal segments (CCC range 0.31-0.56)., Conclusions: A high level of agreement and reproducibility for global but not for basal regional or segmental LS was found with two vendor-dependent software products. This finding may help to reinforce clinical acceptance of GLS in everyday clinical practice., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new drugs acting at the dopamine receptors (DR) as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) can behave as selective D2 dopaminergic alkaloids. In the present study we have synthesized five aporphine compounds and five phenanthrene alkaloids and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR. Phenanthrene type alkaloids, in particular the 3,4-dihydroxy- and 3,4-methylenedioxy derivatives, displayed high selectivity towards D2 DR. Therefore, they are potential candidates to be used in the treatment of schizophrenia (antagonists) or Parkinson's disease (agonists) due to their scarce D1 DR-associated side effects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Previous studies have reported inconsistencies between echocardiographic parameters of severity in aortic valve stenosis (AS). Peak aortic valve velocity (Vmax ) strongly predicts outcome in AS patients. This study was therefore designed to identify the cutoff values of echocardiographic parameters of severity corresponding to a Vmax ≥ 3 m/sec, ≥4 m/sec, 5 m/sec, or 5.50 m/sec in a large cohort of patients with normal flow (NF) AS., Methods and Results: We retrospectively reviewed the echocardiograms of 528 consecutive patients with normal flow (NF) AS, left ventricular (LV) ejection fraction ≥0.50, and NF (stroke volume index > 35 mL/m²). The values of mean pressure gradient (MPG), aortic valve area (AVA), and indexed aortic valve area (IAVA) corresponding to Vmax ≥ 3 m/sec obtained from receiver operating characteristic (ROC) curves analysis were 22 mmHg, 1.15 cm(2) , and 0.60 cm(2) /m(2) , respectively. While a cutoff of Vmax ≥ 4 m/sec to define severe AS was consistent with a value of 39 mmHg for MPG, corresponding values for AVA and IAVA of 0.90 cm² and 0.48 cm²/m², respectively, were substantially different from those recommended in current guidelines. MPG ≥60 and 65 mmHg, AVA ≤0.76 and ≤0.68 cm², and IAVA ≤0.41 and ≤0.35 cm(2) /m(2) were related to a Vmax ≥5 and ≥5.5 m/sec (very severe AS), respectively., Conclusions: Guidelines recommended cutoff values for AVA and IAVA are not consistent with those of Vmax and MPG. The results of this study may serve as safeguard in case of apparent inconsistencies between echocardiographic parameters of severity in NF AS., (© 2012, Wiley Periodicals, Inc.)

We report the case of a 73-year-old man admitted for refractory heart failure following implantation of a dual-chamber pacemaker. Three-dimensional (3D) echocardiography with speckle tracking area strain identified severe left ventricular (LV) dysfunction and LV dyssynchrony following right ventricular pacing. As the patient's clinical condition rapidly worsened despite optimal medical treatment, a cardiac resynchronization therapy (CRT) pacemaker was successfully implanted as rescue therapy. Symptoms rapidly regressed and echocardiographic assessment following CRT demonstrated an immediate improvement in LV systolic function, confirmed at 9-month follow-up with evidence of reverse remodeling. New imaging technologies such as 3D echocardiography with speckle tracking area strain may help to identify and follow up patients who will benefit from CRT as rescue therapy., (© 2012, Wiley Periodicals, Inc.)

Background: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery, with increased risk of embolic events, haemodynamic instability, haemorrhagic complications and prolonged hospital stay., Aims: We sought to assess the value of preoperative left ventricular global longitudinal strain (GLS) for the prediction of POAF in a series of patients with severe symptomatic aortic stenosis who underwent aortic valve replacement (AVR)., Methods: Fifty-eight consecutive patients (52% men) aged 73±9 years, with severe symptomatic aortic stenosis (aortic valve area<1cm(2) or<0.5cm(2)/m(2)), in sinus rhythm, who underwent AVR were prospectively included in three centres between 2009 and 2010. Complete preoperative echocardiography was performed in all patients, including global and segmental longitudinal strain using two-dimensional speckle tracking., Results: The POAF incidence was 28/58 (48%). On univariate analysis, aortic valve area (P=0.04), preoperative E/e' ratio (P=0.04) and GLS (P=0.005) were associated with the occurrence of POAF. Chronic obstructive pulmonary disease (P=0.05), preoperative statin treatment (P=0.09), age≥80 years (P=0.09), left ventricular ejection fraction (P=0.09) and systolic pulmonary artery pressure (P=0.06) tended to increase the risk of POAF. The best GLS cut-off value for the prediction of POAF was -15% (82% sensitivity, 53% specificity, area under the curve 0.72). On multivariable analysis, GLS>-15% was the only independent predictor of POAF (odds ratio 7.74, 95% confidence interval [1.15-52.03]; P=0.035)., Conclusions: Incidence of POAF is high after AVR for severe aortic stenosis. Our results suggest an additive value of the study of left ventricular myocardial deformation to classical clinical and echocardiographic variables for the prediction of POAF in this setting., (Copyright © 2012. Published by Elsevier Masson SAS.)