Francis Juthier

Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure

BACKGROUND Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI. METHODS AND RESULTS In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001). CONCLUSION Our results demonstrate that, in patients with CAD but without heart failure or acute MI, the level of aldosterone is strongly and independently associated with mortality and the occurrence of acute ischaemic events.

Atherosclerotic-like process in aortic stenosis: Activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration

BACKGROUND We recently demonstrated in an experimental model the expression of tissue factor (TF) in aortic valves. Thrombin, generated at the end of the TF-initiated coagulation cascade, has been shown to cleave the anti-calcific osteopontin (OSP) liberating the pro-inflammatory OSP N-half. OBJECTIVES We hypothesized that TF might play an important role in calcific aortic valve stenosis (AS) through thrombin generation and hence evaluated the valvular expression of TF and its inhibitor (TF pathway inhibitor), α-thrombin, OSP and its thrombin-cleaved form (OSP N-half). METHODS Calcified aortic valves were obtained from patients undergoing valve replacement. Protein expression was evaluated by immunostaining and measured using ELISA kits. Transcripts were analyzed by RT-PCR. RESULTS We included 52 patients (31 men; age 70 ± 10 years; aortic valve area index 0.35 ± 0.13 cm(2)/m(2)). Immunohistochemistry revealed that TF, OSP and α-thrombin expressions were associated with calcifications at the aortic side of the leaflets. There was an overexpression in calcified regions as compared to non-calcified zones of TF (733.3 ± 70.5 pg/mg vs. 429.4 ± 73.2 pg/mg; p<0.0001), OSP (88.9 ± 12.7 ng/mg vs. 15.0 ± 3.3 ng/mg; p<0.0001) and OSP N-half (0.41 ± 0.06 pmol/mg vs. 0.056 ± 0.011 pmol/mg; p<0.0001). Additionally, both TF and α-thrombin expressions were associated with OSP N-half (r=0.52; p<0.0001 and r=0.33; p=0.019, respectively). CONCLUSIONS Aortic leaflet TF and α-thrombin expressions and their association with the thrombin-cleaved form of OSP, are a new and important feature of AS. We hypothesize that TF may be involved in the mineralization process of aortic valves by enhancing the generation of the pro-inflammatory OSP N-half through thrombin induction. This pathway deserves further studies to address its implication in the aortic valve calcification process.

Modified Ross operation with reinforcement of the pulmonary autograft: Six-year results

OBJECTIVE The Ross procedure is widely used for aortic valve disease in patients who are still growing and young adults with active lifestyles or the desire for pregnancy. The need for autograft reoperation remains the principal limitation of the procedure. Autograft inclusion in a polyester tube prosthesis has been proposed with good postoperative results, but the durability of these technical modifications has not been assessed. We report the midterm results of pulmonary autograft reinforcement with a Valsalva Gelweave Dacron tube (Terumo Cardiovascular Systems Inc, Ann Arbor, Mich). METHODS Since 1992, we have performed 322 Ross operations; 12 patients underwent a modified Ross procedure with the autograft included in a Valsalva Gelweave Dacron tube. The mean age of these patients was 29.7 +/- 10.8 years (range, 15.3-46.5 years). The mean aortic crossclamp time was 126 +/- 11 minutes (range, 110-142 minutes). The mean follow-up was 4 +/- 1.4 years (range 1.7-5.8 years). RESULTS No perioperative deaths were observed, and all patients are alive and doing well. No significant autograft regurgitation was recorded during follow-up. The mean diameters of the autograft annulus and the neosinus of Valsalva were 23.3 +/- 2.6 mm and 32.6 +/- 3.3 mm, respectively, at discharge, and 24.0 +/- 1.9 mm and 33.6 +/- 3.3 mm, respectively, at the last control (P = .32 and P = .08, respectively). CONCLUSION These results support that this technical modification of the Ross operation might be proposed for patients at risk of autograft dilatation when an inclusion technique is not feasible.

Clinical and echocardiographic correlates of plasma B-type natriuretic peptide levels in patients with aortic valve stenosis and normal left ventricular ejection fraction.

Background: Several studies suggest that BNP testing may help define the timing of aortic valve surgery in patients with aortic valve stenosis (AVS) prior onset of overt LV systolic dysfunction. The aim of this study was to identify clinical and echocardiographic correlates of plasma BNP levels in a large cohort of patients with AVS and preserved LV ejection fraction. Method and results: One hundred thirty‐five consecutive patients were prospectively included in the present study (Mean age 73 ± 13 years old, 66 (49%) male). Eighty‐nine patients (66%) had severe AVS (aortic valve area <0.6 cm2/m2 BSA). Plasma BNP levels, clinical and comprehensive Doppler echocardiography evaluation was performed in all patients. Independent clinical correlates of plasma BNP levels (R2= 0.19) were older age (P < 0.0001) and presence of AVS symptoms (P = 0.004). Independent echocardiographic correlates of plasma BNP levels (R2= 0.38) were E/Ea ratio (P = 0.01), LV mass index (P = 0.018), left atrial surface (P < 0.0001) and systolic pulmonary artery pressure (sPAP; P = 0.004). Overall, independent correlates of plasma BNP levels (R2= 0.47) were older age (P = 0.001), known coronary artery disease (P = 0.047), increased LV mass index (P = 0.001), left atrial enlargement (P = 0.002), and increased sPAP (P = 0.003). Conclusions: In patients with AVS and normal LV ejection fraction, plasma BNP predominantly reflects the clinical and echocardiographic consequences of afterload burden imposed on the left ventricle rather than the severity of valve stenosis, per se. (Echocardiography 2011;28:695‐702)

Post-Procedural Aortic Regurgitation in Balloon-expandable and Self-Expandable TAVR Procedures: Analysis of Predictors and Impact on Long-Term Mortality: Insights from the FRANCE2 Registry

Background— Significant postprocedural aortic regurgitation (AR) is observed in 10% to 20% of cases after transcatheter aortic valve replacement (TAVR). The prognostic value and the predictors of such a complication in balloon-expandable (BE) and self-expandable (SE) TAVR remain unclear. Methods and Results— TAVR was performed in 3195 consecutive patients at 34 hospitals. Postprocedural transthoracic echocardiography was performed in 2769 (92%) patients of the eligible population, and these patients constituted the study group. Median follow-up was 306 days (Q1–Q3=178–490). BE and SE devices were implanted in 67.6% (n=1872) and 32.4% (n=897). Delivery was femoral (75.3%) or nonfemoral (24.7%). A postprocedural AR≥grade 2 was observed in 15.8% and was more frequent in SE (21.5%) than in BE-TAVR (13.0%, P=0.0001). Extensive multivariable analysis confirmed that the use of a SE device was one of the most powerful independent predictors of postprocedural AR≥grade 2. For BE-TAVR, 8 independent predictors of postprocedural AR≥grade 2 were identified including femoral delivery (P=0.04), larger aortic annulus (P=0.0004), and smaller prosthesis diameter (P=0.0001). For SE-TAVR, 2 independent predictors were identified including femoral delivery(P=0.0001). Aortic annulus and prosthesis diameter were not predictors of postprocedural AR for SE-TAVR. A postprocedural AR≥grade 2, but not a postprocedural AR=grade 1, was a strong independent predictor of 1-year mortality for BE (hazard ratio=2.50; P=0.0001) and SE-TAVR (hazard ratio=2.11; P=0.0001). Although postprocedural AR≥grade 2 was well tolerated in patients with AR≥grade 2 at baseline (1-year mortality=7%), it was associated with a very high mortality in other subgroups: renal failure (43%), AR<grade 2 at baseline (31%), low transaortic gradient (35%), or nonfemoral delivery (45%). Conclusions— Postprocedural AR≥grade 2 was observed in 15.8% of successful TAVR and was the strongest independent predictor of 1-year mortality. The use of the SE device was a powerful independent predictor of postprocedural AR≥grade 2.Background— Significant postprocedural aortic regurgitation (AR) is observed in 10% to 20% of cases after transcatheter aortic valve replacement (TAVR). The prognostic value and the predictors of such a complication in balloon-expandable (BE) and self-expandable (SE) TAVR remain unclear. Methods and Results— TAVR was performed in 3195 consecutive patients at 34 hospitals. Postprocedural transthoracic echocardiography was performed in 2769 (92%) patients of the eligible population, and these patients constituted the study group. Median follow-up was 306 days (Q1–Q3=178–490). BE and SE devices were implanted in 67.6% (n=1872) and 32.4% (n=897). Delivery was femoral (75.3%) or nonfemoral (24.7%). A postprocedural AR≥grade 2 was observed in 15.8% and was more frequent in SE (21.5%) than in BE-TAVR (13.0%, P =0.0001). Extensive multivariable analysis confirmed that the use of a SE device was one of the most powerful independent predictors of postprocedural AR≥grade 2. For BE-TAVR, 8 independent predictors of postprocedural AR≥grade 2 were identified including femoral delivery ( P =0.04), larger aortic annulus ( P =0.0004), and smaller prosthesis diameter ( P =0.0001). For SE-TAVR, 2 independent predictors were identified including femoral delivery( P =0.0001). Aortic annulus and prosthesis diameter were not predictors of postprocedural AR for SE-TAVR. A postprocedural AR≥grade 2, but not a postprocedural AR=grade 1, was a strong independent predictor of 1-year mortality for BE (hazard ratio=2.50; P =0.0001) and SE-TAVR (hazard ratio=2.11; P =0.0001). Although postprocedural AR≥grade 2 was well tolerated in patients with AR≥grade 2 at baseline (1-year mortality=7%), it was associated with a very high mortality in other subgroups: renal failure (43%), AR<grade 2 at baseline (31%), low transaortic gradient (35%), or nonfemoral delivery (45%). Conclusions— Postprocedural AR≥grade 2 was observed in 15.8% of successful TAVR and was the strongest independent predictor of 1-year mortality. The use of the SE device was a powerful independent predictor of postprocedural AR≥grade 2. # CLINICAL PERSPECTIVE {#article-title-26}

Myocardial involvement in systemic capillary leak syndrome: first demonstration by pathologic findings:

This case vignette relates the unknown association between systemic capillary leak syndrome, namely Clarkson’s syndrome, and acute cardiac dysfunction. ‘Central extra-corporeal life support (ECLS)’ was needed for the management of an intractable cardiogenic shock. The acute cardiac condition completely resolved within few days. Pathology showed diffuse interstitial edema within the myocardium suggestive of cardiac involvement of the disease.

The Presence of Apoptotic Bone Marrow Cells Impairs the Efficacy of Cardiac Cell Therapy

Injection of autologous bone marrow cells into infarcted myocardium has been proposed to limit the deterioration of cardiac function following myocardial infarction (MI); unfortunately, the beneficial effects observed have been modest. One of the limiting factors is believed to be poor local survival of the injected cells, but the potential impact of apoptosis among the injected cells has yet to be assessed. Therefore, this study aimed to quantify the apoptosis rate in bone marrow mononuclear cells (BMMCs) prepared for cardiac therapy, and to analyze their effects in vitro on cardiomyoblast apoptosis and in vivo on cardiac function recovery following MI. Using rabbit BMMCs prepared by Ficoll gradient, apoptotic cells were detected via Annexin V (AnV) staining. The effects of depleting the apoptotic cell population by means of AnV magnetic beads was tested in vitro after coculture with cardiomyoblasts (H9c2 cells) and in vivo after cell injection into the infarcted area. Left ventricular ejection fraction and scar extent were assessed by echography and histology 2 months later. After Ficoll gradient isolation, 37.3% (33.4–37.9%) of BMMCs were found to be apoptotic (ApoBase BMMCs). AnV depletion decreased the proportion of apoptotic cells to 20% (17.6–32%) (ApoLow BMMCs). Rabbits treated in vivo with ApoLow BMMCs after MI presented with significantly improved left ventricular ejection fraction [41.4% (41.0–43.6%) vs. 34.6% (34.6–35.9%), p = 0.03), reduced scar extent [20.4% (17.9–24.3%) vs. 25.6% (17.9–27.9%), p = 0.057], and reduced rate of cardiomyocyte apoptosis compared to those treated with ApoBase BMMCs. H9c2 apoptosis was found to be higher after coculture with ApoBase than with ApoLow BMMCs [25.6% (22.6–29.6%) vs. 10.1% (6.6–12.6%), p = 0.03], a result partially reproduced by cocultures with microparticle-rich supernatants from BMMCs. The presence of apoptotic cells among BMMCs impairs the efficacy of cardiac cell therapy after MI, an effect possibly mediated by apoptotic microparticles.

Prospective assessment of multiple cardiac papillary fibroelastomas: An echocardiographic and surgical study

Multiple cardiac papillary fibroelastomas (PFEs) are thought to account for less than 10% of patients with PFE. We aimed at evaluating the frequency and location of multiple PFEs and the reliability of transthoracic (TTE) and transoesophageal (TEE) echocardiography in diagnosing multiple PFEs. Twenty-six consecutive patients (52±14 years, 65% males) with pathologically confirmed PFE had 21 PFEs diagnosed by TTE, 33 by TEE, and 62 at surgery. Eight patients (31%) had multiple PFEs found either by TEE or at surgery. Aortic valve was involved in 75% of patients with multiple PFEs and left ventricle in 38% of patients. The sensitivity of TTE in diagnosing any PFEs was 51.3% and 76.9% for TEE. Our study emphasizes the high frequency of multiple PFEs, the need of TEE for all presumed PFE and the need for careful assessment of left-sided endocardial surfaces, especially of the aortic valve, during PFE excision.

Post aortic dissection: Gap between activity recommendation and real life patients aerobic capacities

BACK GROUND Regular exercise at a safe level, i.e. 3-5 metabolic equivalents, is recommended to improve blood pressure control and quality of life even after aortic dissection, although aerobic exercise capacities in these patients are unexplored yet. METHODS We prospectively collected data from 105 patients with a history of post aortic dissection referred for a cardiopulmonary exercise testing (CPX) aiming to guide exercise rehabilitation. RESULTS The population was composed of 76% of male, with a mean age of 57.9±12.4years. There were an equal distribution between the two type of dissection (47% of type A and 53% of type B aortic dissection). No cardiac event occurred during or after CPX. One third of patients have normal aerobic exercise capacity defined as peak oxygen uptake upper than 85% of their predicted capacity. Mean oxygen uptake peak was quite low 19.2±5.2ml/kg/min (5.5±1.5 metabolic equivalents). Aerobic capacity was limited by cardiac chronotropic incompetence in 42% or peripheral deconditioning in 45%. Blood pressure remained in an acceptable range during the exercise. Systolic and diastolic blood pressures were respectively 151±20 and 77±13mmHg at first ventilatory threshold. CONCLUSIONS CPX is a safe exploration in patients with post aortic dissection syndrome. Given the fact that most of these patients are faced with significant alteration of aerobic capacities, the recommended daily practice of moderate exercise at 3-5 METS should be adapted and personalized to each patient thanks to CPX.

Response to Letter Regarding Article, “Postprocedural Aortic Regurgitation in Balloon-Expandable and Self-Expandable Transcatheter Aortic Valve Replacement Procedures: Analysis of Predictors and Impact on Long-Term Mortality: Insights From the FRANCE2 Registry”

We thank Drs Iqbal and Serruys for their interesting comments on our study.1 Transcatheter aortic valve replacement is a very good alternative to conventional surgical replacement in patients with aortic stenosis at increased risk for surgery.2,3 As efficient as it is, transcatheter aortic valve replacement has important limitations, including postprocedural aortic regurgitation (AR). Our study was designed to (1) describe the rate of postprocedural AR evaluated at discharge in a large series of consecutive patients treated with balloon-expandable (BE) and self-expandable devices, (2) analyze the predictors of postprocedural ARs in the overall population for each device, and (3) analyze the impact of postprocedural ARs on clinical outcome. The results of our study1 and others2 demonstrate clearly that postprocedural AR≥moderate as evaluated by echocardiography at discharge is frequent (15%) and is an independent predictor of long-term mortality. Our study demonstrates also that the clinical significance of a postprocedural AR≥moderate is …