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Author(s): Di Tullio, Marco R; Qian, Min; Thompson, John LP; Labovitz, Arthur J; Mann, Douglas L; Sacco, Ralph L; Pullicino, Patrick M; Freudenberger, Ronald S; Teerlink, John R; Graham, Susan; Lip, Gregory YH; Levin, Bruce; Mohr, Jay P; Buchsbaum, Richard; Estol, Conrado J; Lok, Dirk J; Ponikowski, Piotr; Anker, Stefan D; Homma, Shunichi; WARCEF Investigators | Abstract: AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range g60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

A high pulse pressure (PP) is associated with adverse cardiovascular (CV) outcomes; however, this relationship may be reversed in patients with heart failure with reduced ejection fraction (HFREF).Patients from the WARCEF trial with left ventricular ejection fraction ≤35% were included. PP was divided into tertiles: ≤42, 42-54 and54 mm Hg. Age and ejection fraction adjusted Kaplan-Meier curves were generated to evaluate the relationship between PP and outcomes [mortality, CV mortality, stroke and HF hospitalizations (HFH)]. Cox proportional hazards models were created incorporating PP as a continuous variable. The interaction of PP with New York Heart Association (NYHA) functional class was examined. Linear and restricted cubic splines were used to study nonlinear association between PP and outcomes.We included 2,299 patients with a mean(±SD) follow-up of 3.5 ± 1.8 years. The lowest tertile of PP (≤42 mm Hg) was associated with significantly higher CV mortality and HFH. Cox proportional hazards models showed a reduction in CV death and HFH with higher PP, with adjusted hazard ratios (HR) of 0.91 (P = 0.02) and 0.93 (P = 0.04) per 10 mm Hg increase in PP. This relationship was more pronounced in subjects with NYHA functional class III-IV. Spline analysis showed that the association between PP and CV mortality and HFH was only seen at PP values lower than 40 mm Hg.In patients with advanced HFREF, a low PP (40 mm Hg) portends a worse prognosis, whereas a high PP (50 mm Hg) predicts a relatively favourable prognosis.

AIMS The aim of this study was to determine whether the CHA2 DS2 -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm. METHODS AND RESULTS CHA2 DS2 -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2 DS2 -VASc score was associated with increased hazard of death or ischaemic stroke events [hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13-1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11-1.29, P < 0.001]. Similar increased hazards for higher CHA2 DS2 -VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2 DS2 -VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage. CONCLUSIONS The CHA2 DS2 -VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy.

BACKGROUND Real time three-dimensional (3D) echocardiography allows the assessment of left ventricular (LV) mechanical dyssynchrony and may be useful in predicting response to cardiac resynchronization therapy. However, reproducibility of 3D dyssynchrony in past reports varied widely. We evaluated intra- and interobserver reproducibility of parameters of LV mechanical dyssynchrony by 3D echocardiography and explored the impact of image quality as a possible source of variability. METHODS LV volumes and ejection fraction (LV EF) were measured by 3D echocardiography in 90 subjects. LV mechanical dyssynchrony was calculated as the standard deviation of the time-to-minimum segmental volume (Tmsv) over 16 (SDI16) and 12 (SDI12) segments and as the maximum time-difference in Tmsv over 16 (Dif16), 12 (Dif12), and 2 (DifS-L) segments. Opposing wall delay in peak myocardial systolic velocity (S-L delay) by tissue Doppler imaging (TDI) was also evaluated. RESULTS Feasibility of 3D measurements was 88.9%. Intra- and interobserver intraclass correlation coefficients were excellent for LV volumes, LV EF, and S-L delay (all ≥ 0.90), very good for SDI16 (0.83 and 0.85), moderate to good for SDI12, Dif16, Dif12, and DifS-L (0.51-0.81). No systematic bias was present between readings for 3D dyssynchrony, but limits of agreement resulted fairly large for most parameters with the exception of SDI16, which showed reproducibility slightly lower than TDI. Suboptimal image quality was a significant source of variability in 3D-dyssynchrony assessment. CONCLUSIONS The 3D assessment of LV volumes and dyssynchrony was feasible in our community-based cohort. SDI16 was the most reproducible among 3D-dyssynchrony parameters and the least affected by image quality.

To assess the independent and combined effects of diabetes and hypertension on left ventricular (LV) diastolic function in a community-based cohort at high cardiovascular risk.Two-dimensional echocardiography was performed in 708 subjects from the Cardiac Abnormalities and Brain Lesions (CABL) study. Peak diastolic early (E) and late (A) transmitral flow, and tissue Doppler-derived early mitral annulus velocity (E') were recorded, and E/A and E/E' ratios were calculated. The population was divided into four groups: those without hypertension or diabetes (HT-/DM-), those with only hypertension (HT), only diabetes (DM), and with hypertension plus diabetes (HT + DM). In multivariate analysis, hypertension and diabetes were independent predictors of worse diastolic function. The coexistence of hypertension and diabetes was associated with greater impairment of diastolic function (higher E/E' ratio than HT-/DM-, HT, or DM, all P0.05), independent of covariates. The negative, synergistic effect of hypertension and diabetes on LV diastolic function was present both in lean participants and in overweight/obese ones. An E/E' ratio15, suggestive of increased LV filling pressure, was found in 2.2% of HT-/DM-, 8.9% of HT, 5.9% of DM, and 14.7% of HT + DM (P0.01).Hypertension and diabetes are independently associated with impaired LV diastolic function, independent of the effect of overweight/obesity and other covariates. Their coexistence results in a negative synergistic effect on LV diastolic mechanics and is associated with higher LV filling pressures than either condition alone.

BACKGROUND: Noninvasive and accurate assessment of mitral valve anatomy has become integral in the presurgical evaluation of patients with mitral valve prolapse (MVP). Recently developed real time three-dimensional (RT3D) ultrasound allows online acquisition, rendering, and can provide accurate information on cardiac structures. We sought to evaluate the feasibility of RT3D for the assessment of MVP segments when compared with transesophageal echocardiography (TEE) and intraoperative findings. METHODS: We examined 42 patients with MVP using RT3D, two-dimensional (2D) transthoracic echocardiography (TTE) and TEE. For RT3D analysis, cropping planes were used to slice the 3D volume on line to visualize the prolapsed segments of the mitral valve leaflets. The mitral valve was divided into six segments based on the American Society of Echocardiography's recommendations. Two experienced cardiologists evaluated echocardiographic images. RESULTS: Adequate RT3D images of the mitral valve were acquired in 40 out of 42 patients. The sensitivity and specificity of RT3D for defining prolapsed segments when compared with TEE were 95% and 99%, respectively (anterior leaflet: 96% and 99%, posterior leaflets: 93% and 100%, respectively). The sensitivity and specificity of TTE were 93% and 97%, respectively (anterior leaflet: 96% and 98%, posterior leaflets: 90% and 97%, respectively). Interobserver agreement for RT3D (Kappa 0.95, 95% confidence interval [CI] 0.91-1.00) was significantly greater than for TTE (Kappa 0.85, 95% CI 0.78-0.93) (P < 0.05). The elapsed time for completion of RT3D (14.4 +/- 2.8 min) was shorter than for TEE (26.4 +/- 4.7 min, P < 0.0001) and TTE (19.0 +/- 3.1 min, P< 0.0001). CONCLUSIONS: RT3D is fast, accurate, and highly reproducible for assessing MVP.

Objective Accelerated atherosclerosis is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Altered coronary microvascular function may act as a marker of changes that predispose to the development of significant coronary vascular disease. The purpose of this study was to compare coronary flow reserve (CFR) in a group of premenopausal women with SLE and a group of age-, sex-, and race-matched healthy control subjects. Methods Coronary flow velocity in 18 premenopausal women with SLE (mean ± SD age 29.4 ± 5.9 years) and 19 matched healthy controls (mean ± SD age 28.2 ± 4.3 years) was assessed by transthoracic Doppler echocardiography after an overnight fast. The CFR was calculated as the ratio of hyperemic to baseline coronary blood flow velocity in the left anterior descending coronary artery. Hyperemia was induced by intravenous administration of adenosine triphosphate. Results The mean ± SD duration of SLE was 8.2 ± 7.2 years (range 0.25–25 years), and the mean ± SD score on the Systemic Lupus Erythematosus Disease Activity Index was 11.0 ± 5.3 (range 4.0–21.0). Adequate recordings of flow velocity in the left anterior descending artery under both conditions were obtained using an ultrasound procedure in all study subjects. CFR was significantly lower in SLE patients as compared with control subjects (mean ± SD 3.4 ± 0.8 versus 4.5 ± 0.5; P < 0.0001). Conclusion These findings provide evidence that coronary vasomotor function is impaired in patients with SLE and support the notion that many of these young patients have subclinical coronary artery disease.

Objective. This study evaluated variables relevant to creating myocardial lesions using high-intensity focused ultrasound (HIFU). Without an effective means of tracking heart motion, lesion formation in the moving ventricle can be accomplished by intermittent delivery of HIFU energy synchronized by electrocardiographic triggering. In anticipation of future clinical applications, multiple lesions were created by brief HIFU pulses in calf myocardial tissue ex vivo. Methods. Experiments used f-number 1.1 spherical cap HIFU transducers operating near 5 MHz with in situ spatial average intensities of 13 and 7.4 kW/cm 2 at corresponding depths of 10 and 25 mm in the tissue. The distance from the HIFU transducer to the tissue surface was measured with a 7.5-MHz A-mode transducer coaxial and confocal with the HIFU transducer. After exposures, fresh, unstained tissue was dissected to measure visible lesion length and width. Lesion dimensions were plotted as functions of pulse parameters, cardiac structure, tissue temperature, and focal depth. Results. Lesion size in ex vivo tissue depended strongly on the total exposure time but did not depend strongly on pulse duration. Lesion width depended strongly on the pulse-to-pulse interval, and lesion width and length depended strongly on the initial tissue temperature. Conclusions. High-intensity focused ultrasound creates well-demarcated lesions in ex vivo cardiac muscle without damaging intervening or distal tissue. These initial studies suggest that HIFU offers an effective, noninvasive method for ablating myocardial tissues to treat several important cardiac diseases.

OBJECTIVES We sought to evaluate the effect of acute hyperglycemia on coronary microcirculation by noninvasive measurement of coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography (TTDE). RESEARCH DESIGN AND METHODS Measurements of CFVR using TTDE and levels of plasma glucose and serum insulin and lipids were determined before and 1 hour after loading with oral glucose (75-g glucose) in 10 young healthy males (mean age, 30 +/- 2 years) or an artificial sweetener in five of the 10 subjects without coronary risk factors. RESULTS In all subjects, the levels of plasma glucose and serum insulin significantly increased after glucose loading compared with baseline (5.1 +/- 0.6 vs 7.6 +/- 1.2 mM/l, 6 +/- 3 vs 49 +/- 13 microU/ml, respectively; P < 0.0001). CFVR was significantly decreased 1 hour after acute oral glucose loading (4.4 +/- 0.7-3.8 +/- 0.7, respectively; P < 0.01). There was no significant change in CFVR after loading with an artificial sweetener (4.4 +/- 0.6-4.4 +/- 0.5 cm/sec). CONCLUSIONS TTDE revealed that acute hyperglycemia induced by oral glucose loading suppresses CFVR in healthy young male subjects. This result suggests that acute hyperglycemia may have adverse effects on coronary microcirculation.

Introduction: The Endovascular Valve Edge-to-Edge REpair STudies (EVEREST) are investigating a percutaneous technique for edge-to-edge mitral valve repair with a repositionable clip. The effects on the mitral valve gradient (MVG) and mitral valve area (MVA) are not known. Methods: Twenty seven patients with moderate to severe or severe mitral regurgitation (MR) were enrolled. Echocardiography was performed preprocedure, at discharge, and at 1, 6, and 12 months. Mean MVG was measured by Doppler and MVA by planimetry and pressure half-time, and evaluated in a central core laboratory. Pre- and postclip deployment, simultaneous left atrial/pulmonary capillary wedge and left ventricular pressures were obtained in eight patients. Results: Three patients did not receive a clip, six patients had their clip(s) explanted by 6 months (none for mitral stenosis), and four were repaired with two clips. Results are notable for a slight increase in mean MVG by Doppler postclip deployment (1.79 ± 0.89 to 3.31 ± 2.09 mm Hg, P < 0.01) and an expected decrease in MVA by planimetry (6.49 ± 1.61 to 4.46 ± 2.14 cm2, P < 0.001) and by pressure half time (4.35 ± 0.98 to 3.01 ± 1.42 cm2, P < 0.05). There were no significant changes in hemodynamic parameters postclip deployment by direct pressure measurements. There was no change in MVA by planimetry from discharge to 12 months (3.90 ± 1.90 to 3.79 ± 1.54 cm2, P = 0.78). Conclusions: Echocardiographic and hemodynamic measurements after percutaneous mitral valve repair with the MitraClip show an expected decrease in mitral valve area with no evidence of clinically significant mitral stenosis either immediately after clip deployment or after 12 months of follow-up. © 2006 Wiley-Liss, Inc.

Objectives/Hypothesis: The traditional blind passage of a transesophageal echocardiography probe transorally through the hypopharynx is considered safe. Yet, severe hypopharyngeal complications during transesophageal echocardiography at several institutions led the authors to investigate whether traditional probe passage results in a greater incidence of hypopharyngeal injuries when compared with probe passage under direct visualization. Study Design: Randomized, prospective clinical study. Methods: In 159 consciously sedated adults referred for transesophageal echocardiography, the authors performed transesophageal echocardiography with concomitant transnasal videoendoscopic monitoring of the hypopharynx. Subjects were randomly assigned to receive traditional (blind) or experimental (optical) transesophageal echocardiography. The primary outcome measure was frequency of hypopharyngeal injuries (hypopharyngeal lacerations or hematomas), and the secondary outcome measure was number of hypopharyngeal contacts. Results: No perforation occurred with either technique. However, hypopharyngeal lacerations or hematomas occurred in 19 of 80 (23.8%) patients with the traditional technique (11 superficial lacerations of pyriform sinus, 1 laceration of pharynx, 12 arytenoid hematomas, 2 vocal fold hematomas, and 1 pyriform hematoma) and in 1 of 79 patients (1.3%) with the optical technique (superficial pyriform laceration) (P = .001). All traumatized patients underwent flexible laryngoscopy, but none required additional intervention. Respectively, hypopharyngeal contacts were more frequent with the traditional than with the optical technique at the pyriform sinus (70.0% vs. 10.1% [P = .001]), arytenoid (55.0% vs. 3.8% [P = .001]), and vocal fold (15.0% vs. 3.86% [P = .016]). Conclusion: Optically guided trans-esophageal echocardiography results in significantly fewer hypopharyngeal injuries and fewer contacts than traditional, blind transesophageal echocardiography. The optically guided technique may result in decreased frequency of potentially significant complications and therefore in improved patient safety.

The automated contour tracking (ACT) method has been developed for the automated measurement of area volume using the energy minimization method without tracing a region of interest. The purpose of this study was to compare the ACT method and left ventriculography (LVG) for the measurement of left ventricular (LV) function in the clinical setting. An apical four-chamber view was visualized by two-dimensional echocardiography and recorded for off-line analysis in 14 patients with high-quality images who underwent LVG. The ACT method automatically traces the endocardial border from the recorded images and calculates LV volumes (end-diastole and end-systole) and ejection fraction (EF). Both ACT and LVG were compared by linear regression analysis for the measurement of EF. EF determined by the ACT method agreed well with that by LVG (r = 0.96, y = 0.94x + 4.6, standard error of the estimate = 3.9%). The mean difference between the ACT and LVG was –1.4%± 7.3%.In conclusion, the ACT method is reliable for noninvasive estimation of EF in high-quality images. This suggests that this new technique may be useful in the automated quantification of LV function. (ECHOCARDIOGRAPHY, Volume 20, May 2003)

Twenty-one explanted fixed hearts (14 dogs and 7 pigs) were examined to validate newly developed real-time three-dimensional (RT3D) echocardiography for measurement of left ventricular (LV) mass in vitro and to compare its accuracy and variability with those of conventional echocardiographic measurements. There was an excellent correlation and high degree of agreement for the determination of LV mass between RT3D echocardiography and true mass measurement (r = 0.98; standard error of the estimate [SEE] = 7.3 g; absolute difference [AD] = 2.8 g; y = 1.00 x -4.0, interobserver variability; 5.0%). The conventional echocardiographic methods yielded weaker correlations, larger standard errors, and interobserver variability (area-length method: r = 0.90; SEE = 13.3 g; AD = 13.2 g; 13.3 % / truncated ellipsoid method: r = 0.91; SEE = 14.7 g; AD = 10.5 g; 7. 9% / M-mode: r = 0.91; SEE = 16.2 g; AD = 9.4 g; 15.3%). Determination of LV mass by RT3D echocardiography has a high degree of accuracy and is superior to conventional one- and two-dimensional echocardiographic methods.

The fourth heart sound (S4) has been associated with vigorous atrial contraction. However, the presence of S4 has not been previously correlated with quantitated left atrial filling fraction. In this study, the presence of an auscultatory S4 was compared with the Doppler echocardiographically quantitated left atrial filling fraction in 41 consecutive patients in whom S4 was judged to be present or absent according to the consensus of cardiologists. Left atrial filling fraction in patients with S4 was 49% and was significantly greater than 33% found in patients without S4 (p less than 0.005). Using atrial filling fraction of 35% as a dividing line, S4 had a sensitivity of 84% and a specificity of 75% for determining left atrial filling fraction greater than or equal to 35%. Furthermore, of 25 patients with S4, 21 (84%) had atrial filling fraction greater than or equal to or less than 35%, and of 16 patients without S4, 12 (75%) had atrial filling fraction less than 35%. Thus, the presence or the absence of S4 is quantitatively related to the left atrial filling fraction and appears to predict atrial filling fraction greater than or equal to or less than 35% reasonably well.

To determine the serial changes in T1 and T2 relaxation times of myocardial infarction, and their relationship to observed changes in water content, regional myocardial blood flow, and histopathology, rabbits were studied at 14 time intervals ranging from 30 min to 6 months after coronary artery ligation. All values were compared to a control group. Hearts were subdivided into infarct and normal segments for measurement of blood flow, water content, and relaxation times (20-MHz spectrometer); other hearts were excised intact for histopathologic studies. T1 relaxation time of infarcted myocardium did not change significantly compared to control over the 6-month study period. T2 relaxation time increased (P < 0.0001) at 3 days and returned to baseline by 2 months. Consonant with the increase in T2 of infarct, nuclear magnetic resonance (NMR) images at 3 days demonstrated an increase in signal intensity of infarct compared to surrounding normal myocardium. At 6 months, marked myocardial thinning was observed without changes in signal intensity. Changes in T2 of infarcted myocardium were not related to changes in water content or seventy of ischemia, but correlated best with infarct healing and scar formation as detected on histopathology. In conclusion, the findings of this study indicate that T2 relaxation time of the infarcted myocardium increases markedly at 3 days and remains elevated for 2 months. These changes correlate best with the onset and progression of infarct healing. These data demonstrate the potential of T2-weighted NMR imaging for assessing healing patterns following ischemic myocardial injury. © 1988 Academic Press, Inc.