Christophe de Meester

Natural History of Paradoxical Low-Gradient Severe Aortic Stenosis

Background—Up to 30% of patients with severe aortic stenosis (SAS; indexed aortic valve area <0.6 cm2/m2) present with low transvalvular gradient despite a normal left ventricular ejection fraction. Presently, there is intense controversy as to the prognostic implications of such findings. Accordingly, the aim of the present work was to compare the natural history of patients with paradoxical low-gradient (PLG) or high-gradient (HG) SAS. Methods and Results—We prospectively studied 349 patients with SAS and preserved left ventricular ejection fraction. Patients were categorized into HG-SAS (n=144) and PLG-SAS (n=205) according to mean transvalvular gradient (mean gradient >40 or ⩽40 mm Hg). Primary end points were all-cause mortality and echocardiographic disease progression. To evaluate natural history, patients undergoing aortic valve replacement were censored at the time of surgery (n=92). During a median follow-up of 28 months, 148 patients died. Kaplan–Meier survival curves showed better survival in PLG-SAS than in HG-SAS, both in the overall population (48% versus 31%; P<0.01) and in the asymptomatic subgroup (59% versus 35%; P<0.02). In asymptomatic patients, Cox analysis identified age, diabetes mellitus, left atrial volume, and mean gradient as independent predictors of death. Finally, at last echocardiographic follow-up, PLG-SAS demonstrated significant increases in mean gradient (from 29±6 to 38±11 mm Hg; P<0.001). Conclusions—Our study indicates that PLG-SAS is a less malignant form of AS compared with HG-SAS, because their spontaneous outcome is better. We further demonstrated that patients with PLG-SAS are en route toward the more severe HG-SAS form, because the majority of them evolve into HG-SAS over time.

Incidence, Determinants, and Prognostic Impact of Operative Refusal or Denial in Octogenarians With Severe Aortic Stenosis

BACKGROUND 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. METHODS 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. RESULTS 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 p < 0.001 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. CONCLUSIONS 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.

Twenty-Year Outcome after Mitral Repair Versus Replacement for Severe Degenerative Mitral Regurgitation. Analysis of a Large, Prospective, Multicenter International Registry.

Background: Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation. However, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative mitral regurgitation with a flail leaflet. Methods: MIDA (Mitral Regurgitation International Database) is a multicenter registry enrolling patients with degenerative mitral regurgitation with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1709) and replacement (n=213) overall, by propensity score matching, and by inverse probability-of-treatment weighting. Results: At baseline, patients undergoing MV repair were younger, had more comorbidities, and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching and inverse probability-of-treatment weighting, the 2 treatments groups were balanced, and absolute standardized differences were usually <10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement in both the entire population (1.3% versus 4.7%; P<0.001) and the propensity-matched population (0.2% versus 4.4%; P<0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement in both the entire population (46% versus 23%; P<0.001) and the matched population (41% versus 24%; P<0.001). Similar superiority of MV repair was obtained in patient subsets on the basis of age, sex, or any stratification criteria (all P<0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications. Conclusions: Among patients with degenerative mitral regurgitation with a flail leaflet referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival, and fewer valve-related complications compared with MV replacement.

Low contact force and force–time integral predict early recovery and dormant conduction revealed by adenosine after pulmonary vein isolation

Aim After pulmonary vein isolation (PVI), dormant conduction (DC) is present in at least one vein in a substantial number of patients. The present study seeks to determine whether there is a relationship between poor contact forces (CF) and the presence of DC after PVI. Methods and results This prospective, operator-blinded, non-randomized dual-centre trial enrolled 34 consecutive patients with paroxysmal atrial fibrillation who were candidates for PVI. Radiofrequency (RF) energy was delivered by using an irrigated-tip force-sensing ablation catheter (Tacticath®, St Jude Medical) at pre-defined target power. The operators were blinded to the CF data at all times. A total of 1476 RF applications were delivered in 743 pre-defined PV segments. For each application, the precise location of the catheter was registered and the following data were extracted from the Tacisys® unit: application duration, minimum contact force, maximum contact force, average contact force (CF), and force–time integral (FTI). Sixty minutes after PVI, spontaneous early recovery (ER) of the left atrium (LA) to PV conduction was evaluated. In the absence of ER, the presence of a DC was evaluated by using intravenous adenosine (ATP). In the 34 patients recruited (23 males; mean age: 62 ± 9 years), all PVs were successfully isolated. At the end of the 60 min waiting period, 22 patients demonstrated at least one spontaneous ER or DC under ATP. The mean CF and FTI per PV segment differed significantly among the different veins but the sites of ER and DC were evenly distributed. However, both the minimum, the first and the mean CF and FTI per PV segment were significantly lower in the PV segments presenting either ER or DC as compared with those without ER or DC (mean CF: 4.9 ± 4.8 vs. 12.2 ± 1.65 g and mean FTI: 297 ± 291 vs. 860 ± 81 g s, P < 0.001 for both). Using multivariate analysis, both the mean CF and the FTI per lesion remained significantly associated with the risk of ER or DC. Moreover, a CF < 5 g per PV segment predicted ER+ and DC+ with a sensitivity of 71% and specificity of 82%. In contrast, ER and DC were very unlikely if RF application was performed with a mean CF > 10 g (negative predictive value: 98.7%). Conclusion Both a low CF and a low FTI are associated with the ER of the PVI and DC after PVI.

Impact of preoperative symptoms on postoperative survival in severe aortic stenosis: implications for the timing of surgery

BACKGROUND The impact of symptoms on the natural history of patients with severe aortic stenosis (SAS) has been well documented. By contrast, the implications of preoperative symptoms on postoperative outcomes remain poorly defined. METHODS The long-term survival of 812 patients greater than 65 years old with SAS undergoing bioprosthetic aortic valve replacement (AVR) was analyzed according to their preoperative symptoms. RESULTS Operative mortality was larger in New York Heart Association (NYHA) III-IV than in NYHA I-II patients (10% vs 6%, p = 0.036). Abrupt symptomatic deterioration from NYHA I to NYHA III-IV within the month preceding surgery was observed in 18% of NYHA III-IV patients and resulted in an increased operative mortality (17% vs 5% in NYHA I, p = 0.035). Long-term survival was also significantly worse in NYHA III-IV than in NYHA I-II patients (56% vs 72%, p = 0.002). Reduced long-term survival of NYHA III/IV patients was observed in subgroups with a left ventricular ejection fraction (LVEF) 0.50 or greater (58 vs. 74%, p = 0.008) and in those with a systolic pulmonary artery pressure (SPAP) less than 40 mm Hg (60% vs 74%, p = 0.014). By contrast, the presence of class III-IV symptoms did not influence outcome in patients with a LVEF less than 0.50 (51 vs. 55%, p = 0.34) or with a SPAP 40 mm Hg or greater (43% vs 48%, p = 0.78). CONCLUSIONS In patients with SAS, preoperative NYHA III-IV symptoms, particularly of recent onset, are independently associated with excess short- and long-term postoperative mortality. This was particularly evident in patients with normal LV function or pulmonary artery pressures. These findings plead in favor of an earlier surgical correction of SAS, before the onset of severe symptoms, especially in low-risk patients.

Valve repair improves the outcome of surgery for chronic severe aortic regurgitation: a propensity score analysis.

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.

Long-term follow-up of DDD and VDD pacing : a prospective non-randomized single-centre comparison of patients with symptomatic atrioventricular block.

AIMS This prospective non-randomized single-centre registry compared clinical outcome, pacing parameters, and long-term survival in patients receiving VDD or DDD pacemaker (PMs) for symptomatic atrioventricular (AV) block. METHODS AND RESULTS Single-lead VDD (n= 166) and DDD (n= 254) PMs were implanted in 420 successive patients with isolated AV block between January 2001 and December 2009. At the end of the follow-up period [median 25 (1-141) months], there was no difference in the incidence of atrial fibrillation [11.2% in the VDD group; 11.4% in the DDD group (P= 0.95)], myocardial infarction [31.1% in the VDD group; 25.2% in the DDD group (P= 0.20)], or dilated cardiomyopathy [9.9% in the VDD group; 8.9% in the DDD group (P= 0.74)]. At last follow-up, 65.9% of the VDD PMs and 89.3% of the DDD PMs were still programmed in their original mode with good atrial sensing. Due to permanent atrial fibrillation, 7.9% patients out of the VDD group had been switched to VVIR mode and 8.7% patients out of the DDD group to VVIR or DDIR mode. The P-wave amplitude was poor (sensed P-wave <0.5 mV) in 19.1% of the VDD PM and 1.6% of the DDD PM (P< 0.001) and 7.1% of the VDD patients and 0.4% of the DDD patients had been switched to VVIR pacing mode due to P-wave undersensing and AV dissociation (P= 0.003). Symptomatic atrial undersensing requiring upgrading was similar in both groups. The overall survival, adjusted for age, was not significantly different in the VDD and the DDD group (log rank: 0.26). Moreover, Cox survival analysis excluded the pacing mode as a significant predictor of mortality [hazard ratio (HR) = 0.79, confidence interval (CI) (0.46-1.35), P= 0.39]. CONCLUSION Comparing VDD and DDD pacing, a significantly larger number of VDD-paced patients developed poor atrial signal detection without clinical impact. However, atrial under sensing did not influence the incidence of atrial fibrillation, myocardial infarction, dilated cardiomyopathy, or mortality.

Cardiac myocyte β3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling

Aims Human and mouse cardiac beta3-adrenergic receptors (beta3AR) exert antipathetic effects to those of beta1-2AR stimulation. We examined their role in modulating myocardial remodelling, particularly fibrosis in response to haemodynamic stress. Methods and results Mice with cardiac myocyte-specific expression of beta3AR (ADRB3-tg) or tamoxifen-inducible homozygous deletion (c-Adrb3-ko, with loxP-targeted Adrb3) were submitted to transaortic constriction. A superfusion assay was used for proteomic analysis of paracrine mediators between beta3AR-expressing cardiac myocytes and cardiac fibroblasts cultured separately. We show that cardiac beta3AR attenuate myocardial fibrosis in response to haemodynamic stress. Interstitial fibrosis and collagen content were reduced in ADRB3-tg, but augmented in c-Adrb3-ko. ADRB3 and collagen (COL1A1) expression were also inversely related in ventricular biopsies of patients with valve disease. Incubation of cardiac fibroblasts with media conditioned by hypertrophic myocytes induced fibroblast proliferation, myo-differentiation, and collagen production. These effects were abrogated upon ADRB3 expression in myocytes. Comparative shotgun proteomic analysis of the myocyte secretomes revealed a number of factors differentially regulated by beta3AR, among which connective tissue growth factor [CTGF (CCN2)] was prominently reduced. CTGF was similarly reduced in stressed hearts from ADRB3-tg, but increased in hearts from c-Adrb3-ko mice. CTGF expression was mediated by reactive oxygen species production which was reduced by ADRB3 expression in vitro and in vivo. This antioxidant and anti-fibrotic effect involved beta3AR coupling to the neuronal isoform of nitric oxide synthase (nNOS) in cardiac myocytes, as both were abrogated upon nNOS inhibition or Nos1 homozygous deletion. Conclusion Cardiac beta3AR protect from fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress-dependent paracrine signaling to fibroblasts. Specific agonism at beta3AR may offer a new therapeutic modality to prevent cardiac fibrosis.

The role of echocardiography in aortic valve repair

Echocardiography is the imaging method of choice for evaluating aortic valve repair for aortic regurgitation (AR). This article will discuss the role of echocardiography in the assessment of the severity, hemodynamics and mechanism(s) of AR, along with its role in the perioperative assessment of aortic valve repair.

Prevalence and Prognostic Impact of Valve Area-Gradient Patterns in Patients ≥80 Years With Moderate-to-Severe Aortic Stenosis (from the Prospective BELFRAIL Study).

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, p <0.01). 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.