Role of Quantitation of Saline Bubble Studies in Patients with Liver Cirrhosis.

OBJECTIVE: Microbubble contrast echocardiography with a late positive signal enables the detection of intrapulmonary vascular dilation, including hepatopulmonary syndrome, in patients with end-stage liver disease. We assessed the relationship between the severity of bubble study and clinical outcome. METHODS: We retrospectively analyzed 163 consecutive patients with liver cirrhosis who underwent an echocardiogram with bubble study from 2018 to 2021. Patients who were diagnosed with a late positive signal were divided into three groups: grade 1 (1-9 bubbles), grade 2 (10-30 bubbles) and grade 3 (>30 bubbles). RESULTS: Fifty-six percent of the patients had a late positive bubble study (grade 1: 31%, grade 2: 23%, grade 3: 46%). Patients with grade 3 had a significantly higher international normalized ratio, model for end-stage liver disease score and Child-Pugh score and a lower peripheral oxygen saturation compared with patients with a negative study. In patients undergoing liver transplant (LT), survival rates were similar among the groups (3-mo: >87%, 1-y: >87%, 2-y: >83%). However, survival rate was lower in grade 3 patients without LT (3-mo: 81%, 1-y: 64%, 2-y: 39%). CONCLUSION: Patients with grade 3 had much worse mortality without LT compared with other groups. However, after LT, all grades had equal survival. Therefore, patients with grade 3 may be considered as higher priority for LT.

Optimal Quantification of Functional Mitral Regurgitation: Comparison of Volumetric and Proximal Isovelocity Surface Area Methods to Predict Outcome.

Background Effective orifice area (EOA) ≥0.2 cm2 or regurgitant volume (Rvol) ≥30 mL predicts prognostic significance in functional mitral regurgitation (FMR). Both volumetric and proximal isovelocity surface area (PISA) methods enable calculation of these metrics. To determine their clinical value, we compared EOA and Rvol derived by volumetric and PISA quantitation upon outcome of patients with FMR. Methods and Results We examined the outcome of patients with left ventricular ejection fraction <35% and moderate to severe FMR. All had a complete echocardiogram including EOA and Rvol by both standard PISA and volumetric quantitation using total stroke volume calculated by left ventricular end-diastolic volume×left ventricular ejection fraction and forward flow by Doppler method: EOA=Rvol/mitral regurgitation velocity time integral. Primary outcome was all-cause mortality or heart transplantation. We examined 177 patients: mean left ventricular ejection fraction 25.2% and 34.5% with ischemic cardiomyopathy. Echo measurements were greater by PISA than volumetric quantitation: EOA (0.18 versus 0.11 cm2), Rvol (24.7 versus 16.9 mL), and regurgitant fraction (61 versus 37 %) respectively (all P value <0.001). During 3.6±2.3 years' follow-up, patients with EOA ≥0.2 cm2 or Rvol ≥30 mL had a worse outcome than those with EOA <0.2 cm2 or Rvol <30 mL only by volumetric (log rank P=0.003 and 0.004) but not PISA quantitation (log rank P=0.984 and 0.544), respectively. Conclusions Volumetric and PISA methods yield different measurements of EOA and Rvol in FMR; volumetric values exhibit greater prognostic significance. The echo method of quantifying FMR may affect the management of this disorder.

Clinical and Echocardiographic Predictors of Reduced Survival in Patient with Functional Mitral Regurgitation.

Functional mitral regurgitation (FMR) is associated with a poor outcome in patients with reduced left ventricular ejection fraction (LVEF). Two recent studies of percutaneous mitral valvular repair therapy reported disparate results, likely due in part to variable risk among FMR patients. The aim of this study is to define echocardiographic factors of prognostic significance in FMR patients, and particularly to compare ischemic and nonischemic FMR. We followed three hundred sixteen consecutive patients (age 60 ± 14 years, men 70%) with FMR and LVEF ≤ 35% between January 2010 and December 2015 (mean follow-up 3.7 years). Patients were categorized into ischemic (39.6%) and nonischemic (60.4%). MR was graded according to the American Society of Echocardiography guidelines. Although echo findings were similar between ischemic and nonischemic patient, the incidence of death, heart transplantation (HT), or LVAD implantation was higher in ischemic than in nonischemic patients (Log rank p = 0.001). In age and gender adjusted multivariate (11 variables) Cox regression analysis, left atrium volume index (LAVI) was associated with death, HT, or LVAD with hazard ratio of 2.1 for patients with FMR (p = 0.003). LAVI greater than 48.7 mL/m2 predicts adverse outcome in both nonischemic and ischemic FMR (AUC 0.62, p < 0.001). Combined ischemic FMR with LAVI ≥ 48.7 mL/m2 had the highest incident rate of all groups. In conclusion, despite similar LV function and MR severity, ischemic FMR patients had higher mortality than nonischemic patients. Of all echocardiographic parameters, an LAVI ≥ 48.7 mL/m2 predicted adverse clinical outcome.

Development of a Translatable Ultrasound Molecular Imaging Agent for Inflammation.

This study details the development, characterization and non-clinical efficacy of an ultrasound molecular imaging agent intended for molecular imaging of P-selectin in humans. A targeting ligand based on a recently discovered human selectin ligand was manufactured as fusion protein, and activity for human and mouse P- and E-selectin was evaluated by functional immunoassay. The targeting ligand was covalently conjugated to a lipophilic anchor inserted into a phospholipid microbubble shell. Three lots of the targeted microbubble drug product, TS-07-009, were produced, and assays for size distribution, zeta potential and morphology were established. The suitability of TS-07-009 as a molecular imaging agent was evaluated in vitro in a flow-based adhesion assay and in vivo using a canine model of transient myocardial ischemia. Selectivity for P-selectin over E-selectin was observed in both the human and murine systems. Contrast agent adhesion increased with P-selectin concentration in a dynamic adhesion assay. Significant contrast enhancement was observed on ultrasound imaging with TS-07-009 in post-ischemic canine myocardium at 30 or 90 min of re-perfusion. Negligible enhancement was observed in resting (no prior ischemia) hearts or with a control microbubble 90 min after ischemia. The microbubble contrast agent described here exhibits physiochemical properties and in vivo behavior suitable for development as a clinical imaging agent.

Systematic Assessment of the Impact of Ultrasound-Enhancing Agents upon Measurements of Cardiac Size and Function by Echocardiography.

BACKGROUND: Echocardiography with an ultrasound-enhancing contrast agent (CON) is a powerful tool for identifying the endocardial border. However, the precise relationship of measurements obtained from CON to the reference values of two-dimensional unenhanced echocardiography (BASL) remains undefined, especially regarding wall thickness. The aim of this study was to systematically determine the differences between unenhanced and enhanced images for a broad range of left ventricular (LV) measurements and to define reference values for the relationship between the two methods. METHODS: We examined the echocardiograms of 624 consecutive patients in whom CON was performed for clinical indications. We excluded 192 patients in whom studies were technically difficult for measurement by either or both methods. Echocardiograms were from standard parasternal and apical views according to American Society of Echocardiography guidelines. Recordings were measured for wall thickness and chamber dimension in 343 patients and for LV volumes and ejection fraction in 212 patients. RESULTS: LV wall thickness measurements were systematically reduced with a bias of 0.2 cm with limits of agreement (LOA) from -0.5 to 0.16 cm in interventricular septal thickness, and from -0.46 to 0.13 cm in posterior wall thickness in CON. LV dimensions and volumes systematically increased with a bias of 0.2 cm (LOA, -0.19 to 0.58 cm) and 14 to 16 mL (LOA, -11.9 to 42.8 mL), respectively. LV ejection fraction systematically decreased with a bias of 3.4% (LOA, -13.5% to 6.8%) in CON compared to BASL. All differences showed normal distribution in the Kolmogorov-Smirnov test. CONCLUSION: CON yields significantly different measurements of cardiac size and function compared to unenhanced imaging. These data define the systematic differences in measurements between CON and BASL images; the range of differences is narrow. These differences may influence management when the measurement value is a borderline.

Predictive Factors for Progression of Mitral Regurgitation in Asymptomatic Patients With Mitral Valve Prolapse.

Risk factors predicting progression from low grade to severe mitral regurgitation (MR), which is a guideline criterion for surgical intervention, remain unknown. We hypothesized that abnormalities of cardiac structure and function may predict progression in MR severity. We followed 82 asymptomatic mitral valve prolapse (MVP) patients (65 ± 12 years, 51% men) with mild or moderate MR (36 mild, 46 moderate, mean LVEF: 62%), without significant co-morbidities. We examined clinical findings and 13 echo measurements. The primary end point was progression to severe MR. In a mean follow-up period of 4.5 ± 2.7 years, mortality and heart failure development were similar for mild and moderate MR. No mild MR patient progressed to severe, but 23 moderate MR patients (50.0%) progressed to severe with 9 patients (39.1%) who underwent surgery. No clinical variables were predictive for progression. Only mean mitral annulus diameter (apical 4 and 2 chamber) was predictive for progression to severe MR (hazards ratio 1.14, 95% confidence interval 1.03 to 1.26, p = 0.01). A cut-off annulus diameter of 39.6 mm had a good accuracy (area under the curve 0.78, sensitivity 100%, and specificity 63.8%) for progression to severe. In conclusion, over a 4.5-year period, 50% of asymptomatic MVP patients with moderate MR, but none with mild, progressed to severe MR. Only mitral annular dimension predicted progression of moderate to severe MR, and values >39.6 mm predicted progression accurately. Mitral annulus diameter may be of value in identifying asymptomatic MVP patients at risk of developing severe MR.

The Prevalence of Lipoprotein(a) Measurement and Degree of Elevation Among 2710 Patients With Calcific Aortic Valve Stenosis in an Academic Echocardiography Laboratory Setting.

Lipoprotein(a; Lp[a]) and its associated oxidized phospholipids are causal, genetic risk factors for calcific aortic valve stenosis (CAVS). We determined the prevalence of Lp(a) measurement among 2710 patients with CAVS and 1369 control patients (∼50% of study group) without CAVS with an echocardiogram between January 2010 and February 2016 in an academic echocardiography laboratory. Lipoprotein(a) measurements were performed at a referral laboratory using an isoform-independent assay. The prevalence of any Lp(a) measurement was 4.6% (124 of the 2710) in patients with CAVS and 3.1% (42 of the 1369) in the control group ( P = .021). In patients with CAVS, mean (standard deviation) Lp(a) levels were 38 (54) mg/dL and median (interquartile range) Lp(a) levels were 14 (6-48) mg/dL. Of the 124 patients with CAVS having Lp(a) measurements, 83 (66.9%) had Lp(a) <30 mg/dL and 41 (33.1%) had Lp(a) ≥30 mg/dL. This study reflects low physician testing of Lp(a) levels in CAVS. Given the role of Lp(a) as a causal risk factor for CAVS, and the ongoing development of therapies to normalize Lp(a) levels, our results suggest that Lp(a) measurements in CAVS should be more widely obtained in clinical practice.

Electrocardiogram and echocardiogram findings in runners completing a half marathon.

OBJECTIVE: The purpose of this study was to prospectively evaluate electrocardiograms (ECGs) before and after running a half marathon to characterize the changes that occur after exertion. Echocardiograms were also done postrace on selected runners. METHODS: Volunteer runners older than 18 years completed a questionnaire detailing demographic and medical history. Prerace ECGs were performed at a prerace symposium and postrace ECGs were performed within 15 minutes of the participants' completion of the race. Echocardiograms were performed on a random sampling of runners who were judged to have abnormal or changed postrace ECGs. RESULTS: Eighty-seven runners were enrolled and completed the study. There were 46 males (53%) and 41 females (47%). Fifty-four (62%) runners had changes noted in their ECGs. The most common changes noted were atrial enlargement (37 runners). Other abnormalities seen on the ECGs included new conduction abnormalities, new Q waves, nonspecific ST/T-wave changes, and resolution of previous abnormalities that were seen on initial ECG. There was no statistically significant difference between runners with ECG changes and runners without ECG changes when comparing sex, age, previous marathon experience, exercise, history of exercise-induced chest pain, medical history, and family history of heart disease. Twenty runners with changed or abnormal postrace ECGs had postrace echocardiograms, and 8 were abnormal. Of the abnormal echocardiograms, 2 runners had normal but changed postrace ECGs and 4 runners had abnormalities that were inconsistent with what was seen on ECG. CONCLUSION: Our study suggests that ECG abnormalities and changes can occur in distance runners, but their significance is unclear.

Triggered replenishment imaging reduces variability of quantitative myocardial contrast echocardiography and allows assessment of myocardial blood flow reserve.

Assessment of replenishment kinetics (RK) following ultrasound-induced destruction of contrast microbubbles allows quantification of myocardial blood flow reserve (MBFR) applying the model f (t) = A (1 - e(-betat)), with parameter beta describing mean flow velocity and parameter A representing blood volume. However, few data on the variability and reproducibility of RK in a clinical setting are available. Therefore, we examined 30 patients in a rest-adenosine protocol in one center. Off-line quantification of real-time perfusion imaging (RTPI) and triggered replenishment imaging (TRI) was performed at two sites and compared with coronary angiography and flow reserve measurements. Parameter A was found to be robust in all investigated segments (coefficient of variation (CV) < 7.2%+/- 5.1). Variability was lowest for parameter beta using TRI in apical segments (CV 6.5%+/- 5.2, P < 0.01). Highest CV was found with RTPI in lateral segments (CV : 39.8%+/- 40.6). Concerning day-to-day reproducibility both methods revealed similar results within range of heterogeneity of myocardial blood flow. Both sites obtained significantly lower MBFR in patients with flow-limiting CAD, compared to subjects without (P < 0.01). Correlation of both sites showed close relationship (y = 0.88x + 0.45, r = 0.83, P < 0.0001), without systematic bias. TRI significantly reduces variability of RK in quantitative MCE. Assessment of MBFR allows investigator-independent evaluation of CAD.

Comparison of open- and closed-chest canine model for quantification of coronary stenosis severity by myocardial contrast echocardiography.

RATIONALE AND OBJECTIVES: The objective of the present study was to compare the data regarding the ability of real-time myocardial contrast echocardiography (MCE) to assess altered myocardial blood flow produced by graded coronary stenoses between open- and closed-chest canine models. MATERIALS AND METHODS: Three grades of left anterior descending coronary artery stenosis and occlusion were created in 6 open- and 6 closed-chest canine models. MCE used FS-069 infusion and real-time imaging. Myocardial signal intensity versus time plots were fitted to a 1-exponential function to obtain the peak signal intensity (A) and rate of signal intensity rise (b) for quantification of myocardial blood flow. RESULTS: The value of b obtained from closed-chest canine models (without stenosis = 0.995 +/- 0.087, mild stenosis = 0.968 +/- 0.076, moderate stenosis = 0.569 +/- 0.077, severe stenosis = 0.288 +/- 0.032, occlusion = 0.085 +/- 0.031) was not significantly different from that obtained from open-chest canine models (without stenosis = 1.028 +/- 0.107, mild stenosis = 0.998 +/- 0.098, moderate stenosis = 0.601 +/- 0.055, severe stenosis = 0.321 +/- 0.029, occlusion = 0.079 +/- 0.028) at any grade of stenosis (P = 0.09, 0.08, 0.44, 0.11, 0.74, respectively). CONCLUSIONS: In myocardial regions where attenuation of the ultrasound beam and artifacts produced by the chest wall are minimal, the data from transthoracic MCE in the closed-chest model may show values similar to those from MCE in the open-chest model.

Contrast echocardiography can assess risk area and infarct size during coronary occlusion and reperfusion: experimental validation.

OBJECTIVES: We sought to validate the ability of real-time myocardial contrast echocardiography (MCE) measures of opacification defect and contrast refilling parameters to estimate risk area (RA) and infarct area (IA) during coronary occlusion and reperfusion. BACKGROUND: No data exist establishing the accuracy of MCE in determining RA and IA size. We hypothesized that in the setting of coronary occlusion, MCE should identify RA as a perfusion defect early after bubble destruction, collateral flow to viable myocardium as opacification late during refilling and IA as absent opacification. METHODS: Three hours of coronary occlusion and reperfusion were each produced in 11 dogs in which real-time MCE was performed during intravenous infusion of Sonovue (Bracco). Real-time contrast echocardiography was performed at baseline, during occlusion and reperfusion. Early (BEGIN) and end (END) images from a FLASH refilling sequence were acquired, as well as late refilling images (LATE) 1 min after FLASH. Real-time contrast echocardiography defect size and quantitative refilling parameters were compared with RA and IA determined by tissue staining. RESULTS: During occlusion, defect size varied with refilling time; defects from BEGIN images correlated best to RA and those from LATE images to IA. Refilling parameters, but not LATE peak intensity, did not predict the IA size during occlusion. During reperfusion, defects from BEGIN images were well correlated to RA and END images to IA, whereas peak plateau intensity and refilling slope parameters predicted IA size. CONCLUSIONS: Real-time contrast echocardiography defect size varies throughout microbubble refilling. Appropriately selected defect sizes and refilling parameters provide estimates of RA and IA during coronary occlusion and reperfusion.