Anne-Catherine Pouleur

Pathogenesis of Sudden Unexpected Death in a Clinical Trial of Patients With Myocardial Infarction and Left Ventricular Dysfunction, Heart Failure, or Both

Background— The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI. Methods and Results— To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (&khgr;2=23.3, P<0.0001). Conclusions— Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Assessment of subendocardial vs. subepicardial left ventricular rotation and twist using two-dimensional speckle tracking echocardiography: comparison with tagged cardiac magnetic resonance

AIMS The aim of this article is to evaluate the accuracy and reproducibility of two-dimensional speckle tracking echocardiography (2D-STE) for the estimation of left ventricular (LV) twist, using tagged cardiac magnetic resonance (cMR) as the reference standard, and to assess how much 2D-STE rotational parameters are affected by the level at which measurements are made within the LV. METHODS AND RESULTS Forty-three patients with various heart diseases and 10 healthy volunteers underwent cMR and 2D-STE on the same day. With both methods, basal and apical time-rotation curves were generated at endocardial, midwall, and epicardial levels. By using the most apical cMR short-axis cross-section as a comparator, apical rotation was significantly underestimated by 2D-STE. When 2D-STE and cMR short-axis cross-sections were matched for their internal dimensions, measurements of endocardial, midwall, and epicardial twists no longer differ between cMR and 2D-STE (12.6 +/- 5.9 vs. 12.5 +/- 5.7 degrees , 10.5 +/- 4.6 vs. 9.7 +/- 4.1 degrees , and 8.9 +/- 4.0 vs. 8.4 +/- 3.7 degrees , respectively, all P = ns). CONCLUSION Compared with tagged cMR, 2D-STE underestimates apical rotation and LV twist. This is related to the inability of 2D-STE to image the real LV apex in most of the patients. However, when 2D-STE and cMR data are compared at similar acquisition levels, both techniques provide similar values.

Functional Anatomy of Aortic Regurgitation Accuracy, Prediction of Surgical Repairability, and Outcome Implications of Transesophageal Echocardiography

Background— For patients with aortic regurgitation (AR), aortic valve sparing or repair surgery is an attractive alternative to valve replacement. In this setting, accurate preoperative delineation of aortic valve pathology and potential repairability is of paramount importance. The aim of the present study was to assess the diagnostic value of preoperative transesophageal echocardiography (TEE) in defining the mechanisms of AR, as identified by surgical inspection, and in predicting repairability, by using the final surgical approach as reference. Methods and Results— One hundred and sixty-three consecutive patients (117 males, mean age: 58±14 years) undergoing AR surgery were included. Mechanisms of AR were categorized by TEE and surgical inspection as follows: type 1, aortic dilatation; type 2, cusp prolapse; and type 3, restrictive cusp motion or endocarditis. At surgery, mechanisms of AR were type 1 in 41 patients, type 2 in 62, and type 3 in 60. Agreement between TEE and surgical inspection was 93% (&kgr;=0.90). Valve sparing or repair was performed in 125 patients and valve replacement in 38 patients. TEE correctly predicted the final surgical approach in 108/125 (86%) patients undergoing repair and in 35/38 (93%) patients undergoing replacement. The gross anatomic classification of AR lesions by TEE was determinant of valve repairability and postoperative outcome (4-year freedom from > grade 2 AR, reoperation, or death, P=0.04). Conclusions— TEE provides a highly accurate anatomic assessment of all types of AR lesions. In addition, the functional anatomy of AR defined by TEE is strongly and independently predictive of valve repairability and postoperative outcome.

Assessment of Left Ventricular Mass and Volumes by Three-Dimensional Echocardiography in Patients with or without Wall Motion Abnormalities: Comparison against Cine Magnetic Resonance Imaging

Aim: To evaluate if three-dimensional echocardiography (3-DE) is as accurate and reproducible as cine magnetic resonance imaging (cMR) in estimating left ventricular (LV) parameters in patients with and without wall motion abnormalities (WMA). Methods: 83 patients (33 with WMA) underwent 3-DE and cMR. 3-DE datasets were analysed using a semi-automatic contour detection algorithm. The accuracy of 3-DE was tested against cMR in the two groups of patients. All measurements were made twice by two different observers. Results: LV mass by 3-DE was similar to that obtained by cMR (149 (SD 42) g vs 148 (45) g, p = 0.67), with small bias (1 (28) g) and excellent interobserver agreement (−2 (31) g vs 4 (26) g). The two measurements were also highly correlated (r = 0.94), irrespective of WMA. End-diastolic and end-systolic LV volumes and ejection fraction by 3-DE and cMR were highly correlated (r = 0.97, 0.98, 0.94, respectively). Yet, 3-DE underestimated cMR end-diastolic volumes (167 (68) ml vs 187 (70) ml, p<0.001) and end-systolic volumes (88 (56) ml vs 101 (65) ml, p<0.001), but yielded similar ejection fractions (50% (14%) vs 50% (16%), p = 0.23). Conclusion: 3-DE permits accurate determination of LV mass and volumes irrespective of the presence or absence of WMA. LV parameters obtained by 3-DE are also as reproducible as those obtained by cMR. This suggests that 3-DE can be used to follow up patients with LV hypertrophy and/or remodelling.

Prognostic Significance of LGE by CMR in Aortic Stenosis Patients Undergoing Valve Replacement

BACKGROUND Prior 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. OBJECTIVES This study was conducted to evaluate whether LGE-CMR can predict post-operative survival in patients with severe AS undergoing aortic valve replacement (AVR). METHODS We 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). RESULTS LGE 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. CONCLUSIONS The 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.

Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction : impact of revascularization therapy.

OBJECTIVES The purpose of this study was to evaluate the impact of myocardial viability assessment by delayed-enhanced cardiac magnetic resonance (DE-CMR) and of revascularization therapy on survival in patients with coronary artery disease (CAD) and low ejection fraction (EF). BACKGROUND Prior studies have shown that DE-CMR predicts recovery of left ventricular (LV) dysfunction after revascularization. METHODS The authors prospectively evaluated survival of 144 consecutive patients (130 males, age 65 ± 11 years) with CAD and LV dysfunction (EF: 24 ± 7%) undergoing DE-CMR. Eighty-six patients underwent complete revascularization of dysfunctional myocardium (79 coronary artery bypass grafting, 7 percutaneous coronary intervention), whereas 58 patients remained under medical treatment. RESULTS Over the 3-year median follow-up, 49 patients died. Three-year survival was significantly worse in medically treated patients with dysfunctional viable than with nonviable myocardium (48% vs. 77% survival, p = 0.02). By contrast, in revascularized patients, survival was similar whether myocardium was viable or not (88% and 71% survival, respectively, p = NS). Hazard of death of viable myocardium remaining under medical treatment versus complete revascularization was 4.56 (95% confidence interval [CI]: 1.93 to 10.8). Cox multivariate analysis indicated that interaction of revascularization and viability provided significant additional value (chi-square test = 13.1, p = 0.004) to baseline predictors of survival (New York Heart Association functional class, wall motion score, and peripheral artery disease). More importantly, in 43 pairs of propensity score-matched patients, hazard of death (hazard ratio: 2.5 [95% CI: 1.1 to 6.1], p = 0.02) remained significantly higher for medically treated patients rather than for those with fully revascularized viable myocardium. CONCLUSIONS Without revascularization, presence of dysfunctional viable myocardium by DE-CMR is an independent predictor of mortality in patients with ischemic LV dysfunction. This observation may be useful for pre-operative selection of patients for revascularization.

Mechanisms of Recurrent Aortic Regurgitation After Aortic Valve Repair: Predictive Value of Intraoperative Transesophageal Echocardiography

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.

Relationship between improvement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MADIT-CRT trial

AIMS To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT. METHODS AND RESULTS We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). CONCLUSION Cardiac resynchronization therapy resulted in a significant improvement in both LV dyssynchrony and contractile function measured by GLS compared with ICD only and these improvements were associated with better subsequent outcomes.

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Background— &bgr;1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. &bgr;3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Methods and Results— Mice with cardiac myocyte-specific expression of human &bgr;3-AR (&bgr;3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). &bgr;3-TG and WT had similar morphometric and hemodynamic parameters at baseline. &bgr;3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in &bgr;3-TG mice, which also had less re-expression of fetal genes and transforming growth factor &bgr;1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of &bgr;3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, &bgr;3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Conclusions— Cardiac-specific overexpression of &bgr;3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac &bgr;3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

Dyssynchrony, Contractile Function, and Response to Cardiac Resynchronization Therapy

Background—Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. Methods and Results—We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ⩽30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ⩽−8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. Conclusions—Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.