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OBJECTIVES: The authors sought to characterize the functional and structural myocardial phenotypes of patients with moderate-to-severe aortic stenosis (AS) and to determine whether severe paradoxical low-gradient AS (LG-AS) is specifically associated with left ventricular (LV) remodeling and fibrosis. BACKGROUND: Recently, it was suggested that severe paradoxical LG-AS is a more advanced form of AS, with greater reduction of longitudinal deformation, adverse LV remodeling, and more interstitial fibrosis. METHODS: The study population includes 147 patients with moderate-to-severe AS and a normal LV ejection fraction, and 75 normal control subjects. They prospectively underwent 2-dimensional speckle-tracking echocardiography and cardiac magnetic resonance to evaluate myocardial deformation, LV remodeling, and age- and sex-adjusted extravascular volume fraction (ECV, %). Among AS patients, 18 had moderate AS, 74 had severe high-gradient AS (HG-AS), and 55 had severe paradoxical LG-AS. RESULTS: Reduced longitudinal and circumferential deformation was observed in 21% and 6% of the AS patients, respectively. Multivariate analyses identified increased ECV (ß = 1.99; p = 0.001) and the absence of normal LV geometry (ß = -1.37; p = 0.007) and as independent predictors of reduced longitudinal deformation. Increased ECV was an independent predictor of reduced circumferential deformation (ß = 2.19; p = 0.001). Over a median follow-up of 29 months, reduced longitudinal deformation (hazard ratio: 0.82; p = 0.023) and higher transvalvular gradients (hazard ratio: 1.05; p < 0.001) increased the risk of death or need for aortic valve replacement. LV hypertrophy was more frequently observed among patients with severe HG-AS (65%) than among the other AS patients (14%; p < 0.001). On average, ECV was within normal limits and did not differ among gradient-area subgroups. When present, increased ECV was associated with reduced longitudinal deformation. CONCLUSIONS: This study's data show that patients with severe paradoxical LG-AS less frequently display reduced longitudinal deformation, LV hypertrophy, or myocardial fibrosis than patients with HG-AS. Also, interstitial fibrosis only occurs when reduced longitudinal deformation and severe HG-AS are present together. Finally, this study suggests that reduced longitudinal deformation and higher transvalvular gradients adversely affect patients' outcomes.

Objectives This study sought to compare the prognostic value of 2-dimensional (2D) right ventricular (RV) speckle tracking (STE) against cardiac magnetic resonance (CMR) RV ejection fraction (EF) and feature tracking (FT) and conventional echocardiographic parameters on overall and cardiovascular (CV) survival in patients with heart failure with reduced EF (HFrEF). Background Prior works showed that RV systolic function predicts prognosis in HFrEF. 2D RVSTE had recently been proposed as new echocardiographic method to evaluate RV dysfunction. Methods A total of 266 patients with HFrEF (mean LVEF 23 ± 7%, 60 ± 14 years of age; 29% women) underwent RV function assessment using CMR and 2D echocardiography and were followed for a primary endpoint of overall death and secondary endpoint of CV death. Results Average CMR-RVEF was 42 ± 15%, average STE RV global longitudinal strain (STE-RVGLS) was −18.0 ± 4.9%, and average CMR-FT-RVGLS was −11.8 ± 4.3%. After a median follow-up of 4.7 years, 102 patients died, 84 of a CV cause. RVEF, FT-RVGLS, tricuspid annulus plane systolic excursion (TAPSE), fractional area change (FAC), and STE-RVGLS were significant univariate predictors of overall and cardiac death. In multivariate Cox regression, age, ischemic etiology, diabetes, New York Heart Association functional class III to IV, and beta-blocker treatment were independent clinical predictors of overall mortality. CMR-RVEF (chi-square to enter = 3.9; p 15 mm, 1.6 (95% CI: 1.02 to 2.49) for FAC >39%, 1.93 (95% CI: 1.25 to 2.99) for RVEF >41%, and 1.87 (95% CI: 1.10 to 3.19) for CMR-FT-RVGLS Conclusions 2D RVGLS provides strong additional prognostic value to predict overall and CV mortality in HFrEF, with higher predictive value than CMR-RVEF, CMR-FT-RVGLS, TAPSE, or FAC. This supports use of STE-RVGLS to identify higher-risk HFrEF patients.

Aortic valve surgery in non-elderly patients represents a very challenging patient population. The younger the patient is at the point of aortic valve intervention, the longer their anticipated life expectancy will be, with longer exposure to valve-related complications and risk for re-operation. Although the latest international guidelines recommend aortic valve repair in patients with aortic valve insufficiency, what we see in the real world is that the vast majority of these aortic valves are replaced. However, current prosthetic valves has now been shown to lead to significant loss of life expectancy for non-elderly patients up to 50% for patients in their 40s undergoing mechanical aortic valve replacement. Bioprostheses carry an even worse long-term survival, with higher rates of re-intervention. The promise of trans-catheter valve-in-valve technology is accentuating the trend of bioprosthetic implantation in younger patients, without yet the appropriate evidence. In contrast, aortic valve repair has shown excellent outcomes in terms of quality of life, freedom from re-operation and freedom from major adverse valve-related events with similar life expectancy to general population as it is also found for the Ross procedure, the only available living valve substitute. We are at a time when the paradigm of aortic valve surgery needs to change for the better. To better serve our patients, we must acquire high quality real-world evidence from multiple centers globally - this is the vision of the AVIATOR registry and our common responsibility.

OBJECTIVES: This study sought to determine the best left ventricular ejection fraction (LVEF) cutoff value to predict long-term mortality in patients with asymptomatic or minimally symptomatic severe aortic stenosis (AS) and LVEF ≥50% under conservative management and after surgical correction of AS. BACKGROUND: Aortic valve replacement (AVR) is a Class I indication in asymptomatic patients with severe AS and LVEF

Introduction We aimed to compare concordant high gradient (HG) aortic stenosis (AS) (aortic valve area [AVA] Background Despite the lack of evidences, European guidelines have suggested that discordant HG-AS should be considered as severe AS. Method We included 2701 patients (mean age 76 years) with HG-AS (2606 concordant and 95 discordant) and preserved ejection fraction (EF). Results After adjustment, patients with discordant HG-AS experienced lower 5-year survival than those with concordant HG-AS [HR (95%CI) = 1.59(1.04–2.56)]. The one and five-year cumulative incidence of aortic valve replacement (AVR) was lower for discordant HG-AS (61 ± 5% and 83 ± 4% versus 82 ± 1% and 90 ± 1% for concordant HG-AS, P Fig. 1 ). Conclusion In clinical practice, patients with discordant HG-AS are less referred for AVR and later than those with concordant HG-AS resulting in excess mortality. Consequently, after exclusion of a reversible high flow status, discordant HG-AS should be considered as severe AS and managed as such. Concordant versus discordant high-gradient AS.

Aims To analyze the relationship between chronic kidney disease(CKD) stages and all-cause and cardiovascular mortality and evaluate the effect of aortic-valve replacement(AVR) versus conservative management according to kidney function in patients with severe aortic stenosis(AS). Methods and results This analysis included 4119 patients with severe AS. The population was divided into four groups according to the baseline estimated glomerular filtration rate: no CKD, mild CKD, moderate CKD, and severe CKD. The five-year survival rate was 71 ± 1% for patients without CKD, 62 ± 2% for those with mild CKD, 54 ± 3% for those with moderate CKD, and 34 ± 4% for those with severe CKD (P Fig. 1 ). Conclusion In severe AS, moderate and severe CKD are associated with increased mortality and decreased referral to AVR. AVR markedly reduces all-cause and cardiovascular mortality, regardless of the CKD stage. Therefore, CKD should not discourage physicians from considering AVR.

Background: Myocardial contraction fraction (MCF) is a volumetric measure of myocardial shortening independent of left ventricular size and geometry. This multicenter study investigates the usefulness of MCF for risk stratification in low-gradient severe aortic stenosis with preserved ejection fraction. Methods: We included 643 consecutive patients with low-gradient severe aortic stenosis with preserved ejection fraction in whom MCF was computed at baseline and analyzed mortality during follow-up. Results: Throughout follow-up with medical and surgical management (34.9 [16.1–65.3] months), lower MCF tertiles had higher mortality than the highest tertile. Eighty-month survival was 56±4% for MCF>41%, 41±4% for MCF 30% to 41%, and 40±4% for MCFP 41%. The optimal MCF cutoff point for mortality prediction was 41%. Age, body mass index, Charlson index, peak aortic velocity, and ejection fraction were independently associated with mortality. MCF (χ 2 to improve 10.39; P =0.001), provided greater additional prognostic value over the baseline parameters than stroke volume (SV) index (χ 2 to improve 5.41; P =0.042), left ventricular mass index (χ 2 to improve 2.15; P =0.137), or global longitudinal strain (χ 2 to improve 3.67; P =0.061). MCF outperformed ejection fraction for mortality prediction. When patients were classified by SV index and MCF, mortality risk was low when SV index was ≥30 mL/m 2 and MCF>41%, higher for patients with SV index ≥30 mL/m 2 and MCF≤41% (adjusted hazard ratio, 1.47 [1.05–2.07]) and extremely high for patients with SV index 2 (adjusted hazard ratio, 2.29 [1.45–3.62]). Conclusions: MCF is a valuable marker of risk in low-gradient severe aortic stenosis with preserved ejection fraction and could improve decision-making, especially in normal-flow low-gradient severe aortic stenosis with preserved ejection fraction.

Background Limited data are available regarding the prognostic value of right ventricular (RV) systolic dysfunction (RVSD) in patients with coronary artery disease. Our objective was to evaluate the effect of RVSD assessed by cardiac magnetic resonance on survival of patients with low left ventricular (LV) ejection fraction (EF) undergoing coronary bypass grafting (CABG). Methods We prospectively assessed overall and cardiovascular death of 107 consecutive patients (94 men; age, 66 ± 10 years) undergoing CABG who had a LVEF of 0.35 or less by cardiac magnetic resonance before CABG. Results Mean LVEF was 0.25 ± 0.07, and mean RVEF was 0.46 ± 0.16. RVSD, defined by RVEF of 0.35 or less, was present in 32 patients (30%). In-hospital mortality rate (n = 8) was significantly higher in patients with RVSD (18.7% vs 2.7%, p = 0.004). Over a median follow-up of 4.7 years, 44 patients died, 33 of a cardiovascular cause. The primary end point of cardiovascular death was reached by 15 of 32 patients with RVSD and 18 of 75 patients without RVSD (47% vs 24%, p = 0.019). Univariate survival analysis showed that age, New York Heart Association Functional Classification, diabetes, estimated glomerular filtration rate, LVEF, LV indexed end-diastolic volume, RVEF, RV indexed end-diastolic volume, RV systolic function, and The Society of Thoracic Surgeons risk score were independent predictors of the primary end point of cardiovascular death. By multivariable analysis, the Society of Thoracic Surgeons risk score (hazard ratio, 1.32; 95% confidence interval, 1.13 to 1.55; p = 0.001) and RVSD (hazard ratio, 2.14; 95% confidence interval, 1.06 to 4.31; p = 0.034) remained significant independent predictors of cardiovascular death. Conclusions RVSD strongly and independently predicts cardiovascular death in patients with coronary artery disease and low EF undergoing CABG. Evaluation of RV function should thus be part of preoperative evaluation of such patients.

Right ventricular (RV) strain has emerged as an accurate tool for RV function assessment and is a powerful predictor of survival in patients with heart failure with reduced ejection fraction. However, its prognostic impact in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. The aim of this study was to compare the prognostic value of RV global longitudinal strain (RVGLS) by two-dimensional speckle-tracking echocardiographic (STE) imaging in patients with HFpEF against conventional RV function parameters. Patients with HFpEF were prospectively recruited, and 149 of 183 (81%) with analyzable STE RVGLS images constituted the final study population (mean age, 78 ± 9 years; 61% women), compared with 28 control subjects of similar age and sex. All control subjects and 120 patients also underwent cardiac magnetic resonance imaging. Patients were followed up for a primary end point of all-cause mortality and first heart failure hospitalization, and Cox regression analysis was performed. Mean STE RVGLS was significantly altered in patients with HFpEF compared with control subjects (-21.7 ± 4.9% vs -25.9 ± 4.2%, P -17.5%). During a mean follow-up period of 30 ± 9 months, 91 patients with HFpEF (62%) reached the primary end point. A baseline model was created using independent predictors of the primary end point: New York Heart Association functional class III or IV, hemoglobin level, estimated glomerular filtration rate, and the presence of moderate or severe tricuspid regurgitation. Impaired STE RVGLS provided significant additional prognostic value over this model (χ to enter = 7.85, P = .005). Impaired tricuspid annular plane systolic excursion and fractional area change, however, did not. In patients with HFpEF, impaired RVGLS has strong prognostic value. STE RVGLS should be considered for systematic evaluation of RV function to identify patients at high risk for adverse events.

Objectives The management of asymptomatic patients with severe aortic regurgitation remains controversial. Accordingly, the aim of the present study was to assess the long-term outcomes and incidence of cardiac complications among asymptomatic patients with severe aortic regurgitation who underwent operation early, in the absence of any class I or class IIa guideline triggers, or were managed conservatively and eventually underwent operation whenever these triggers appeared. Methods A total of 160 consecutive asymptomatic patients (50 ± 17 years) with severe aortic regurgitation were prospectively followed up for a median of 7.2 years. Overall and cardiovascular survivals and the need for repeat aortic regurgitation surgery were evaluated in an "early surgery" group (n = 91) and a "conservatively managed" group (n = 69). Results Ten-year overall (91% ± 4% vs 89% ± 5%, P = .87) and cardiovascular (96% ± 2% vs 96% ± 3%, P = .79) survivals were similar among the early surgery and conservatively managed groups. Conservatively managed patients were further sub-stratified according to the regularity and quality of their follow-up. Patients who were regularly followed up by a certified cardiologist had a better 10-year overall survival than patients undergoing no or a looser follow-up (95% ± 5% vs 79% ± 10%, P = .045). Multivariate Cox proportional hazards analysis identified age ( P = .003) and male gender ( P = .024) as independent predictors of survival. Early surgical management was not a predictor of outcome ( P = .45). Conclusions Our results show that the outcome of asymptomatic patients with severe aortic regurgitation is not different between an early surgical and a more conservative strategy, provided that the conservatively managed patients are regularly followed up and timely referred to surgery as soon as operative triggers develop. This suggests that surgery should not be recommended in patients with aortic regurgitation who do not meet current guidelines for intervention.

Although degenerative aortic valve stenosis (AS) is common with increasing age, limited data exist regarding the prevalence and prognostic impact of its various valve area-gradient patterns in patients ≥80 years. To test this, echocardiograms were obtained in 542 randomly selected subjects aged ≥80 years recruited in the Belgium Cohort Study of the Very Elderly study (BFC80+). Subjects were divided into 3 groups: no or mild AS, moderate AS, and severe AS. Patients with severe AS were further stratified into those with high mean gradients (HG-AS) and those with paradoxically low mean gradients (LG-AS). Prevalence of moderate-to-severe AS was 14.7% and that of severe AS was 5.9%. In patients with severe AS, most (72%) exhibited paradoxical LG-AS. All patients with severe HG-AS were asymptomatic at the time of inclusion, whereas 48% of those with severe paradoxical LG-AS had significant symptoms. During follow-up, there were 2 aortic valve replacements and 230 deaths, of which 100 (43%) were of cardiovascular origin. Five-year overall survival rate was significantly worse in severe HG-AS than in any of the other groups (22 ± 14% vs 62 ± 2% in no or mild AS, 48 ± 7% in moderate AS, and 43 ± 10% in severe paradoxical LG-AS, p0.01). Survival rate was similar among severe paradoxical LG-AS with and without low flow. In conclusion, in this large population-based sample of subjects ≥80 years, the prevalence of severe AS was 5.9%. Most of these subjects presented with the severe paradoxical LG-AS and a third of them were symptomatic. In this elderly community, severe HG-AS is a major determinant of prognosis, even in the absence of symptoms, whereas severe paradoxical LG-AS seems to behave similarly to moderate AS.

Low-gradient (LG), low-flow (LF), severe aortic stenosis (AS) with preserved ejection fraction (PEF) is considered by some authors as an advanced form of AS associated with very poor outcome. The aim of this Doppler echocardiographic study was to investigate changes over time in the hemodynamic severity of LG/LF AS with PEF. We retrospectively identified in 2 academic centers 59 patients who had 2 Doppler echocardiographic examinations without an intervening event. After a median follow-up of 2 (interquartile range [IQR] 1.3 to 3.5) years, progression was observed with increase in mean Doppler gradient (MDG; from 27 [23 to 32] to 37 [28 to 44] mm Hg; p

Objectives The purpose of this study was to evaluate the impact of hypertrabeculation and left ventricular (LV) myocardial noncompaction phenotype by cardiac magnetic resonance (CMR) on outcomes of patients with nonischemic dilated cardiomyopathy (DCM). Background Myocardial trabeculations and noncompaction are increasingly observed in patients with DCM, but their prognostic impact remains unknown. Methods We prospectively evaluated outcomes of 162 consecutive patients (102 men; age 55 ± 15 years; ejection fraction [EF] 25 ± 8%) with DCM undergoing CMR. The amount of noncompaction was quantified as noncompacted/compacted (NC/C) length in the long-axis view and as the ratio of NC/C mass in the short-axis view and compared against 48 healthy control subjects (age 60 ± 10 years). Results Fifty-eight DCM patients (36%) had NC/C length ≥2.3, and 71 (44%) had NC/C mass greater than the 95% confidence interval (CI) of control subjects. NC/C length and NC/C mass did not correlate with any clinical, echocardiographic, or CMR parameters. Over a 3.4-year median follow-up, 29 patients experienced major adverse cardiovascular events (MACE) (12 cardiovascular deaths, 8 heart transplantations, 4 LV assist device implantations, and 5 resuscitated cardiac arrests or appropriate device shocks). Cox univariate analysis identified smoking, New York Heart Association functional class, blood pressure, LV and right ventricular end-diastolic and end-systolic volumes, LV EF, right ventricular EF, and late gadolinium enhancement as predictors of MACE. In multivariate analysis, only LV EF and late gadolinium enhancement were independent predictors of MACE-free survival (hazard ratio: 0.922, 95% CI: 0.878 to 0.967, p = 0.001 and HR: 1.096, 95% CI: 1.004 to 1.197, p = 0.04, respectively). Neither NC/C length nor NC/C mass had significant predictive value for MACE-free survival, either unadjusted or after adjustment for baseline variables. Also, there was no difference in cardioembolic event rate between groups with high and low NC/C length or mass. Conclusions Cardiovascular outcomes of adult patients with nonischemic DCM do not appear to be influenced by the degree of trabeculation. This argues against a noncompaction phenotype designating a more severe form of DCM.

Background For patients with aortic regurgitation (AR), aortic valve (AV) repair represents an attractive alternative to AV replacement (AVR), because it does not expose patients to the risk of prosthetic valve complications. Although the durability of AV repair has been documented, its prognosis has not yet been compared with prognosis of AVR. Methods We performed a propensity score analysis to match patients who underwent surgical correction of severe AR by either AVR or AV repair between 1995 and 2012. After matching, 44 pairs of patients were compared regarding baseline characteristics; overall survival; operative survival; cardiac events, including reoperations; recurrent AR; and New York Heart Association functional class at final follow-up. Results Operative mortality was similar in the AV repair and AVR groups (2% vs 5%; P = .56). Kaplan-Meier survival analysis indicated a significantly better overall 9-year survival after AV repair than after AVR (87% vs 60%; P = .007). Cox proportional survival analysis demonstrated that the choice of treatment was an independent predictor of postoperative survival. Finally, AV repair resulted in a slight increase, albeit not statistically significant, in reoperation rate (8% vs 2%; log rank P = .35). Conclusions AV repair significantly improves postoperative outcomes in patients with AR and whenever feasible should probably be the preferred mode of surgical correction.

BackgroundPrior studies have shown that late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) can detect focal fibrosis in aortic stenosis (AS), suggesting that it might predict higher mortality risk.ObjectivesThis study was conducted to evaluate whether LGE-CMR can predict post-operative survival in patients with severe AS undergoing aortic valve replacement (AVR).MethodsWe prospectively evaluated survival (all-cause and cardiovascular disease related) according to LGE-CMR status in 154 consecutive AS patients (96 men; mean age: 74 ± 6 years) without a history of myocardial infarction undergoing surgical AVR and in 40 AS patients undergoing transcatheter aortic valve replacement (TAVR).ResultsLGE was present in 29% of patients undergoing surgical AVR and in 50% undergoing TAVR. During a median follow-up of 2.9 years, 21 patients undergoing surgical AVR and 20 undergoing TAVR died. In surgical AVR, the presence of LGE predicted higher post-operative mortality (odds ratio: 10.9; 95% confidence interval [CI]: 1.2 to 100.0; p = 0.02) and worse all-cause survival (73% vs. 88%; p = 0.02 by log-rank test) and cardiovascular disease related survival (85% vs. 95%; p = 0.03 by log-rank test) on 5-year Kaplan-Meier estimates of survival after surgical AVR. Multivariate Cox analysis identified the presence of LGE (hazard ratio: 2.8; 95% CI: 1.3 to 6.9; p = 0.025) and New York Heart Association functional class III/IV (hazard ratio: 3.2; 95% CI: 1.1 to 8.1; p < 0.01) as the sole independent predictors of all-cause mortality after surgical AVR. The presence of LGE also predicted higher all-cause mortality (p = 0.05) and cardiovascular disease related mortality (p = 0.03) in the subgroup of patients without angiographic coronary artery disease (n = 110) and higher cardiovascular disease related mortality in 25 patients undergoing transfemoral TAVR.ConclusionsThe presence of LGE indicating focal fibrosis or unrecognized infarct by CMR is an independent predictor of mortality in patients with AS undergoing AVR and could provide additional information in the pre-operative evaluation of risk in these patients.

The early diastolic transmitral velocity/tissue Doppler imaging mitral annular early diastolic velocity (E/e') ratio is used to estimate left ventricular (LV) filling pressures at rest. However, there are only limited data that validate its use during exercise. Accordingly, the aim of this study was to test the ability of E/e' to estimate pulmonary capillary wedge pressure (PCWP) during symptom-limited exercise in patients with LV systolic dysfunction. Forty patients with severe LV dysfunction and heart failure symptoms (54 ± 12 years, 28 men) underwent simultaneous Doppler assessment of E/e' and right-sided cardiac catheterization at rest and during a symptom-limited exercise test, at steady state levels of 30%, 60%, and 90% of their maximal exercise capacity. During exercise, all 40 patients successfully completed stage 1, yielding 40 pairs of data for comparison. Eighteen patients also successfully completed stage 2, and 5 patients also made it through stage 3, yielding 23 additional data pairs. In total, there were thus 63 pairs of data available during exercise. With exercise, heart rate increased from 77 ± 14 to 112 ± 21 beats/min. Septal E/e' at rest correlated well with PCWP at rest (r = 0.75, p0.01). PCWP at rest also correlated with resting mitral deceleration time (r = 0.32, p0.01) and with the transmitral E/A ratio (r = 0.74, p0.01). During exercise, the correlation between septal E/e' and PCWP was weaker (r = 0.57, p0.01) and was shifted to the right. This rightward shift was observed in patients with both separated or merged E and A velocities. In conclusion, in patients with severe LV dysfunction, although E/e' allows accurate estimation of PCWP at rest, it appears less reliable for estimating LV filing pressure during exercise.

BACKGROUND: Platelet activation requires sweeping morphologic changes, supported by contraction and remodeling of the platelet actin cytoskeleton. In various other cell types, AMP-activated protein kinase (AMPK) controls the phosphorylation state of cytoskeletal targets. OBJECTIVE: To determine whether AMPK is activated during platelet aggregation and contributes to the control of cytoskeletal targets. RESULTS: We found that AMPK-α1 was mainly activated by thrombin, and not by other platelet agonists, in purified human platelets. Thrombin activated AMPK-α1 ex vivo via a Ca(2+) /calmodulin-dependent kinase kinase β (CaMKKβ)-dependent pathway. Pharmacologic inhibition of CaMKKβ blocked thrombin-induced platelet aggregation and counteracted thrombin-induced phosphorylation of several cytoskeletal proteins, namely, regulatory myosin light chains (MLCs), cofilin, and vasodilator-stimulated phosphoprotein (VASP), three key elements involved in actin cytoskeletal contraction and polymerization. Platelets isolated from mice lacking AMPK-α1 showed reduced aggregation in response to thrombin, and this was associated with defects in MLC, cofilin and VASP phosphorylation and actin polymerization. More importantly, we show, for the first time, that the AMPK pathway is activated in platelets of patients undergoing major cardiac surgery, in a heparin-sensitive manner. CONCLUSION: AMPK-α1 is activated by thrombin in human platelets. It controls the phosphorylation of key cytoskeletal targets and actin cytoskeletal remodeling during platelet aggregation

Current guidelines recommend aortic valve replacement (AVR) as a Class I indication in asymptomatic severe aortic stenosis (AS) when left ventricular (LV) function is impaired, when other cardiac surgery is planned, or when valve-related symptoms are induced by exercise. For asymptomatic patients

Background The pathophysiology and clinical significance of low gradient severe aortic stenosis [SAS] despite normal EF, also referred to as paradoxical low gradient [PLG]-SAS, is controversial. It has been suggested that PLG- SAS was associated with higher degree of interstitial myocardial fibrosis and worse outcome as compared to high-gradient (HG)-SAS. Methods To verify this, we obtained myocardial biopsies and measured myocardial extravascular volume fraction (ECV, %) from cMR Modified Look-Locker imaging (MOLLI) T1 mapping at 3T in 155 consecutive patients with moderate to severe AS [22 moderate AS, 75 HG-SAS, 58 PLG-SAS, including 24 low flow (LF) and 34 normal flow (NF) PLG-SAS]. ECV values were compared to those measured in 33 normal age-matched controls. Results ECV correlated with the amount of interstitial fibrosis (IF) on histology (r = 0.75, P Fig. 1 ]. Conclusion Our results demonstrate that the amount of IF, measured by histology or MOLLI is similar among controls and patients with SAS. These data do not support the contention that PLG-SAS is associated with higher degree of IF.

Background LV global longitudinal strain (GLS) is significantly altered in HFpEF and is a powerful predictor of outcome according to a recent meta-analysis. Aim We sought to determine the evolution of GLS across the spectrum of AHA HF stages and to analyze the correlation of GLS with other clinical, biological and imaging variables and its prognostic value in HFpEF. Methods GLS was assessed by 2D speckle-tracking echocardiography in 172 patients with HFpEF stage C (78 ± 10 yrs, 38%men), 22 stage B (73 ± 10 yrs, 32%men), 56 stage A (63 ± 16 yrs, 52% men) and 20 healthy volunteers (38 ± 12 yrs, 55% men). Impaired GLS was defined as −16.6%, corresponding to 2 SD below the mean value of age and sex matched controls. All patients underwent 2D echo and cMR. Patients were followed up for a composite outcome of mortality and first HF hospitalization. Results Mean GLS was −20.1 ± 1.0%, −19.8 ± 1.6%, −19.1 ± 2.6% and −16.6 ± 3.0% in volunteers, stage A, stage B and stage C respectively (P for trend Fig. 1 ). In HFpEF stage C, 86 patients (50%) had an impaired GLS. They had higher NTproBNP (P = 0.002), higher sST2 (P = 0.023), higher incidence of AF (55% vs. 36%, P = 0.014), lower LVEF (P Conclusion There is a continuum in GLS impairment across the spectrum of AHA HF stages confirming the role of a subclinical myocardial dysfunction in HFpEF. Impaired GLS was associated with RV dysfunction and NTproBNP but not with clinical outcomes in HFpEF.

Introduction Right ventricle strain has emerged as an accurate tool for RV function assessment and is a strong predictor of survival in HFrEF. The impact of RV strain assessed by cMR in HFpEF is unknown. Objective We sought to analyze RV strain by cMR in controls and HFpEF and to analyze its prognostic value. Methods Between January 2015 and June 2017, we prospectively enrolled 100 consecutive patients with HFpEF (79 ± 8 years, 59% women) and 64 controls (56 ± 20 years, 52% women). All patients underwent 2D echo and 3Tesla cMR in sinus rhythm. A four-chamber view was analyzed by 2D feature tracking to evaluate the global longitudinal strain of RV (RV-GLS). HFpEF patients were followed up for a combined outcome of all-cause mortality and first HF hospitalization. Results In HFpEF, mean RV-GLS was significantly lower than in controls (−14.6 ± 4.6% vs. −17.0 ± 3.9%; P = 0.007) ( Fig. 1 ). Due to poor tracking quality, 28 controls (44%) and 19 HFpEF patients (19%) were excluded from the analysis. In univariate linear regression analysis, NTproBNP (R = 0.36, P = 0.001), E wave velocity (R = 0.29, P = 0.001), E/e’ ratio (R = 0.28, P = 0.002), RV fractional area change (R = −0.29, P = 0.001), TAPSE (R = −0.24, P = 0.006), indexed LA volume (R = 0.27, P = 0.003), LVEF (R = −0.32, P = 0.001), indexed LV mass (R = 0.36, P = 0.001), RVEF by cMR (R= −0.45, P Conclusion RV-GLS assessed by cMR feature tracking is significantly different between controls and HFpEF patients and is associated with RVEF and NTproBNP. However, RV GLS was not associated with poor outcome in HFpEF.

Background Aortic valve replacement (AVR) is a class I indication in asymptomatic patients with severe AS and LVEF Purpose The aim of this study was to determine the best left ventricular ejection fraction (LVEF) cut-off to predict long-term mortality in patients with asymptomatic or minimally symptomatic severe aortic stenosis (AS) and LVEF ≥ 50% under conservative management and after surgical correction of AS. Methods This analysis includes 1678 patients with preserved (≥50%) LVEF and no or minimal symptoms, diagnosed with severe AS. The population was divided into 3 groups: LVEF Results Five-year survival rate was 72 ± 2% for patients with LVEF ≥60%, 74 ± 2% for patients with LVEF between 55 and 59% and 59 ± 4% for patients with LVEF Conclusion LVEF is a powerful predictor of survival in a population of AS patients with no or minimal symptoms at diagnosis and LVEF ≥ 50%. Patients with LVEF

Eukaryotic elongation factor 2 (eEF-2) and mammalian target of rapamycin (mTOR)–p70 ribosomal protein S6 kinase (p70S6K) signaling pathways control protein synthesis and are inhibited during myocardial ischemia. Intracellular acidosis and AMP-activated protein kinase (AMPK) activation, both occurring during ischemia, have been proposed to participate in this inhibition. We evaluated the contribution of AMPKα2, the main cardiac AMPK catalytic subunit isoform, in eEF2 and mTOR–p70S6K regulation using AMPKα2 KO mice. Hearts were perfused ex vivo with or without insulin, and then submitted or not to ischemia. Insulin pre-incubation was necessary to activate mTOR–p70S6K and evaluate their subsequent inhibition by ischemia. Ischemia decreased insulin-induced mTOR–p70S6K phosphorylation in WT and AMPKα2 KO mice to a similar extent. This AMPKα2-independent p70S6K inhibition correlated well with the inhibition of PKB/Akt, located upstream of mTOR–p70S6K and can be mimicked in cardiomyocytes by decreasing pH. By contrast, ischemia-induced inhibitory phosphorylation of eEF-2 was drastically reduced in AMPKα2 KO mice. Interestingly, AMPKα2 also played a role under normoxia. Its deletion increased the insulin-induced p70S6K stimulation. This p70S6K over-stimulation was associated with a decrease in inhibitory phosphorylation of Raptor, an mTOR partner identified as an AMPK target. In conclusion, AMPKα2 controls cardiac p70S6K under normoxia and regulates eEF-2 but not the mTOR–p70S6K pathway during ischemia. This challenges the accepted notion that mTOR–p70S6K is inhibited by myocardial ischemia mainly via an AMPK-dependent mechanism.

Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 +/- 1.0% to 34.5 +/- 1.1%) versus standard of care alone (from 27.8 +/- 2.0% to 28.0 +/- 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 +/- 3.0 ml vs. -8.8 +/- 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 +/- 18 m vs. -15 +/- 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238) (C) 2013 by the American College of Cardiology Foundation

BACKGROUND: Little is known about the relationship between cardiac dysfunction and poor functioning in the elderly. This study sought to describe the prevalence of cardiac dysfunction in the very elderly and to investigate the correlation between echocardiographic abnormalities and indicators of poor functioning. METHODS: A cross-sectional analysis within the BELFRAIL (BF(C80+)) study of 567 subjects aged 80years and older. The clinical research assistant performed an examination including performance testing, questionnaires and technical examinations. Echocardiography was performed at the subject’s home by a cardiologist using a portable system. RESULTS: The mean age of the participants was 84.7years and 62.9% were women. Severe cardiac dysfunction was found in 19.3% and was defined as systolic dysfunction (5.8%), valvular heart disease (10.4%) or isolated severe diastolic dysfunction (3.1%). Severe cardiac dysfunction showed to be an independent identifier of poor performance (OR 1.8 (95% CI 1.1-3.2)), a low LAPAQ (LASA Physical Activity Questionnaire) score (OR 1.9 (95% CI 1.2-3.3)) and a high GDS-15 (Geriatric Depression Scale) score (OR 1.7 (95% CI 1.0-2.9)). This relationship was mainly explained by the independent correlation between aortic stenosis and poor functioning. Classic indicators of systolic and diastolic dysfunction were not able to identify participants with poor functioning. CONCLUSION: This study shows the very elderly represent a heterogeneous group of subjects with a high prevalence of comorbidities, among whom poor functioning might be triggered by multiple causes. Severe cardiac dysfunction, and more specifically aortic stenosis, showed an independent relationship with poor functioning.

Heart failure of ischemic origin has become increasingly common over the last decade because of the improved survival of patients with acute myocardial infarction. Revascularization with coronary bypass grafting or percutaneous coronary intervention plays a pivotal role in patients with ischemic cardiomyopathy, although these interventions are often associated with relatively high peri-procedural risk. The pathophysiological substrate of ischemic cardiomyopathy is heterogeneous, varying from predominantly hibernating myocardium to irreversible scarring. There is evidence to suggest that patients with hibernating myocardium benefit most from revascularization, whereas medical therapy is associated with an adverse prognosis. Therefore, noninvasive testing is recommended by relevant guidelines to guide optimal management in these patients. However, the role of noninvasive testing has recently been challenged. There are various imaging modalities available that provide information on different aspects of the disease, and therefore, they differ significantly in sensitivity and specificity. In clinical practice, choosing among the different imaging modalities can be difficult. Cardiac magnetic resonance has evolved into a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar. This paper reviews the indications, accuracy, and clinical utility of the available imaging techniques, with a special focus on cardiac magnetic resonance in ischemic cardiomyopathy, and provides an outlook on how this field might evolve in the future.

Cardiovascular diseases are still the primary causes of mortality in the United States and in Western Europe. Arterial thrombosis is triggered by a ruptured atherosclerotic plaque and precipitates an acute vascular event, which is responsible for the high mortality rate. These rupture-prone plaques are called “vulnerable plaques.” During the past decades, much effort has been put toward accurately detecting the presence of vulnerable plaques with different imaging techniques. In this review, we provide an overview of the currently available invasive and noninvasive imaging modalities used to detect vulnerable plaques. We will discuss the upcoming challenges in translating these techniques into clinical practice and in assigning them their exact place in the decision-making process.

Aortic stenosis (AS) is a common valve disease in octogenarians. Previous studies have shown that aortic valve replacement (AVR) is frequently not performed in these patients. This study investigated the incidence, determinants, and prognostic impact of AVR refusal or denial in these patients.Between 2000 and 2007, 163 octogenarians (mean age, 84 ± 3 years) with severe AS and an indication for operation according to guidelines were prospectively included in an echocardiographic registry. Among these, 97 underwent AVR, and 66 were treated conservatively.Logistic regression analysis identified older age, a lower transaortic pressure gradient, a larger aortic valve area, and the presence of diabetes as independent predictors of AVR refusal or denial. Patients who underwent AVR had a 30-day mortality of 9%. Overall 5-year survival was 66% in AVR patients vs 31% in those treated conservatively (log rank p0.001 vs AVR). After adjustment for the propensity score, patients undergoing AVR still had a better outcome than conservatively treated patients (hazard ratio, 0.56; 95% confidence interval, 0.29 to 0.91; p = 0.022). In addition to the therapeutic decision, Cox regression analysis also identified low body weight, New York Heart Association class III/IV, and the logistic European System for Cardiac Operative Risk Evaluation as independent predictors of outcome in the overall series.About 40% of octogenarians with severe AS and a definite indication for operation either refuse or are denied AVR. AVR refusal or denial has a profound impact on long-term prognosis, resulting in a twofold excess mortality, even after adjustment for the propensity score.

Mobilization of stem cells and progenitor cells from the bone marrow (BM) into the peripheral blood (PB) by granulocyte-colony-stimulating factor (G-CSF) is being investigated for cardiac regeneration in ischemic heart disease. However, hematopoietic (HPC), mesenchymal (MPC) and endothelial (EPC) progenitor mobilization have not been optimized and the effect of G-CSF on myocardial perfusion and cardiac function in a normal heart has never been studied.Normal mice were injected daily for 1-10 days with subcutaneous recombinant human G-CSF. PB and BM were evaluated for HPC and EPC by flow cytometry and HPC and MPC by hematopoietic (CFU-GM) and mesenchymal (CFU-F) colony assays. Echocardiography, microSPECT imaging, cardiac catheterization and immunohistochemistry were performed in mice treated for 10 days.HPC and CFU-GM in PB peaked after 2 days, CFU-F after 4 days and EPC after 3 days. Thereafter, while HPC temporally decreased before showing a second peak, EPC remained detectable only at low levels. In BM, hematopoietic stem cells (HSC) and CFU-GM did not increase much overall but peaked twice on days 2 and 7. EPC (peak on day 7) production increased in the BM, but CFU-F formation declined considerably after day 2. G-CSF enhanced myocardial perfusion and vascularization but impaired hemodynamic performance of the heart through apparently increased ventricular wall rigidity.G-CSF induces the mobilization of HPC, EPC and CFU-F progenitors in PB according to very different patterns, and has a significant impact on perfusion and function of the normal heart.

ObjectivesTo better understand the quantitative relationship of recovery of regional and global dysfunction after revascularization in chronic infarcts with variable transmural extent of necrosis by delayed enhanced cardiac magnetic resonance.BackgroundStudies relating transmurality of delayed enhanced magnetic resonance to functional recovery in dysfunctional myocardium using semiquantitative Likert scales have demonstrated the intermediate likelihood (50% probability) of recovery of dysfunction in subendocardial scars.MethodsForty-two patients with chronic left ventricular dysfunction due to coronary artery disease underwent tagged and delayed enhanced magnetic resonance before and 10 ± 7 months after revascularization (coronary artery bypass graft: 35, percutaneous transluminal coronary angioplasty: 7). Left ventricular ejection fraction and regional mid-myocardial Eulerian radial thickening strain (Err) and mid-myocardial, subendocardial, and subepicardial Eulerian circumferential shortening strain (Ecc) strains were quantified in 16 segments per patient before and after revascularization and related to pre-operatively measured transmurality of necrosis.ResultsAt baseline, 256 of 672 segments were dysfunctional, having −10%) mid-myocardial Ecc. The magnitude of recovery of mid-myocardial Ecc (r = −0.33, p < 0.01) was inversely correlated with transmurality of necrosis before revascularization. Segments with

Urotensin II (UII) a potent vasoactive peptide is upregulated in the failing heart and promotes cardiomyocytes hypertrophy, in particular through mitogen-activated protein kinases. However, the regulation by UII of GSK-3beta, a recognized pivotal signaling element of cardiac hypertrophy has not yet been documented. We therefore investigated in adult cardiomyocytes, if UII phosphorylates GSK-3beta and Akt, one of its upstream regulators and stabilizes beta-catenin, a GSK-3beta dependent nuclear transcriptional co-activator. Primary cultures of adult rat cardiomyocytes were stimulated for 48h with UII. Cell size and protein/DNA contents were determined. Phosphorylated and total forms of Akt, GSK-3beta and the total amount of beta-catenin were quantified by western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the chemical phosphatidyl-inositol-3-kinase inhibitor, LY294002, and urantide, a competitive UII receptor antagonist. UII increased cell size and the protein/DNA ratio, consistent with a hypertrophic response. UII also increased phosphorylation of Akt and its downstream target GSK-3beta. beta-Catenin protein levels were increased. All of these effects of UII were prevented by LY294002, and urantide. The UII-induced adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathways and is accompanied by the stabilization of the beta-catenin. All these effects are abolished by competitive inhibition of the UII receptor, consistent with new therapeutic perspectives for heart failure treatment.

Background Soluble suppression of tumorigenicity 2(sST2) receptor is a well-known biomarker implicated in inflammatory diseases. It has already been shown that sST2 is associated with worse outcome in HFrEF. Objective We sought to evaluate the association of sST2 with clinical, laboratory and imaging findings and its prognostic value in HFpEF. Methods Between January 2015 and June 2017, we prospectively enrolled 137 consecutive HFpEF patients (79 ± 8 years, 61% women). Elevated sST2 was determined by an age and sex-adjusted cutoff value (55 ng/ml) corresponding to mean + 2 SD in 31 controls (75 ± 6years, 61% women). All patients underwent complete 2D echo and cMR and were followed up for a composite outcome of mortality and first HF hospitalization. Results Median sST2 level was 44.5 ng/ml (IQR: 31.6–62.2 ng/ml). Elevated sST2 patients (n = 46) had an impaired right ventricular (RV) function (FAC 39 ± 10% vs. 43 ± 8%, P = 0.017; RVEF by cMR 53.5 ± 9.8% vs. 58.1 ± 7.8%, P = 0.008) and a higher proportion with pathologic RV/RA gradient (n = 20 (40%) vs. n = 23 (26%), P = 0.034). They were similar for other clinical, laboratory and imaging characteristics. Multivariate logistic analysis showed that only RVEF by cMR was associated with high sST2 level (OR: 0.94 [0.89–0.99], P = 0.010). During a mean follow-up of 20 ± 8months, 71 patients (52%) reached the combined end point. Cox analysis identified GFR, hemoglobin, sST2, use of loop diuretic and E/e’ ratio as significant predictors of outcome. Only GFR (HR = 0.98 [0.96–0.99], P Kaplan Meier event free survival curve showed that high sST2 HFpEF patients had poorer prognosis than low sST2 patients (P = 0.001, Fig. 1 ). Conclusions In HFpEF, sST2 is associated with impaired RV function and with a poorer prognosis with higher rate of mortality and first HF hospitalization.

Background Previous studies have shown that, in patients with severe aortic stenosis (SAS), global longitudinal strain (GLS), as assessed by speckle tracking echocardiography (STE), is often reduced. The present study aimed to understand the mechanisms underlying this reduction by using stress-shortening relationships. Method Ninety-nine patients with isolated SAS (36% men, 69 ± 11 years) and 75 healthy volunteers (HV) underwent resting 2D-echo and STE to measure GLS, global circumferential strain (GCS), rate-corrected mean velocity of fiber shortening (Vcfc), and end-systolic wall stress (ESWS). Stress-GLS, GCS or Vcfc relationships were constructed using the HV data and fitted to a linear regression. The relative position of individual SAS patients on these relationships was calculated and used as a load-independent index of myocardial contractility (unloaded GLS,GCS or Vcfc). At the time of surgery, myocardial biopsy was obtained to quantify interstitial fibrosis. Results GLS and Vcfc were lower in SAS than HV (−17 ± 3 vs. −20 ± 2%, P 5.4%), a real gradient is draw between the groups. The more fibrosis they have, the worse the longitudinal and circumferential functions are altered for a given afterload ( Fig. 1 ). Conclusion In HV, longitudinal function is less afterload-dependent than circumferential function. In SAS, reduced longitudinal or circumferential function is a marker of interstitial fibrosis and LV remodeling.

Recent studies showed that right ventricular systolic dysfunction (RVSD) predicts worse prognosis in patients with heart failure (HF). We thus sought to evaluate the prognostic value of RVSD assessed by cardiac magnetic resonance (CMR) in HF patients with low ejection fraction due to idiopathic (DCM

AIMS: The management of asymptomatic severe mitral regurgitation remains controversial. The aim of the study was to assess the long-term survival, incidence of cardiac complications, factors that predict outcome, and effect of mitral surgery on the long-term prognosis of patients with asymptomatic severe mitral regurgitation amenable to valve repair. METHODS: One hundred ninety-two asymptomatic patients (mean age 63 +/- 13 years) with severe degenerative mitral regurgitation diagnosed by 2-dimensional echocardiography between 1990 and 2001 were prospectively followed for a median of 8.5 years. RESULTS: Overall, cardiovascular, and event-free survival was evaluated in 2 groups of patients: a "conservative approach" group (n = 67) and an "early surgery" group (n = 125). Outcomes were also analyzed among patients with atrial fibrillation, pulmonary hypertension, or both, as well as in patients free of any mitral regurgitation complications. In the whole population, 10-year overall survival was significantly lower with the conservative approach than early surgery (50% +/- 7% vs 86% +/- 4%, log-rank < 0.0001). Similar results were obtained in the subgroups with atrial fibrillation and/or pulmonary hypertension. The 10-year propensity-matched score-adjusted hazards ratio for overall mortality, cardiac mortality, and cardiovascular events for the conservative treatment were 5.21, 4.83, and 4.40, respectively. CONCLUSION: Our results show that the outcome of asymptomatic patients with severe degenerative mitral regurgitation is better with an early surgical approach rather than a more conservative treatment strategy.

OBJECTIVES: The aim of the present study was to examine the intraoperative echocardiographic features associated with recurrent severe aortic regurgitation (AR) after an aortic valve repair surgery. BACKGROUND: Surgical valve repair for AR has significant advantages over valve replacement, but little is known about the predictors and mechanisms of its failure. METHODS: We blindly reviewed all clinical, pre-operative, intraoperative, and follow-up transesophageal echocardiographic data of 186 consecutive patients who underwent valve repair for AR during a 10-year period and in whom intraoperative and follow-up echo data were available. After a median follow-up duration of 18 months, 41 patients had recurrent 3+ AR, 23 patients presented with residual 1+ to 2+ AR, and 122 had no or trivial AR. In patients with recurrent 3+ AR, the cause of recurrent AR was the rupture of a pericardial patch in 3 patients, a residual cusp prolapse in 26 patients, a restrictive cusp motion in 9 patients, an aortic dissection in 2 patients, and an infective endocarditis in 1 patient. RESULTS: Pre-operatively, all 3 groups were similar for aortic root dimensions and prevalence of bicuspid valve (overall 37%). Patients with recurrent AR were more likely to display Marfan syndrome or type 3 dysfunction pre-operatively. At the opposite end, patients with continent AR repair at follow-up were more likely to have type 2 dysfunction pre-operatively. After cardiopulmonary bypass, a shorter coaptation length, the degree of cusp billowing, a lower level of coaptation (relative to the annulus), a larger diameter of the aortic annulus and the sino-tubular junction, the presence of a residual AR, and the width of its vena contracta were associated with the presence of AR at follow-up. Multivariate Cox analysis identified a shorter coaptation length (odds ratio [OR]: 0.8, p = 0.05), a coaptation occurring below the level of the aortic annulus (OR: 7.9, p < 0.01), a larger aortic annulus (OR: 1.2, p = 0.01), and residual aortic regurgitation (OR: 5.3, p = 0.01) as risk factors of repair failure. CONCLUSIONS: Our results demonstrate that intraoperative transesophageal echocardiography can be used to identify patients undergoing AR repair who are at increased risk for late repair failure.

BACKGROUND: Cusp prolapse management is important in aortic valve (AV) sparing and repair to achieve durable results. We analyzed the midterm outcomes of two different techniques for trileaflet AV prolapse repair. METHODS: Between 1996 and 2008, 376 patients underwent elective AV repair: 88 with trileaflet AV (23%) had cusp prolapse repair, plication technique was performed in 34 (39%), resuspension technique in 33 (37%) and plication plus resuspension in 21 (24%). One cusp was repaired in 55 (62%), 2 cusps in 18 (21%), and 3 cusps in 15 (17%). RESULTS: No hospital deaths occurred. Patients undergoing resuspension with or without plication had more preoperative aortic insufficiency (AI; p = 0.01) and multiple cusp prolapses (p = 0.01). During follow-up (median, 41 months), 4 deaths occurred and 2 were cardiac related. Overall survival at 5 years was 95% +/- 5%. Two patients needed AV reoperation because of recurrent AI or AI plus AV stenosis. Recurrent AI grade > or =3+ developed in 4 patients; 1 with moderate AV stenosis. Freedom from reoperation at 5 years was 100% for plication, 96% +/- 4% for resuspension, and 93% +/- 7% for plication plus resuspension (p = 0.6); respective freedom from AI > or =3+ at 3 years was 100%, 92% +/- 8%, and 89% +/- 11% (p = 0.8). CONCLUSIONS: Cusp plication or resuspension are efficient and durable techniques to correct cusp prolapse in the trileaflet AV. Plication is typically the first choice because of its ease of use and lower risk of overcorrection; however, free margin resuspension is useful in specific situations.

BACKGROUND: Repair of rheumatic mitral valves has met with limited success because hemodynamic obstruction may persist after repair because of residual diseased leaflet tissue and lack of suppleness. Over the past decade, we have developed and implemented an aggressive approach to rheumatic mitral valve repair with radical excision of the diseased leaflets area, and subvalvular apparatus and subsequent reconstruction, with the objective of removing all diseased valvular tissue. METHODS: From July 1996 to June 2007, 78 patients underwent mitral valve repair for rheumatic valve disease. Over the same time interval, 54 patients underwent mitral valve replacement. Mean age was 56.4 +/- 16 years. Clinical follow-up (mean 60 +/- 36 months) was complete in 100% of patients, and echocardiographic follow-up (mean 52 +/- 37 months) was 96% complete. RESULTS: There was no hospital mortality or early reoperations. Overall survival was 94% +/- 6% at 8 years, and 95% of patients were in New York Heart Association functional class II or less. Three patients (4%) required reoperation for mitral restenosis and 2 underwent re-repair. At 8 years of follow-up, freedom from cardiac death and mitral valve reoperation were 98% +/- 2% and 94% +/- 5%, respectively. Freedom from valve-related events at 5 and 10 years was 90% +/- 8% and 86% +/- 11%, and freedom from significant mitral regurgitation was 98% +/- 2% at 5 years and 83% +/- 9% at 8 years. CONCLUSIONS: A more aggressive approach to resection of diseased valvular tissue with subsequent reconstruction is feasible, with good midterm results, and may extend the scope of valve repair in rheumatic disease patients.

Ultrasound-targeted microbubble destruction (UTMD) can cause left ventricular (LV) dysfunction and tissue alterations in rats when high ultrasound (US) energy and long duration of imaging are used. However, the mechanism underlying these alterations remains unclear. The aim of the present work was to investigate the possible role of ischemia in the pathogenesis of the UTMD-induced LV damages in rats. To address this issue, rat hearts were exposed in situ to perfluorocarbon-enhanced sonicated dextrose albumin (PESDA) and US at peak negative pressures of 0.6, 1.2 or 1.8 MPa for 1, 3, 9, 15 or 30 min. Blood pressure and electrocardiogram were continuously recorded during insonation. LV function was assessed before and immediately after US exposure, as well as at 24 h and 7 d. At each time point, groups of rats were euthanized and their hearts were harvested for morphologic analysis. Rats exposed to either PESDA alone or US alone showed no functional or morphologic abnormalities. By contrast, rats exposed to both PESDA and US exhibited transient LV dysfunction, transient ST-segment elevation, premature ventricular contractions, microvascular ruptures, contraction band necrosis and morphologic tissue damage. These bio-effects were spontaneously and completely reversible by one week, except in the groups exposed to the highest peak negative pressure for the longest duration, in which mild dysfunction persisted and interstitial fibrosis developed. In conclusion, simultaneous exposure of rat hearts to PESDA and US in vivo results in significant bio-effects that are similar to myocardial ischemia, including transient regional LV dysfunction, transient ST-segment elevation and myocyte contraction band necrosis. (E-mail: vanoverschelde@card.ucl.ac.be).

Chronic ischemic left ventricular dysfunction is present in a number of clinical syndromes in which myocardial revascularization results in an improvement of left ventricular function, patients' functional class, and their survival. Early diagnosis of and treatment of viability is essential. Coronary arteriography is of limited value in diagnosis of viability. Noninvasive testing is essential for diagnosis, which can be matched to the pathophysiologic changes that occur in hibernating myocardium. However, no single test has a perfect, or near perfect, sensitivity and specificity, and thus, a combination of tests are usually needed. Algorithms are developed to integrate these tests in clinical decision making.

Besides its usefulness for the detection of exercise-induced ischemia, conventional exercise testing may help to predict the onset of clinical events and the need for surgery in asymptomatic patients with cardiac-valvular disease. Doppler echocardiography examination during exercise recently emerged as a new stress testing modality that may add useful information regarding dynamism of LV function, valve disease severity and pulmonary circulation. Few studies have demonstrated a correlation between the results of exercise Doppler echocardiography and clinical outcome. Preliminary experience needs to be confirmed to warrant routine use of Doppler echocardiography examination during exercise in the evaluation of patients with cardiac-valve disease. (C) 2008 Elsevier Masson SAS. All rights reserved.

Background Paradoxical low gradient (PLG) severe aortic stenosis (SAS) is a recently described subset of SAS, which is a matter of intense debate. Some authors indeed consider this new entity as a more advanced form of SAS, whereas others believe the opposite. To get further insight into the pathophysiology of PLG SAS, we compared the weight of the valves explanted at the time of surgery (AVR) and the degree of valve calcification among consecutive patients with PLG SAS and high-gradient (HG) SAS. Methods We prospectively recruited 38 consecutive patients (20 men; mean age: 73 yrs) with isolated non-rheumatic SAS (indexed aortic valve area (AVAi) Results PLG and HG SAS had similar baseline characteristics with the exception of AVAi which was higher (0.44±0.06 vs 0.36±0.10 cm2m2, p=0.008) and MG which was lower (32±7 vs 55±12 mmHg, p 0.90) and in-vivo (r2=0.71) Agatston scores. Interestingly, valves explanted from patients with PLG SAS were lighter (1.58±0.65 vs 2.65±1,24g, p=0.001) and showed lower ex-vivo Agatston scores (363±282 vs 1211±840, p Conclusion The valves weight and degree of valve calcification reported in our study indicate that PLG SAS valves are less severely affected than HG SAS valves. These data thus reinforce the hypothesis that PLG SAS is a lesser advanced form of aortic stenosis than HG SAS.

BackgroundDespite the absence of randomized studies comparing mitral valve (MV) repair and replacement, international guidelines strongly recommend MV repair as the optimal surgical treatment for severe degenerative mitral regurgitation (dMR). Yet, the level of evidence supporting these recommendations is low, owing to the lack of available clinical trial data. In this context, analysis of large multicenter registries becomes critical.ObjectiveTo compare very long-term survival among patients (pts) undergoing MV repair versus replacement for the treatment of severe dMR using the technique of propensity score (PS) matching to reduce bias in nonrandomized cohorts.MethodsThe Mitral Regurgitation International DAtabase (MIDA) is a prospective multicenter registry that includes 2,569 consecutive pts with dMR, who were recruited in 6 tertiary centers (France, Italy, Belgium, and the United States) between 1980 and 2005. Among these, we identified 1,922 pts who underwent mitral surgery, including 1,709MV repairs and 213MV replacements. We compared operative mortality and overall survival in both the entire study population and in 615 PS-matched (2:1) pts.ResultsOperative mortality was lower after MV repair than after MV replacement, both in the entire population (2 vs 7%; p=0.001) and in the PSmatched pts (4 vs 8%; p=0.04). Similarly, 20-year survival was better after MV repair than after MV replacement, both in the entire population (46% [(95% CI, 39%-52%] vs 23% [95% CI, 14%-32%], p

Background A key detrimental characteristic of left ventricular (LV) remodelling is fibrosis. The pathogenesis of cardiac fibrosis includes migration of cardiac fibroblasts. Remodelling of actin cytoskeleton is a hallmark of the migrating cells. AMP-activated protein kinase (AMPK) regulates actin cytoskeleton organization and has been shown to influence LV remodelling. In this study, we investigated whether A-769662, a pharmacological AMPK activator, modulates human cardiac fibroblast (HCF) migration and adhesion by affecting actin organization. Methods Single-cell migration was assessed by time-lapse imaging. Focal adhesions (FA) were visualized by immunofluorescence together with fluorescent phalloidin to stain actin filaments. Phosphorylation state of myosin regulatory light chains (MLC) was determined by western blot analysis and immunofluorescent staining. RhoA activity was assessed using a pull down method. Results A-769662 significantly decreased HCF motility, in an AMPKα1- dependent manner. In addition, A-769662-treated cells shifted from an elongated shape, characterized by leading and trailing edges, to a more polygonal one with numerous and thicker stress cables, mainly dorsal fibres and transverse arcs. This was accompanied by markedly increased cell adhesion and focal adhesion size. Concomitantly, AMPKα1 activation also resulted in a sustained activation of RhoA that was associated with a significant increase in MLC phosphorylation and its colocalization with transverse arcs. Conclusion We postulate that A-769662 counteracts HCF migration through an AMPK-dependent sustained activation of the RhoA/MLC pathway, promoting actin polymerization and contraction. Myosin II-generated tension into FA is expected to promote their maturation and subsequently alter migration.