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BACKGROUND. Echocardiography is the primary noninvasive technique for left ventricular (LV) strain measurement. MRI has potential advantages, although reference ranges and thresholds to differentiate normal from abnormal left ventricular global longitudinal strain (LVGLS), left ventricular global circumferential strain (LVGCS), and left ventricular global radial strain (LVGRS) are not yet established. OBJECTIVE. The purpose of our study was to determine the mean and lower limit of normal (LLN) of MRI-derived LV strain measurements in healthy patients and explore factors potentially influencing these measurements. EVIDENCE ACQUISITION. PubMed, Embase, and Cochrane Library databases were searched for studies published through January 1, 2020, that reported MRI-derived LV strain measurements in at least 30 healthy individuals. Mean and LLN measurements of LV strain were pooled using random-effects models overall and for studies stratified by measurement method (feature tracking [FT] or tagging). Additional subgroup and meta-regression analyses were performed. EVIDENCE SYNTHESIS. Twenty-three studies with a total of 1782 healthy subjects were included. Pooled means and LLNs for all studies were -18.6% (95% CI, -19.5% to -17.6%) and -13.3% (-13.9% to 12.7%) for LVGLS, -21.0% (-22.4% to -19.6%) and -15.6% (-17.0% to -14.3%) for LVGCS, and 38.7% (30.5-46.9%) and 20.6% (15.1-26.1%) for LVGRS. Pooled means and LLNs for LVGLS by strain measurement method were -19.4% (95% CI, -20.6% to -18.1%) and -13.1% (-14.2% to -12.0%) for FT and -15.6% (-16.2% to -15.1%) and -13.1% (-14.1% to -12.2%) for tagging. A later year of study publication, increasing patient age, and increasing body mass index were associated with more negative mean LVGLS values. An increasing LV end-diastolic volume index was associated with less negative mean LVGLS values. No factor was associated with LLN of LVGLS. CONCLUSION. We determined the pooled means and LLNs, with associated 95% CIs, for LV strain by cardiac MRI to define thresholds for normal, abnormal, and borderline strain in healthy patients. The method of strain measurement by MRI affected the mean LVGLS. No factor affected the LLN of LVGLS. CLINICAL IMPACT. This meta-analysis lays a foundation for clinical adoption of MRI-derived LV strain measurements, with management implications in both healthy patients and patients with various disease states.

Objectives: The aims of this study were to characterize the interplay between mixed aortic valve disease (MAVD) phenotypes (defined by concomitant severities of aortic stenosis and aortic regurgitation) and left ventricular global longitudinal strain (LV-GLS), and to assess the prognostic utility of LV-GLS in MAVD., Background: Little is known about the way LV-GLS separates MAVD phenotypes and if it is associated with their outcomes., Methods: This observational cohort study evaluated 783 consecutive adult patients with left ventricular ejection fraction ≥50% and MAVD, which was defined as coexisting with at least moderate aortic stenosis and at least moderate aortic regurgitation. We measured the conventional echocardiographic variables and average LV-GLS from apical long, 2- and 4-chamber views. The primary endpoint was all-cause mortality., Results: Mean age of patients was 69 ± 15 years, and 58% were male. Mean LV-GLS was -14.7 ± 2.9%. In total, 458 patients (59%) underwent aortic valve replacement at a median period of 50 days (25th to 75th percentile range: 6 to 560 days). During a median follow-up period of 5.6 years (25th to 75th percentile range: 1.8 to 9.4 years), 391 patients (50%) died. When stratified patients into tertiles according to LV-GLS values, patients with worse LV-GLS had worse outcomes (p < 0.001). LV-GLS was independently associated with mortality (hazard ratio: 1.09; 95% confidential intervals: 1.04 to 1.14; p < 0.001), with the relationship between LV-GLS and mortality being linear., Conclusions: LV-GLS is associated with all-cause mortality. LV-GLS may be useful for risk stratification in patients with MAVD., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with atrial fibrillation (AF) have risk factors that predispose to thoracic aneurysmal disease (TAD) and atherosclerosis. In this study in patients with AF, we assessed the occurrence of incidental TAD and assessed if a validated predictive score used to predict AF, the CHARGE-AF score, was associated with greater aortic dimensions. We also assessed the prevalence of coronary calcification. We conducted a cross-sectional study of 1,000 consecutive patients with AF undergoing chest multidetector CT during evaluation for pulmonary vein isolation. A dilated aortic root or ascending aorta (AA, dimension/ body surface area >2.05 cm/m 2 ) were found in 195 (20%). A total of 12 (1%) had significant aortic aneurysmal enlargement of > 5.0 cm. Advancing age, a bicuspid aortic valve, hypertension, and male gender were associated with increased aortic dimensions. Aortic root dimensions increased linearly (p < 0.001) and ascending aortic dimensions increased nonlinearly across CHARGE-AF deciles (p < 0.001). Nearly two-thirds (63%) had coronary calcification, 38% of whom were not on lipid-lowering therapy. In conclusion, in patients with AF undergoing gated chest CT, 1 in 5 had previously undetected TAD, with a small proportion having significantly aneurysmal dimensions approaching surgical thresholds. Risk factors previously established to increase the propensity to develop AF are also associated with increased TAD. These findings raise the need to consider a surveillance strategy for TAD in patients with AF, particularly in those with other risk factors for aortic disease. A high prevalence of coronary calcium was also detected, representing an opportunity to optimize statin therapy in patients with AF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Left ventricular global longitudinal strain (LVGLS), circumferential strain (LVGCS) and radial strain (LVGRS) are echocardiographic parameters with wide clinical applicability. However, the thresholds for abnormal left ventricular (LV) strains, particularly the lower limits of normal (LLN), are not well established. This meta-analysis determined the mean and LLN of two- (2D) and three-dimensional (3D) LV strain in healthy subjects and factors that influence strain measurements., Methods: We searched PubMed, Embase and Cochrane databases until 31 December 2019 for studies reporting left ventricular (LV) global strain in at least 50 healthy subjects. We pooled means and LLNs of 2D and 3D LV strain using random-effects models, and performed subgroup and meta-regression analysis for LVGLS., Results: Forty-four studies were eligible totaling 8,910 subjects. The pooled means and LLNs (95% confidence intervals) were -20.1% (-20.7%, -19.6%) and -15.4% (-16.0%, -14.7%) respectively for 2D-LVGLS; -21.9% (-23.4%, -20.3%) and -15.3% (-16.9%, -13.8%) respectively for 2D-LVGCS; and 48.4% (43.8%, 53.0%) and 25.5% (17.8%, 33.1%) respectively for 2D-LVGRS. All pooled analyses demonstrated significant heterogeneity, and means and LLNs of and 3D-LV strains differed marginally from 2D. Only vendor software was associated with differences in pooled means and LLN of 2D-LVGLS., Conclusions: In conclusion, pooled means and LLNs of 2D- and 3D-LV global strain parameters in healthy subjects were reported. Based on the pooled LLNs, thresholds for abnormal, borderline and normal strains can be defined, such as less negative than -14.7%, between -14.7% and -16.0% and more negative than -16.0% respectively for 2D-LVGLS, and 2D-LVGLS values are only affected by vendor software., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-711). TKMW received a clinical and research fellowship grant from the National Heart Foundation of New Zealand (number 1775). The other authors have no conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background Concurrent presence of aortic stenosis and aortic regurgitation is termed mixed aortic valve disease (MAVD). Although multiple articles have addressed patients with "isolated" aortic stenosis or aortic regurgitation, the natural history, impact, and outcomes of MAVD are not well defined. Here, we evaluate long-term outcomes in patients with MAVD and cardiovascular adaptations to chronic MAVD. Methods and Results This observational cohort study evaluated 862 adult patients (56.8% male) with preserved left ventricular ejection fraction and at least moderate aortic regurgitation and moderate aortic stenosis. Primary outcome was all-cause mortality. Subgroup analysis was based on treatment modality (aortic valve replacement [AVR] versus medical management). A regression analysis of longitudinal echocardiographic parameters was performed to assess the natural history of MAVD. Mean age was 68±15 years, and mean left ventricular ejection fraction was 58±5%. At 4.6 years (25th-75th percentile range, 1.0-8.7), 58.6% of patients underwent an AVR and 48.8% patients died. In both unadjusted and adjusted Cox survival analysis, AVR was associated with improved survival (hazard ratio, 0.41; 95% CI, 0.34-0.51, P <0.001). Impact of AVR persisted when stratifying the cohort by symptom status and baseline aortic valve area (log rank, P <0.001 for both) and after propensity-score matching (hazard ratio, 0.40; 95% CI, 0.32-0.50; P <0.001). In the longitudinal analysis, there were statistically significant changes over time in aortic valve peak gradient ( P <0.001) and aortic valve area ( P <0.001) and only mild increases in left ventricular end-diastolic ( P <0.007) and -systolic ( P <0.001) volumes. Conclusions MAVD confers a high risk of all-cause mortality. However, AVR significantly reduces this risk independent of aortic valve area, symptom status, and after controlling for confounding variables.

Right ventricular (RV) fibrosis is increasingly recognized as the underlying pathological substrate in a variety of clinical conditions. We sought to employ cardiac magnetic resonance (CMR) techniques of strain imaging and longitudinal relaxation time (T 1 ) mapping to better examine the relationship between RV function and structure. Our aim was to initially evaluate the feasibility of these techniques to evaluate the right ventricle. We then sought to explore the relationship between RV function and underlying fibrosis, along with examining the evolution of RV remodeling according to the amount of baseline fibrosis. Echocardiography was performed in 102 subjects with non-ischemic cardiomyopathy. Right ventricular parameters were assessed including: fractional area change (FAC) and longitudinal strain. The same cohort underwent CMR. Post-contrast T 1 mapping was performed as a marker of fibrosis with a Look-Locker technique using inversion recovery imaging. Mid-ventricular post-contrast T 1 values of the RV free wall, RV septum and lateral LV were calculated using prototype analysis software. Biventricular volumetric data including ejection fraction was measured by CMR using a cine short axis stack. CMR strain analysis was also performed to assess 2D RV longitudinal and radial strain. Simultaneous biochemical and anthropometric data were recorded. Subjects were followed over a median time of 29 months (IQR 20-37 months) with echocardiography to evaluate temporal change in RV FAC according to baseline post-contrast T 1 values. Longitudinal data analysis was performed to adjust for patient loss during follow-up. Subjects (62% men, 51 ± 15 years) had mild to moderately impaired global RV systolic function (RVEF = 39 ± 15%; RVEDV = 187 ± 69 ml; RVESV = 119 ± 68 ml) and moderate left ventricular dysfunction at baseline (LVEF 30 ± 17%). Good correlation was observed between mean LV and RV post-contrast T 1 values (r = 0.652, p < 0.001), with similar post-contrast T 1 values maintained in both the RV free wall and septum (r = 0.761, p < 0.001). CMR RVEF demonstrated a proportional correlation with echocardiographic measures of RV longitudinal function and CMR RV strain (longitudinal r = -0.449, p = 0.001; radial r = -0.549, p < 0.001). RVEF was related to RV post-contrast T 1 values, particularly in those with RV dysfunction (free wall T 1 r = 0.259 p = 0.027; septal T 1 r = 0.421 p < 0.001). RV strain was also related to RV post-contrast T 1 values (r = -0.417, p = 0.002). Linear regression analysis demonstrated strain and post-contrast T1 values to be independently associated with RVEF. Subjects with severe RV dysfunction (CMR RVEF <25%) demonstrated lower RV CMR strain (longitudinal p = 0.018; radial p < 0.001), RV T 1 values (free wall p = 0.013; septum <0.001) and RV longitudinal echocardiography parameters despite no difference in afterload. During follow-up, those with RV free wall post-contrast T 1 values ≥ 350 ms demonstrated ongoing improvement in FAC (Δ6%), whilst values <350 ms were associated with deterioration in RV function (ΔFAC = -5%) (p = 0.026). CMR provides a comprehensive method by which to evaluate right ventricular function. Post-contrast T 1 mapping and CMR strain imaging are technically feasible and provide incremental information regarding global RV function and structure. The proportional relationship between RV function and post-contrast T 1 values supports that myocardial fibrosis is a causative factor of RV dysfunction in NICM, irrespective of RV afterload. This same structural milieu also appears integral to the propensity for both positive and negative RV remodeling long-term, suggestive that this is also determined by the degree of underlying RV fibrosis.

Background: Gravity affects every aspect of cardiac performance. When gravitational gradients are at their greatest on Earth (i.e., during upright posture), orthostatic intolerance may ensue and is a common clinical problem that appears to be exacerbated by the adaptation to spaceflight. We sought to elucidate the alterations in cardiac performance during preload reduction with progressive upright tilt that are relevant both for space exploration and the upright posture, particularly the preload dependence of various parameters of cardiovascular performance., Methods: This was a prospective observational study with tilt-induced hydrostatic stress. Echocardiographic images were recorded at four different tilt angles in 13 astronauts, to mimic varying degrees of gravitational stress: 0° (supine, simulating microgravity of space), 22° head-up tilt (0.38 G, simulating Martian gravity), 41° (0.66 G, simulating approximate G load of a planetary lander), and 80° (1 G, effectively full Earth gravity). These images were then analyzed offline to assess the effects of preload reduction on anatomical and functional parameters., Results: Although three-dimensional end-diastolic, end-systolic, and stroke volumes were significantly reduced during tilting, ejection fractions showed no significant change. Mitral annular e' and a' velocities were reduced with increasing gravitational load (P < .001 and P = .001), although s' was not altered. Global longitudinal strain (GLS; from -19.8% ± 2.2% to -14.7% ± 1.5%) and global circumferential strain (GCS; from -29.2% ± 2.5% to -26.0% ± 1.8%) were reduced significantly with increasing gravitational stress (both P < .001), while the change in strain rates were less certain: GLSR (P = .049); GCSR (P = .55). End-systolic elastance was not consistently changed (P = .53), while markers of cardiac afterload rose significantly (effective arterial elastance, P < .001; systemic vascular resistance, P < .001)., Conclusions: Preload modification with gravitational loading alters most hemodynamic and echocardiographic parameters including e' velocity, GLS, and GCS. However, end-systolic elastance and strain rate appear to be more load-independent measures to examine alterations in the cardiovascular function during postural and preload changes, including microgravity., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Accurate and reproducible quantification of ventricular septal (VS) thickness in hypertrophic cardiomyopathy (HC) is essential for diagnosis, surgical planning, and risk stratification. We sought to compare VS thickness measurements using transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and cardiac magnetic resonance (CMR) in patients with HC. Prospectively reported measurements of VS thickness were compared using analysis of variance and Bland-Altman plots in 90 consecutive patients with HC who underwent a TTE, TEE, and CMR within 3 months. A subset was re-measured on 2 separate occasions by 2 readers to assess inter- and intraobserver variability. There was modest correlation between modalities, with CMR and TTE measurements of VS thickness showing the greatest correlation (CMR vs TTE, r = 0.70; CMR vs TEE, r = 0.60; TTE vs TEE, r = 0.56). Smaller measurements were seen using CMR versus either echocardiographic technique (13% smaller vs TEE, 8% smaller vs TTE, p <0.001 for both). The variability of measurement between modalities was not correlated with the degree of VS thickness. There was significantly lower intraobserver variability with CMR versus echocardiography (p = 0.01 for both), but no difference in interobserver variability. CMR delineated a different area of maximal VS thickness other than the basal anteroseptum more frequently than echocardiography (44% of cases vs 24% for TTE and 11% for TEE). In conclusion, CMR assessment of VS thickness differs significantly from echocardiography in patients with HC, with a systemic bias toward lower measurements seen with CMR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In independent studies, abnormal global longitudinal strain (GLS) and myocardial inflammation or scar detected by 18F-fludeoxyglucose positron emission tomography (FDG-PET) are associated with poor prognosis among patients with high likelihood for cardiac sarcoidosis. However, commonly used imaging modalities have not been evaluated in the same population. Our goals were to examine the relation between GLS and FDG-PET, and to evaluate the incremental prognostic value of these imaging techniques for predicting major adverse cardiac events (MACE) in patients suspected to have cardiac sarcoidosis. We identified patients with systemic sarcoidosis who underwent an echocardiogram and FDG-PET within 60 days. Regional strain (average of base, mid, and apical segmental strains from each of 6 wall regions) was calculated and compared with regional FDG-PET findings. The associations among GLS, FDG-PET findings, and MACE (defined as death, ventricular tachycardia, heart failure hospitalization, or transplantation) were evaluated using a Cox model. Of 84 patients, 51 had abnormal FDG-PET. GLS was impaired in patients with abnormal versus normal FDG-PET (-14.2 ± 4.7% vs -17.9 ± 3.5%, p <0.01). After adjusting for clinical risk factors, both GLS and the number of segments with abnormal perfusion and metabolism on FDG-PET were associated with adverse cardiac events (p <0.01 for both). In conclusion, GLS and regional LS are impaired in patients with abnormal perfusion and metabolism detected using FDG-PET. Additionally, both GLS and abnormal FDG-PET have incremental prognostic value for predicting MACE in patients with systemic sarcoidosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Left atrial (LA) function helps to preserve cardiac output and to control pulmonary capillary wedge pressure in the setting of left ventricular (LV) impairment, but little is known about the contribution of the LA function to ventricular arrhythmia. We sought whether LA booster pump function was associated with arrhythmias in patients undergoing primary prevention implantable cardioverter-defibrillator (ICD) implantation for non-ischaemic dilated cardiomyopathy (NICM), independent of global longitudinal strain (GLS) and mechanical dispersion (MD)., Methods and Results: We identified 124 NICM patients (56 ± 13, 67 male) who underwent echocardiography pre-ICD implantation for primary prevention. The main outcome measure was appropriate ICD therapy (anti-tachycardia pacing or shock). The mitral A-wave was used as an LA functional marker. MD was defined as standard deviation of time to peak strain of each segment. Over a median follow-up of 3.8 ± 2.2 years, 36 patients had appropriate ICD therapy, including 23 shocks. Patients with appropriate ICD therapy had lower A-wave velocity (P < 0.001), larger LA volume (P < 0.001), and impaired circumferential MD (P = 0.006), but similar ejection fraction (EF) (P = 0.40) and GLS (P = 0.11). In sequential Cox proportional hazards models, A-wave, E/A ratio, and GLS were significantly associated with outcomes, independent of age, sex, and cardiac resynchronization therapy defibrillator or left bundle branch block. In nested Cox models, mitral A-wave had a prognostic value incremental to models with LV systolic (EF and GLS) and diastolic functional parameters (E/A, E/e', and LA volume) and MD., Conclusion: LA booster pump function was an independent and incremental predictor of arrhythmias in NICM over GLS and MD, and may aid better risk stratification in this population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Global longitudinal strain (GLS) is used to evaluate left ventricular (LV) performance after chemotherapy. Differentiating between reduction in GLS due to clinical change and normal temporal variability in measurement remains a challenge. We quantified interobserver, test-retest variability of GLS by expert observers in relation to variability of GLS quantified for clinical assessment by sonographers in our laboratory. We examined the temporal variability of GLS in 30 patients with normal LV ejection fraction (LVEF >53%) undergoing chemotherapy in the absence of change in medications and clinical symptoms in up to 5 sequential echocardiograms. GLS was quantified using EchoPAC (GE Healthcare, Milwaukee, Wisconsin) and 2-dimensional biplane LVEF was measured from 4- and 2- chamber views. Interobserver test-retest variability of GLS measured in 10 random patients by 2 expert readers was calculated using a one-way analysis of variance. Square root of mean squared error provided the SEM for temporal variability. Baseline LVEF was 59.3 ± 5.1% and remained relatively unchanged over 12 months, p = 0.87. Temporal variability of GLS measured by sonographers was 1.28% and similar to interobserver test-retest variability of GLS measured by expert observers, 1.12% (p = 0.17). Maximum detectable difference in GLS measured by expert observers was similar to that derived from sequential measurements of GLS (3.2% vs 3.6%, respectively). Temporal variability of GLS among clinically stable patients is 1.28% and similar to interobserver test-retest variability of 1.12% measured by expert observers. In conclusion, a reduction in strain >3.2% during sequential echocardiograms under these conditions may be significant., (Copyright © 2016. Published by Elsevier Inc.)

To assess the utility of cardiac magnetic resonance (MR) imaging in the diagnosis of constrictive pericarditis (CP). This study was approved by the institutional review board, with a waiver of informed consent. A total of 42 consecutive patients (mean age, 55 ± 16 years; 3 women, 39 men) with CP treated with pericardiectomy who had undergone cardiac MR before surgery were evaluated retrospectively. An additional 21 patients were evaluated as a control group; of these, 10 consecutive patients received cardiac MR for reasons other than suspected pericardial disease, and 11 consecutive patients had a history of pericarditis but no clinical suspicion of pericardial constriction. MR imaging parameters were analyzed independently and with a decision tree algorithm for usefulness in the prediction of CP. Catheterization data were also reviewed when available. A model combining pericardial thickness and relative interventricular septal (IVS) excursion provided the best overall performance in prediction of CP (C statistic, 0.98, 100% sensitivity, 90% specificity). Several individual parameters also showed strong predictive value in the assessment of constriction, including relative IVS excursion (sensitivity, 93%; specificity, 95%), pericardial thickness (sensitivity, 83%; specificity, 100%), qualitative assessment of pathologic coupling (sensitivity, 88%; specificity, 100%), diastolic IVS bounce (sensitivity, 90%; specificity, 85%), left ventricle area change (sensitivity, 86%; specificity, 100%), and eccentricity index (sensitivity, 86%; specificity, 90%; all P < 0.001). Strong agreement was observed between catheterization and surgical findings of constriction (97%). Cardiac MR provides robust quantitative and qualitative analysis for the diagnosis of CP.

The benefits of biventricular pacing in patients with cardiac resynchronization therapy (CRT) remain poorly understood in those with right bundle branch block (RBBB). The aim of this study was to examine the differences in several speckle tracking-derived parameters, including left ventricular torsion and longitudinal strain with CRT on and off for patients with underlying left bundle branch block (LBBB) and RBBB. Twelve patients with CRT and RBBB were compared with a similar group of patients with underlying LBBB who were sent for evaluation and atrioventricular optimization. Echocardiographic images were acquired with biventricular pacing on and off. The 2 groups had similar baseline characteristics, including age, the ejection fraction, and QRS duration. During intrinsic conduction (CRT off), patients with LBBB had lower torsion angles than those with RBBB (2.3 ± 1.0° in those with LBBB vs 6.3 ± 1.0° in those with RBBB, p = 0.03) but trended toward improvements in torsional parameters, including torsional angle and peak untwisting velocity with CRT on, whereas these parameters worsened in patients with RBBB. Compared with CRT off, analyses of septal and lateral strain curves showed significant improvements in septal strain during 100% and 200% of systole with CRT on in patients with LBBB, whereas biventricular pacing resulted in a trend toward worsening of septal strain in patients with RBBB. Negligible changes were noted in lateral strain values. In conclusion, CRT favorably improves regional mechanics in patients with LBBB primarily involving the ventricular septum, with a negligible positive impact on cardiac function in patients with underlying RBBB., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The ratio of early transmitral flow velocity (E) to mitral annular velocity (E') is considered a predictor of pulmonary capillary wedge pressure (PCWP). In a previous small study, the paradoxical relation between PCWP and E/E' ratio has been described in patients with constrictive pericarditis (CP). We sought to test this paradoxical relation in a larger cohort. We retrospectively identified 49 patients with surgically confirmed CP (40 men; mean age 61 ± 10 years) who underwent right-sided cardiac catheterization with PCWP measurement, preceded by an echocardiographic study. Of these, 48 patients underwent either computed tomography or magnetic resonance imaging to measure pericardial thickness on the lateral side of the left ventricular wall. Mean interval time between echocardiogram and right-sided cardiac catheterization was 1.5 ± 3.8 days. There were no significant correlations between mean, medial, or lateral E/E' and PCWP (r = -0.17, 95% confidence interval [CI] -0.43 to -0.12; r = -0.17, 95% CI -0.43 to -0.12; and r = -0.12, 95% CI -0.39 to -0.17, respectively). Similarly, there was no correlation between mean E/E' and brain natriuretic peptide (Spearman r = -0.17, p = NS). Patients with increased pericardial thickness (defined as >4 mm) had both lower lateral peak systolic annular velocity (S') and lower lateral S' integral (7.8 ± 2.4 vs 9.6 ± 2.4, p = 0.02 and 13.2 ± 4.2 vs 15.9 ± 4.7, p = 0.04, respectively). In patients with CP, there were no correlations between septal, lateral, or mean E/E' and PCWP. In conclusion, E/E' is not predictive of filling pressures in patients with CP, and perhaps the "annulus paradoxus" phenomenon should be revisited. The relation between the mitral annular velocity and thickness of the parietal pericardium may affect this phenomenon., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Atrial fibrillation (AF) and heart failure (HF) frequently coexist. We have previously demonstrated that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) can be used to control ventricular rate during AF. Due to withdrawal of vagal activity in HF, the therapeutic effects of AVN-VS may be compromised in the combined condition of AF and HF. Accordingly, this study was designed to evaluate the therapeutic effects of AVN-VS to control ventricular rate in AF and HF., Methods and Results: A combined model of AF and HF was created by implanting a dual chamber pacemaker in 24 dogs. A newly designed bipolar electrode was inserted into the ganglionic AVN fat pad and connected to a nerve stimulator for delivering AVN-VS. In all dogs, HF was induced by high rate ventricular pacing at 220 bpm for 4 weeks. AF was then induced and maintained by rapid atrial pacing at 600 bpm after discontinuation of ventricular pacing. These HF + AF dogs were randomized into control (n = 9) and AVN-VS (n = 15) groups. In the latter group, vagal stimulation (310 μs, 20 Hz, 3-7 mA) was delivered continuously for 6 months. Compared with the control, AVN-VS had a consistent effect on ventricular rate slowing (by >50 bpm, all P < 0.001) during the entire 6-month observation period that was associated with left ventricular functional improvement. Moreover, AVN-VS was well tolerated by the treated animals., Conclusions: AVN-VS achieved consistent rate slowing, which was associated with improved ventricular function in a canine AF and HF model. Thus, AVN-VS may be a novel, effective therapeutic option in the combined condition of AF and HF., (© 2012 Wiley Periodicals, Inc.)

Aims: Although left ventricular (LV) relaxation is well recognized as a predictor of mitral annulus (MA) early diastolic (E') velocity, its significance relative to other predictors of E' is less well understood., Methods and Results: We assessed 40 healthy volunteers, 43 patients with acutely decompensated chronic systolic heart failure (HF), and 36 patients with hypertrophic obstructive cardiomyopathy (HOCM) using echocardiography and right or left heart catheterization. Data were obtained at baseline. In addition, in healthy volunteers haemodynamics were varied by graded saline infusion and low body negative pressure, while in HF patients it was varied by vasoactive drug treatment. E- and A-wave velocity (E/A) ratio of the mitral valve inflow, systolic MA velocity integral (s' integral) and E' and late velocity (A') of lateral and septal MA pulsed wave velocities were assessed by echocardiography. Time constant of isovolumic pressure decay τ(0)) was calculated from isovolumic relaxation time/[ln(aortic dicrotic notch pressure) - ln(LV filling pressure)]. In all three groups, s' integral was the strongest predictor of E' (partial r= 0.53-0.79; 0.81 for three groups combined), followed by E/A ratio (partial r= 0.10-0.78; 0.26 for all groups combined) and τ(0) (partial r= -0.1 to 0.023; -0.21 for all groups combined)., Conclusion: In healthy adults, patients with systolic HF, or patients with HOCM, E' is related to LV long-axis function and E/A ratio, a global marker of LV filling. E' appears less sensitive to LV relaxation.

Aims: To determine prognostic significance of global left ventricular (LV) contractile reserve, defined by dobutamine-induced changes of Tei index (Delta Tei), in patients with dilated cardiomyopathy (DCM)., Methods and Results: Thirty-eight patients with idiopathic DCM underwent high-dose (up to 40 microg/kg/min) dobutamine stress echocardiography. Prognostic value of different indices of LV contractile reserve, including Delta Tei, as well as changes of ejection fraction (Delta EF) and wall motion score index (Delta WMSi), was analysed. Patients were followed up for 5 years for cardiac mortality. Patients with preserved contractile reserve, defined by Delta Tei > -0.35, had significantly lower cardiac mortality when compared with those without it (38 vs. 77%, P = 0.02). Also, the Kaplan-Meier survival analysis revealed that patients with contractile reserve had better 5-year survival when compared with those without contractile reserve (log-rank = 6.01, P = 0.014). However, of all examined indices of contractile reserve, Cox's regression analysis identified Delta WMSi as the only independent predictor of 5-year mortality., Conclusion: Our data indicate that the presence of contractile reserve assessed by Delta Tei may identify patients with favourable long-term prognosis. Prognostic value of Delta Tei appears to be similar to Delta EF, but less powerful than Delta WMSi.

Background: Patients with hypertrophic cardiomyopathy (HCM) are predisposed to ventricular tachyarrhythmia (VT); likely due to myocardial fibrosis or disarray. Delayed hyperenhancement magnetic resonance imaging (DHE-MRI) accurately detects myocardial fibrosis (scar). We sought to determine the association between septal thickness, myocardial scar and VT., Methods: Sixty-eight patients (mean age 44 years, 69% males) with documented HCM underwent cine MRI (Siemens Sonata or Avanto 1.5 T scanner, Erlangen, Germany) in short axis, 2, 3 and 4-chamber views and maximal interventricular septal thickness was recorded at end-diastole. Corresponding DHE-MR images (8-10 mm thick) were obtained, approximately 20 min after injection of 0.2 mmol/kg of Gadolinium. Scar was determined semi-automatically (as % of total myocardium) using VPT software (Siemens) and defined as intensity >2 SD above viable myocardium in a 12 segment short-axis model at apex, mid LV and base. Presence of VT (documented on ambulatory ECG monitoring) and history of sudden death were recorded., Results: One patient had a history of sudden death and 9 (13%) had VT on ambulatory ECG monitoring. On DHE-MRI, 39 (57%) patients had myocardial scar. Patients with VT had significantly higher scar %, compared to those without: 14% [6, 19] vs. 6% [0, 10], P = 0.01. On logistic regression, only the size of the scar was a significant predictor of VT (P = 0.03)., Conclusions: HCM subjects with VT have a higher % of myocardial scarring noted on DHE-MRI, independent of septal thickness or beta-blocker use.

Background: Antibodies to the beta1-adrenergic receptor (beta1AR) are detected in a substantial number of patients with idiopathic dilated cardiomyopathy (DCM). The mechanism whereby these autoantibodies exert their pathogenic effect is unknown. Here, we define a causal mechanism whereby beta1AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM., Methods and Results: We used the beta1AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the beta1AR. After transfer into naive male hosts, beta1AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of beta1AR IgG before transfer and by selective pharmacological antagonism of host beta1AR but not beta2AR. We found that beta1AR autoantibodies shifted the beta1AR into the agonist-coupled high-affinity state and activated the canonical cAMP-dependent protein kinase A signaling pathway in cardiomyocytes. These events led to functional alterations in intracellular calcium handling and contractile function. Sustained agonism by beta1AR autoantibodies elicited caspase-3 activation, cardiomyocyte apoptosis, and DCM in vivo, and these processes were prevented by in vivo treatment with the pan-caspase inhibitor Z-VAD-FMK., Conclusions: Our data show how beta1AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.

Speckle-tracking echocardiography (STE) uses a two-dimensional echocardiographic image to estimate two orthogonal strain components. The aim of this study was to assess sensitivity of circumferential (S(circ)) and radial (S(rad)) strains to infarct-induced left ventricular (LV) remodeling and scarring of the LV in a rat. To assess the relationship among S(circ), S(rad), and scar size, two-dimensional echocardiographic LV short-axis images (12 MHz transducer, Vivid 7 echo machine) were collected in 34 Lewis rats 4 to 10 wk after ligation of the left anterior descending artery. Percent segmental fibrosis was assessed from histological LV cross sections stained by Masson trichrome. Ten normal rats served as echocardiographic controls. S(circ) and S(rad) were assessed by STE. Histological data showed consistent scarring of anterior and lateral segments with variable extension to posterior and inferior segments. Both S(circ) and S(rad) significantly decreased after myocardial infarction (P<0.0001 for both). As anticipated, S(circ) and S(rad) were lowest in the infarcted segments. Multiple linear regression showed that segmental S(circ) were similarly dependent on segmental fibrosis and end-systolic diameter (P<0.0001 for both), whereas segmental S(rad) measurements were more dependent on end-systolic diameter (P<0.0001) than on percent fibrosis (P<0.002). STE correctly identifies segmental LV dysfunction induced by scarring that follows myocardial infarction in rats.

In early diastole, pressure is lower in the apex than in the base of the left ventricle (LV). This early intraventricular pressure difference (IVPD) facilitates LV filling. We assessed how LV diastolic IVPD and intraventricular pressure gradient (IVPG), defined as IVPD divided by length, scale to the heart size and other physiological variables. We studied 10 mice, 10 rats, 5 rabbits, 12 dogs, and 21 humans by echocardiography. Color Doppler M-mode data were postprocessed to reconstruct IVPD and IVPG. Normalized LV filling time was calculated by dividing filling time by RR interval. The relationship between IVPD, IVPG, normalized LV filling time, and LV end-diastolic volume (or mass) as fit to the general scaling equation Y = kM beta, where M is LV heart size parameter, Y is a dependent variable, k is a constant, and beta is the power of the scaling exponent. LV mass varied from 0.049 to 194 g, whereas end-diastolic volume varied from 0.011 to 149 ml. The beta values relating normalized LV filling time with LV mass and end-diastolic volume were 0.091 (SD 0.011) and 0.083 (SD 0.009), respectively (P < 0.0001 vs. 0 for both). The beta values relating IVPD with LV mass and end-diastolic volume were similarly significant at 0.271 (SD 0.039) and 0.243 (SD 0.0361), respectively (P < 0.0001 vs. 0 for both). Finally, beta values relating IVPG with LV mass and end-diastolic volume were -0.118 (SD 0.013) and -0.104 (SD 0.011), respectively (P < 0.0001 vs. 0 for both). As a result, there was an inverse relationship between IVPG and normalized LV filling time (r = -0.65, P < 0.001). We conclude that IVPD decrease, while IVPG increase with decreasing animal size. High IVPG in small mammals may be an adaptive mechanism to short filling times.

Background: Coupled pacing (CP), which consists of delivering a premature electrical stimulation to the heart after the effective refractory period of ventricular activation, is a novel method for controlling ventricular rate during atrial fibrillation (AF). It also has been established that CP improves pump function by enhancing external cardiac work and myocardial efficiency., Objective: The purpose of the present study was to determine if two time delays for CP (short and long) would result in similar improvements in ventricular function., Methods: In a canine model, we applied CP at two time delays (CP-S and CP-L) during two stages: sinus rhythm (SR) and acute AF. The cardiac responses to CP during SR served as the nontachycardic and nondepressed control. During both rhythms, we shortened the coupling interval until we obtained maximal contractility, designated CP-S. Next, we increased the delay until we started to see a measurable secondary contraction (left ventricular pressure development of approximately 20 mmHg). These longer delays were designated CP-L., Results: Our results showed that the ventricular rate of intrinsic activation (VRIA) remained decreased despite prolongation of the time delay of CP during both AF and SR. Also, both delays of CP increased left ventricular systolic pressure (LVSP) and dLVP/dt, which are indices of myocardial contractility. In contrast, CP increased external cardiac work only during AF. Prolonging this time delay did not markedly decrease the improvement in external cardiac work. Myocardial O(2) consumption (MVO(2)) did not significantly change as the result of CP during either SR or AF. Finally, myocardial efficiency improved during AF as the result of CP at both time delays., Conclusions: In conclusion, shorter time delays for CP increased contractile strength during both SR and AF. However, extending the time delay of CP had minimal effects on diminishing the improved ventricular pump function and energetics that resulted from CP during AF. Thus, the maximal enhancement of myocardial contractility via CP-S was not needed to maintain the improved ventricular function during acute AF when CP is applied.

We compared the impact of annulus size and valve deformation (tethering) on mitral regurgitation in the animal dilated cardiomyopathy model, and assessed if acute left ventricular volume changes affect mitral annulus dimensions. We performed 3-dimensional echocardiography in 30 open-chest dogs with pacing-induced cardiomyopathy. Mitral annulus area was calculated from its two orthogonal diameters, whereas valve tethering was quantified by valve tenting area measurement. Mitral valve regurgitant volume showed the highest correlation with annulus area (r = 0.64, P < .001), left atrial volume (r = 0.40, P < .01), and left ventricular end-diastolic volume (r = 0.37, P < .01). Regurgitant volume showed poorer correlation with valve tethering in both septolateral and intercommissural planes (r = 0.35 and r = 0.31, P < .05 for both). Annulus dimensions correlated with acute changes of left ventricular end-diastolic volume (r = 0.68, P = .002). Mitral annulus dilation is the strongest predictor of functional mitral regurgitation in this animal dilated cardiomyopathy model.

Objective: We sought to investigate the geometric changes of the mitral annulus during systole in relation to global left ventricular (LV) systolic function using real-time 3-dimensional (3D) echocardiography., Methods: Real-time 3D echocardiography was performed in 23 patients with global LV systolic dysfunction with ejection fraction of 37 +/- 19% and 9 control subjects with ejection fraction of 62 +/- 4%. Volumetric data were divided into 9 rotational apical planes (angle increment = 20 degrees) using 3D software. Nine rotational annular dimensions (ADs) were measured in all planes in early and late systole. Nonplanar angle (NPA) of the annulus between two vectors from two hinge points of the annulus in the anteroposterior plane to the center between two commissures in the commissure-commissure plane was measured during early and late systole. Fractional changes of NPA and AD were defined as changes in percentage during systole., Results: NPA significantly increased during systole (early, 145 +/- 12 degrees; late, 160 +/- 9 degrees; P < .01). Among 9 ADs, 3 anteroposteriorly directed ADs showed the most prominent fractional increases during systole in all patients. Both fractional changes of NPA ( R 2 = 0.87, P < .01) and the anteroposterior dimension, AD 1 ( R 2 = 0.85, P < .01) showed significant positive correlation with global LV systolic function., Conclusions: Real-time 3D echocardiography demonstrated that saddle shape of the mitral annulus was getting enlarged and less nonplanar mainly in the anteroposterior direction during systole. These geometric changes were proportional to the global LV systolic function.

Right ventricular (RV) maximal power (PWR(mx)) is dependent on preload. The objective of this study was to test our hypothesis that the PWR(mx) versus end-diastolic volume (EDV) relationship, analogous to the load-independent stroke work (SW) versus EDV relationship (preload-recruitable SW, PRSW), is linear, with the PWR x-axis intercept (V(0PWR)) corresponding to the PRSW intercept (V(0SW)). If our hypothesis is correct, the preload sensitivity of PWR(mx) could be eliminated by adjusting for EDV and V(0PWR). Ten dogs were instrumented with a pulmonary flow probe, micromanometers, and RV conductance catheter. Data were obtained during bicaval occlusions under various conditions and fitted to PWR(mx) = a.(EDV - V(0PWR))(beta), where a is the slope of the relationship. The PWR(mx) versus EDV relationship did not deviate from linearity (beta = 1.09, P = not significant vs. 1), and V(0PWR) correlated with V(0SW) (r = 0.93, P <0.0001). V(0PRW) was related to steady-state EDV and left ventricular end-diastolic pressure, allowing for estimation of V(0PWR) (V(0Est)) and single-beat PWR(mx) preload adjustment. Dividing PWR(mx) by the difference of EDV and V(0PWR) (PAMP(V0PWR)) eliminated preload dependency down to 50% of the baseline EDV. PWR(mx) adjustment using V(0Est) (PAMP(V0Est)) showed similar preload independency. Enhancing contractility increased PAMP(V0PWR) and PAMP(V0Est) from 176 +/- 52 to 394 +/- 205 W/ml x 10(4) and 145 +/- 51 to 404 +/- 261 W/ml x 10(4), respectively, accompanied by an increase of PRSW from 13.0 +/- 4.5 to 29.7 +/- 16.4 mmHg (all P <0.01). PAMP(V0PWR) and PAMP(V0Est) correlated with PRSW (r = 0.85; r = 0.77; both P <0.001). Numerical modeling confirmed the accuracy of our experimental data. Thus preload adjustment of PWR(mx) should consider a linear PWR(mx) versus EDV relationship with distinct V(0PWR). PAMP(V0PWR) is a preload-independent estimate of RV contractility that may eventually be determined noninvasively.

Cardiac resynchronization therapy improves hemodynamics in selected patients with heart failure. Mechanic asynchrony parameters that may guide patient selection or therapy optimization are still being investigated. A biventricular (BiV) pacemaker was implanted in 34 patients with dilated ischemic, idiopathic, or valvular cardiomyopathy, and a QRS duration of > or =130 milliseconds. Two-dimensional standard and Doppler tissue echocardiography was performed during right ventricular (RV), left ventricular (LV), BiV, and no pacing in a random and blinded manner. LV and BiV pacing increased stroke volume (P <.02 for both) and ejection fraction (P <.001 for both). Regional contractility assessed by displacement, strain rate, and peak systolic strain was improved in some segments (P <.05) during LV and BiV pacing. A homogenization of segmental contractions was observed during LV and BiV pacing as evaluated by net systolic displacement and segmental myocardial performance index. LV and BiV pacing provides benefits that can be quantified by echocardiography.

Background: It has been shown that transient increase in left ventricular stiffness, assessed by Doppler-derived early filling deceleration time, occurs during the first 24 to 48 hours after myocardial infarction but returns to normal within several days. It has been reported that hyperbaric oxygen treatment has a favorable effect on left ventricular systolic function in patients with acute myocardial infarction treated with thrombolysis. However, there are no data on the effects of hyperbaric oxygen on diastolic function after myocardial infarction., Methods: To assess acute and short-term effects of hyperbaric oxygen on left ventricular chamber stiffness, we studied 74 consecutive patients with first acute myocardial infarction who were randomly assigned to treatment with hyperbaric oxygen combined with streptokinase or streptokinase alone. After thrombolysis, patients in the hyperbaric oxygen group received 100% oxygen at 2 atm for 60 minutes in a hyperbaric chamber. All patients underwent 2-dimensional and Doppler echocardiography 1 (after thrombolysis), 2, 3, 7, 21, and 42 days after myocardial infarction., Results: Patient characteristics, including age, sex, risk factors, adjunctive postinfarction therapy, infarct location, and baseline left ventricular volumes and ejection fraction, were similar between groups (P >.05 for all). For both groups, deceleration time decreased nonsignificantly from day 1 to day 3 and increased on day 7 (P <.001, for both groups), increasing nonsignificantly subsequently. The E/A ratio increased in the entire study group throughout the time of study (P <.001, for both groups). The pattern of changes of deceleration time was similar in both groups (P >.05 by analysis of variance), as was in subgroups determined by early reperfusion success., Conclusions: These data in a small clinical trial do not support a benefit of hyperbaric oxygen on left ventricular diastolic filling in patients with acute myocardial infarction treated with thrombolysis.

We assessed the effects of implantation of Myosplint (Myocor, Maple Grove, Minn), a device that changes left ventricular (LV) cross-sectional shape from circular to bilobar, on regional LV function. A total of 10 open-chest dogs with tachycardia-induced cardiomyopathy were studied before and after Myosplint implantation. LV cross-sectional epicardial echocardiography at the papillary muscle level was performed along with acquisition of hemodynamic data. LV normalized thickening, fractional thickening, end-diastolic thickness, and end-diastolic curvatures were calculated for 10 LV segments. Myosplint implantation did not affect LV hemodynamics, but decreased average end-diastolic curvature (P <.0001) and increased its segmental heterogeneity (P <.0001). There was no change in average fractional thickening, whereas normalized thickening increased (P =.05). In contrast, segmental heterogeneity of both normalized and fractional thickening increased (P =.02 and P =.01, respectively). Structural modeling confirmed that Myosplint implantation increases regional stress heterogeneity and curvature heterogeneity. LV cross-sectional shape markedly affects regional LV performance.

Background: Myocor developed a unique system, the Coapsys annuloplasty system, to treat functional mitral regurgitation (MR) without cardiopulmonary bypass (CPB). This study was conducted to test the feasibility of the Coapsys implantation procedure in a canine functional MR model., Methods: Functional MR with heart failure was induced in 9 dogs by rapid ventricular pacing (230 beats/min for 30 +/- 4 days). The Coapsys device, which consists of anterior and posterior epicardial pads connected by a subvalvular chord, was then surgically implanted. Under epicardial echocardiographic guidance, we placed the Coapsys device across the left ventricular chamber using the delivery instrument and needle assembly. We sized the Coapsys device by drawing the posterior leaflet and annulus toward the anterior leaflet with the sizing instrument. Final device size was selected when MR was minimized or eliminated as assessed by 2-dimensional color Doppler echocardiography., Results: In all cases, we successfully implanted the Coapsys device without CPB or atriotomy. MR was reduced an average of 2 grades. No adverse events, such as hemodynamic compromise or structural valve damage, were noted., Conclusion: Coapsys device implantation was feasible and safe on a beating canine heart. All accessory tools used for device implantation were found useful.

Quantification of regional function can be performed using Doppler tissue echocardiography to evaluate myocardial velocity, tissue displacement, strain, and strain rate. Although these techniques have been validated in animal experiments and early clinical trials, there are only limited measurements in healthy populations to use as reference data. In 100 healthy volunteers, left ventricular myocardial velocity, displacement, strain, and strain rate were measured using Doppler tissue echocardiography. Measurements were obtained from basal, mid, and apical segments of walls visualized from left ventricular apical 4- and 2-chamber views. Analysis of covariance was used to examine the effects of age and wall segment position. All parameters showed a strong dependence on wall segment position. Although myocardial velocities and strain rate showed significant dependence on age, displacement and peak systolic strain measures were less affected. Like pulsed Doppler mitral inflow velocity, tissue velocity and strain rate show age-related changes.

Objective: We sought to compare single-beat estimates of contractility indices., Methods: Echocardiography was performed for 6 control patients, 8 patients with dilated cardiomyopathy, and 9 patients with mitral regurgitation (MR). Left ventricular volume waveform, outflow tract velocities, and mitral annulus velocities were recorded with carotid tonometry. Numeric simulations were used to generate the same data while varying contractility, compliance, and MR. Estimates of elastance (normalized systolic and bilinearly approximated), preload-recruitable stroke work, and preload-adjusted maximal power were calculated., Results: Normalized systolic and bilinearly approximated elastance were decreased in patients with dilated cardiomyopathy (P <.005 for both) and MR (P =.0002 and.02, respectively). Preload-recruitable stroke work and preload-adjusted maximal power were decreased in patients with dilated cardiomyopathy only (P <.005 for both). Simulations confirmed that these differences are a result of dissimilar behavior of estimates if MR or compliance change., Conclusions: Single-beat indices are decreased in dilated cardiomyopathy, but in MR show dissimilar behavior.

Although the beneficial effects of ventricular rate (VR) slowing during atrial fibrillation (AF) are axiomatic, the precise relationship between VR and hemodynamics has not been determined. We hypothesized that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) by varying the nerve stimulation intensity could achieve precise graded slowing and permit evaluation of an optimal VR during AF. The aims of the present study were the following: 1) to develop a method for computerized vagally controlled VR slowing during AF, 2) to determine the hemodynamic changes at each level of VR slowing, and 3) to establish the optimal anterograde VR during AF. AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 14 dogs. Four target average VR levels, corresponding to 75%, 100%, 125%, and 150% of the sinus cycle length (SCL), were achieved by computer feedback algorithm. VR slowing resulted in improved hemodynamics and polynomial fit analysis found an optimum for the cardiac output at VR slowing of 87% SCL. We conclude that this novel method can be used to maintain slow anterograde conduction with best hemodynamics during AF.