Sarah Shimoni

Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans.

OBJECTIVES We sought to evaluate the relation of segmental tissue Doppler (TD) velocities to both the regional amount of interstitial fibrosis and the myocyte beta-adrenergic receptor density in humans. BACKGROUND The systolic myocardial velocity (Sm) and early diastolic myocardial velocity (Em) acquired by TD are promising new indexes of left ventricular function. However, their structural and functional correlates in humans are still unknown. METHODS Ten patients with coronary artery disease underwent echocardiographic examination including TD imaging, along with transmural endomyocardial biopsy at the time of coronary bypass surgery (two biopsies per patient for a total of 20 specimens). The specimens were analyzed for percent interstitial fibrosis and beta-adrenergic receptor density. RESULTS Normal segments (n = 8) had a higher beta-adrenoceptor density (2,280 +/- 738 vs. 1,373 +/- 460, p = 0.03) and a lower amount of interstitial fibrosis (13 +/- 3.3% vs. 28 +/- 11.5%, p = 0.002) than dysfunctional segments (n = 12). Myocardial systolic velocity and Em were also significantly higher (9.5 +/- 2.7 vs. 5.9 +/- 1.8 cm/s, p = 0.025 and 11.3 +/- 2.8 vs. 6.4 +/- 2.1 cm/s, p = 0.002, respectively) in normal segments. A significant relationship was present between Em and the beta-adrenergic receptor density (r = 0.78, p < 0.001) and percent interstitial fibrosis (r = -0.7, p = 0.0026), which together accounted for 81% of the variance observed in Em. Likewise, a significant relationship was present between Sm and the beta-adrenergic receptor density (r = 0.68, p < 0.001) and the percent interstitial fibrosis (r = -0.66, p = 0.004) and together accounted for 62% of the variance observed in Sm. CONCLUSIONS Systolic myocardial velocity and Em are strongly dependent on both the number of myocytes and the myocardial beta-adrenergic receptor density.

Real-Time Assessment of Myocardial Perfusion and Wall Motion During Bicycle and Treadmill Exercise Echocardiography: Comparison With Single Photon Emission Computed Tomography

OBJECTIVES We sought to determine the feasibility and accuracy of real-time imaging of myocardial contrast echocardiography (MCE) in detecting myocardial perfusion defects during exercise echocardiography compared with radionuclide tomography. BACKGROUND Ultrasound imaging at a low mechanical index and frame rate (10 to 20 Hz) after intravenous injections of perfluorocarbon containing microbubbles has the potential to evaluate myocardial perfusion and wall motion (WVM) simultaneously and in real time. METHODS One hundred consecutive patients with intermediate-to-high probability of coronary artery disease underwent treadmill (n = 50) or supine bicycle (n = 50) exercise echocardiography. Segmental perfusion with MCE and WM w ere assessed in real time before and at peak exercise using low mechanical index (0.3) and frame rates of 10 to 20 Hz after 0.3 ml bolus injections of intravenous Optison (Mallinckrodt Inc., San Diego, California). All patients had a dual isotope (rest thallium-201, stress sestamibi) study performed during the same exercise session, and 44 patients had subsequent quantitative coronary angiography. RESULTS In the 100 patients, agreement between MCE and single photon emission computed tomography (SPECT) was 76%, while it was 88% between MCE and WM assessment. Compared with quantitative angiography, sensitivity of MCE, SPECT and WM was comparable (75%), with a specificity ranging from 81% to 100%. The combination of MCE and WM had the best balance between sensitivity and specificity (86% and 88%,respectively) with the highest accuracy (86%). CONCLUSIONS The real-time assessment of myocardial perfusion during exercise stress echocardiography can be achieved with imaging at low mechanical index and frame rates. The combination of WM and MCE correlates well with SPECT and is a promising important addition to conventional stress echocardiography.

Identification of Hibernating Myocardium With Quantitative Intravenous Myocardial Contrast Echocardiography Comparison With Dobutamine Echocardiography and Thallium-201 Scintigraphy

Background—There are currently no data on the accuracy of intravenous myocardial contrast echocardiography (MCE) in detecting myocardial hibernation in man and its comparative accuracy to dobutamine echocardiography (DE) or thallium 201 (Tl201) scintigraphy. Methods and Results—Twenty patients with coronary artery disease and ventricular dysfunction underwent MCE 1 to 5 days before bypass surgery and repeat echocardiography at 3 to 4 months. Patients also underwent DE (n=18) and rest-redistribution Tl201 tomography (n=16) before revascularization. MCE was performed using continuous Optison infusion (12 to 16 cc/h) with intermittent pulse inversion harmonics and incremental triggering (1:1 to 1:8). Myocardial contrast intensity (MCI) replenishment curves were constructed to derive quantitative MCE indices of blood velocity and flow. Recovery of function occurred in 38% of dysfunctional segments. MCE parameters of perfusion in hibernating myocardium were similar to segments with normal function and higher than dysfunctional myocardium without recovery of function (P <0.001). The best MCE parameter for predicting functional recovery was Peak MCI×&bgr;, an index of myocardial blood flow (area under the curve, 0.83). MCE parameters were higher in segments with contractile reserve and Tl201 uptake ≥60% (P <0.05) and identified viable segments without contractile reserve by DE. The sensitivity of Peak MCI×&bgr; >1.5 dB/s for recovery of function was 90% and was similar to Tl201 scintigraphy (92%) and any contractile reserve (80%); specificity was higher than for Tl201 and DE (63%, 45%, and 54%, respectively;P <0.05). Conclusions—MCE with intravenous contrast identifies myocardial hibernation in humans. Prediction of viable myocardium with MCE is best using quantification of myocardial blood flow and provides improved accuracy compared with DE and Tl201 scintigraphy.

Diagnostic accuracy and cost-effectiveness of contrast echocardiography on evaluation of cardiac function in technically very difficult patients in the intensive care unit

Echocardiographic assessment of cardiac function can be quite difficult in the intensive care unit and may require transesophageal echocardiography (TEE). We therefore compared harmonic imaging alone or in combination with contrast to TEE in 32 consecutive patients in the intensive care units who were considered technically very difficult (> or =50% of the 16 segments not visualized from any view). Excellent or adequate endocardial visualization was achieved in 13% of segments with fundamental imaging, 34% with harmonic imaging, and 87% with contrast (p < 0.0001); the latter success rate was similar to TEE (87% vs 90%; p = NS). When TEE was used as the standard, agreement in exact interpretation of wall motion increased from 48% for fundamental imaging to 58% with harmonic imaging, and reached 70% with contrast (p <0.0001). Contrast had the best sensitivity (89%) for detecting wall motion abnormalities. Estimation of ejection fraction was possible in 31% with fundamental imaging, 50% with harmonic imaging, and in 97% with contrast. Ejection fraction quantitated by contrast enhancement correlated best with TEE (r = 0.91). Cost-effectiveness analysis revealed that contrast echo was cost-effective compared with TEE in determining regional and global ventricular function, with a cost saving of 3% and 17%, respectively. Thus, contrast echocardiography provides an accurate, safe, and cost-effective alternative to TEE for evaluating ventricular function in technically very difficult studies.

Microvascular Structural Correlates of Myocardial Contrast Echocardiography in Patients With Coronary Artery Disease and Left Ventricular Dysfunction Implications for the Assessment of Myocardial Hibernation

Background—Myocardial contrast echocardiography (MCE) has been used to evaluate myocardial viability. There are no data, however, on the pathological determinants of myocardial perfusion by MCE in humans and the implications of such determinants. Methods and Results—MCE was performed in 20 patients with coronary artery disease and ventricular dysfunction within 24 hours before myocardial biopsy at surgery using a continuous Optison infusion (12 to 16 cc/h), with intermittent pulse inversion harmonics and incremental triggering. Peak myocardial contrast intensity (MCI) and the rate of increase in MCI (&bgr;) were quantitated. Thirty-six transmural myocardial biopsies (2 per patient) were obtained by transesophageal echocardiography. Total microvascular (<100 &mgr;m) density, capillary density and area, arteriolar and venular density, and percent collagen content were quantitated with immunohistochemistry. Peak MCI correlated with microvascular density (r =0.59, P <0.001) and capillary area (r =0.64, P <0.001) and inversely correlated with percent collagen content (r =−0.45, P =<0.01). The best relation was observed when the ratio of peak MCI in the 2 biopsied segments in each patient was compared with the ratio of microvascular density and capillary area (r =0.84 and 0.87, respectively;P <0.001). A significant overlap in microvascular density was seen between segments with and without recovery of function. The new MCE indices of blood velocity (&bgr;) and flow (peak MCI×&bgr;) better identified recovery of function compared with microvascular density and the sole use of peak MCI. Conclusions—Microvascular integrity is a significant determinant of maximal MCI in humans. MCE indices of blood velocity and flow are important parameters that predict recovery of function after revascularization.

Active interstitial remodeling: an important process in the hibernating human myocardium

OBJECTIVES The purpose of this study is to investigate the morphologic characteristics of the cardiac interstitium in the hibernating human myocardium and evaluate whether active remodeling is present and is an important determinant of functional recovery. BACKGROUND Myocardial hibernation is associated with structural myocardial changes, which involve both the cardiomyocytes and the cardiac interstitium. METHODS We evaluated 15 patients with coronary disease with two-dimensional echocardiography and thallium-201 ((201)Tl) tomography before coronary bypass surgery. During surgery, transmural myocardial biopsies were performed guided by transesophageal echocardiography. Myocardial biopsies were stained immunohistochemically to investigate fibroblast phenotype and examine evidence of active remodeling in the heart. RESULTS Among the 29 biopsied segments included in the study, 24 showed evidence of systolic dysfunction. The majority of dysfunctional segments (86.4%) were viable ((201)Tl uptake > or = 60%). After revascularization, 12 dysfunctional segments recovered function as assessed with an echocardiogram three months after bypass surgery. Interstitial fibroblasts expressing the embryonal isoform of smooth muscle myosin heavy chain (SMemb) were noted in dysfunctional segments, predominantly located in border areas adjacent to viable myocardial tissue. Segments with recovery had higher SMemb expression (0.46 +/- 0.16% [n = 12] vs. 0.10 +/- 0.02% [n = 12]; p < 0.05) and a higher ratio of alpha-smooth muscle actin to collagen (0.14 +/- 0.026 [n = 12] vs. 0.07 +/- 0.01 [n = 12]; p < 0.05) compared with segments without recovery, indicating fibroblast activation and higher cellularity of the fibrotic areas. In addition, interstitial deposition of the matricellular protein tenascin, a marker of active remodeling, was higher in hibernating segments than in segments with persistent dysfunction (p < 0.05), suggesting an active continuous fibrotic process. Multiple logistic regression demonstrated a significant independent association between SMemb expression and functional recovery (p < 0.01). CONCLUSIONS Fibroblast activation and expression of SMemb and tenascin provide evidence of continuous remodeling in the cardiac interstitium of the hibernating myocardium, an important predictor of recovery of function after revascularization.

Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium

Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ((201)Tl uptake >/= 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 +/- 3.1 cells/mm(2), n = 12 versus 8.6 +/- 0.9 cells/mm(2), n = 11; P = 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We postulate that revascularization may promote resolution of the ongoing inflammation, preventing further tissue injury and fibrosis.

Altered Adrenergic Receptor Density in Myocardial Hibernation in Humans A Possible Mechanism of Depressed Myocardial Function

Background—Alterations in adrenergic receptor densities can potentially contribute to myocardial dysfunction. Their relevance to myocardial hibernation in humans is unknown. Methods and Results—Accordingly, 22 transmural myocardial biopsies were obtained in 11 patients with ischemic ventricular dysfunction during bypass surgery, guided by transesophageal echocardiography. Patients underwent dobutamine echocardiography (DE) and rest scintigraphic studies before revascularization and DE at 3 to 4 months. &agr;- and &bgr;-receptor density (ARD and BRD) and extent of fibrosis were quantified from the myocardial biopsies. Of the 22 segments, 16 had abnormal rest function and 6 were normal. Severely hypokinetic or akinetic segments showed a 2.4-fold increase in ARD with a concomitant 50% decrease in BRD compared with normal segments. An increase in ARD, a decrease in BRD to a lesser extent, and thus an increase in ARD/BRD ratio were seen in dysfunctional segments with contractile reserve compared with normal segments and were most pronounced in those without contractile reserve (P <0.001). Similar findings were observed if recovery of function or scintigraphic uptake was analyzed as a marker for viability. No significant relation between either ARD or BRD and percent myocardial fibrosis was noted (r =0.37 and −0.39, respectively). Conclusions—Thus, graded and reciprocal changes in &agr;- and &bgr;-adrenergic receptor densities occur in viable, hibernating myocardium and may account in part for the observed depression in resting myocardial function and preserved contractile reserve in this entity.

Deceleration Time in Ischemic Cardiomyopathy

Background—In patients with heart failure secondary to left ventricular (LV) systolic dysfunction, a short deceleration time (DT) successfully predicts clinical outcome. The impact of myocardial viability and revascularization on the mitral inflow velocities, however, is unknown. Methods and Results—Forty patients with ischemic cardiomyopathy underwent 201Tl scintigraphy (SPECT) and 2D, Doppler, and dobutamine echocardiography (DE, to 40 μg · kg−1 · min−1) 2 days before CABG. Echocardiography was repeated 3 months after revascularization to determine recovery of function. Significant correlations were present between DT and LV contractile reserve by DE (r=0.72), scar perfusion defect by SPECT (r=−0.69), and the change in ejection fraction (ΔEF) after surgery (r=0.77) (all P 150 ms effectively identified (sensitivity 79%, specificity 81%) patients with ΔEF ≥5%. The population was divided into 2 groups according to DT: group 1 (DT >150 ms, n=21) and group 2 (DT ≤150 ms, n=19). At baseline, NYHA c...

A New Tool for Automatic Assessment of Segmental Wall Motion Based on Longitudinal 2D StrainCLINICAL PERSPECTIVE: A Multicenter Study by the Israeli Echocardiography Research Group

Background— Identification and quantification of segmental left ventricular wall motion abnormalities on echocardiograms is of paramount clinical importance but is still performed by a subjective visual method. We constructed an automatic tool for assessment of wall motion based on longitudinal strain. Methods and Results— Echocardiograms of 105 patients (3 apical views) were blindly analyzed by 12 experienced readers. Visual segmental scores (VSS) and peak systolic longitudinal strain were assigned to each of 18 segments per patient. Ranges of peak systolic longitudinal strain that best fit VSS (by receiver operating characteristic analysis) were used to generate automatic segmental scores (ASS). Comparisons of ASS and VSS were performed on 1952 analyzable segments. There was agreement of wall motion scores between both methods in 89.6% of normal, 39.5% of hypokinetic, and 69.4% of akinetic segments. Correlation between methods was r =0.63 ( P <0.0001). Interobserver and intraobserver reliability using interclass correlation for scoring segmental wall motion into 3 scores by ASS was 0.82 and 0.83 and by VSS 0.70 and 0.69, respectively. Compared with VSS (majority rule), ASS had a sensitivity, specificity, and accuracy of 87%, 85%, and 86%, respectively. ASS and VSS had similar success rates for correct identification of wall motion abnormalities in territories supplied by culprit arteries. VSS had greater specificity and positive predictive values, whereas ASS had higher sensitivity and negative predictive values for identifying the culprit artery. Conclusions— Automatic quantification of wall motion on echocardiograms by this tool performs as well as visual analysis by experienced echocardiographers, with a greater reliability and similar agreement to angiographic findings. Received December 16, 2008; accepted November 17, 2009. # CLINICAL PERSPECTIVE {#article-title-2}Background—Identification and quantification of segmental left ventricular wall motion abnormalities on echocardiograms is of paramount clinical importance but is still performed by a subjective visual method. We constructed an automatic tool for assessment of wall motion based on longitudinal strain. Methods and Results—Echocardiograms of 105 patients (3 apical views) were blindly analyzed by 12 experienced readers. Visual segmental scores (VSS) and peak systolic longitudinal strain were assigned to each of 18 segments per patient. Ranges of peak systolic longitudinal strain that best fit VSS (by receiver operating characteristic analysis) were used to generate automatic segmental scores (ASS). Comparisons of ASS and VSS were performed on 1952 analyzable segments. There was agreement of wall motion scores between both methods in 89.6% of normal, 39.5% of hypokinetic, and 69.4% of akinetic segments. Correlation between methods was r=0.63 (P<0.0001). Interobserver and intraobserver reliability using interclass correlation for scoring segmental wall motion into 3 scores by ASS was 0.82 and 0.83 and by VSS 0.70 and 0.69, respectively. Compared with VSS (majority rule), ASS had a sensitivity, specificity, and accuracy of 87%, 85%, and 86%, respectively. ASS and VSS had similar success rates for correct identification of wall motion abnormalities in territories supplied by culprit arteries. VSS had greater specificity and positive predictive values, whereas ASS had higher sensitivity and negative predictive values for identifying the culprit artery. Conclusions—Automatic quantification of wall motion on echocardiograms by this tool performs as well as visual analysis by experienced echocardiographers, with a greater reliability and similar agreement to angiographic findings.