Myocardial left ventricular dysfunction in patients with systemic lupus erythematosus: new insights from tissue Doppler and strain imaging.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with high cardiovascular morbidity and mortality. Cardiovascular involvement is frequently underestimated by routine imaging techniques. Our aim was to determine if new echocardiographic imaging modalities like tissue Doppler (TDI), strain rate (SRR), and strain (SRI) imaging detect abnormalities in left ventricular (LV) function in asymptomatic patients with SLE. METHODS: Sixty-seven young patients with SLE (mean age 42 +/- 10 yrs) without typical symptoms or signs of heart failure or angina, and a matched healthy control group (n = 40), underwent standard transthoracic echocardiography, TDI, SRR, and SRI imaging of the LV as well as assessment of disease characteristics. RESULTS: Despite findings within the normal range on routine standard 2-dimensional echocardiography, SLE was associated with significantly impaired systolic and diastolic myocardial velocities of the LV measured by TDI [mean global TDI: systolic (s): 2.9 +/- 0.9 vs 3.9 +/- 0.7 cm/s, p < 0.05; early (e): 4.3 +/- 1.5 vs 6.3 +/- 1.3 cm/s, p < 0.05; late (a): 2.9 +/- 0.8 vs 3.4 +/- 0.8 cm/s, p < 0.05; values +/- SD); SRR (s: -0.8 +/- 0.1 vs -1.1 +/- 0.1 s(-1); e: 1.1 +/- 0.2 vs 1.6 +/- 0.3 s(-1); a: 0.7 +/- 0.1 vs 1.0 +/- 0.2 s(-1); all p < 0.05); and SR (-15.11 +/- 2.2% vs -19.7 +/- 1.9%; p < 0.05) compared to the control group. Further, elevated disease activity, measured with the ECLAM and the SLEDAI score, resulted in significantly lower values for LV longitudinal function measured by SRR and SR, but not by TDI. CONCLUSION: SLE is associated with a significant impairment of systolic and diastolic LV longitudinal function in patients without cardiac symptoms. New imaging modalities provide earlier insight into cardiovascular involvement in SLE and seem to be superior to standard echocardiography to detect subclinical myocardial disease.

Echocardiographic phase imaging to predict reverse remodeling after cardiac resynchronization therapy.

OBJECTIVES: The aim of our study was to investigate whether echocardiographic phase imaging (EPI) can predict response in patients who are considered for cardiac resynchronization therapy (CRT). BACKGROUND: CRT improves quality of life, exercise capacity, and outcome in patients with bundle-branch block and advanced heart failure. Previous studies used QRS duration to select patients for CRT; the accuracy of this parameter to predict functional recovery, however, is controversial. METHODS: We examined 42 patients with advanced heart failure (New York Heart Association [NYHA] functional class III to IV, QRS duration >130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of Delta ESV >or=15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. RESULTS: The Ts-SD and the mean EPI-Index were related to Delta ESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index

Dose-dependent effects of intravenous allogeneic mesenchymal stem cells in the infarcted porcine heart.

Intravenous delivery of mesenchymal stem cells (MSCs) preserves myocardial function after infarction. This dose-escalating study was performed to examine pathologic remodeling and scar formation in a pig model of permanent coronary occlusion without restoration of reperfusion. MSCs labeled with fluorescent dye 48 h or saline (negative control, n = 8) were given intravenously 48 h post proximal left anterior descending artery occlusion. Animals received either autologous or allogeneic MSCs in doses from 1 x 10(3) up to 1 x 10(6) per kg bodyweight from an unrelated donor pig. Infarct size and myocardial function were assessed after 1 month. Morphologic analysis revealed that labeled autologous MSCs migrated in the peri-infarct region resulting in smaller infarct size (19 +/- 7% vs. 32 +/- 7%, p < 0.008) and higher fractional area shortening (33 +/- 7% vs. 21 +/- 3%, p < 0.001). Similarly, allogeneic MSCs had dose-dependent beneficial effects on cardiac function, statistically significant at 1 x 10(5) and 1 x 10(6) cells per kg bodyweight. Autologous as well as allogeneic MSCs specifically "home" to the heart after systemic delivery, leading to limited myocardial infarct size and improved functional outcome, even without coronary reperfusion. Therefore, intravenously administration of MSCs is an attractive minimal-invasive approach for cardiac tissue repair.

Evaluation of myocardial perfusion and deformation in patients with acute myocardial infarction treated with primary angioplasty and stent placement.

PURPOSE: To prospectively compare the usefulness of myocardial perfusion and deformation imaging for the prediction of functional recovery and left ventricular (LV) remodeling in patients with ST-elevation myocardial infarction (STEMI). METHODS: We prospectively examined 36 patients with reperfused STEMI, 12+ or -9 h after primary angioplasty and stent placement. LV function was reevaluated at 4-6 months of follow-up, to assess relative improvement of LV-ejection fraction (DeltaEF%) and increase in end-diastolic volume (DeltaEDV). RESULTS: During the follow-up period, 19 of 36 patients showed LV function improvement (DeltaEF%> or =10%), whereas 10 patients had LV remodeling (DeltaEDV> or =20%). Peak negative strain (epislon (peak)), peak negative strain rate (SRpeak), and myocardial blood flow (Axbeta) correlated with DeltaEF% (r=-0.55, -0.57, and 0.46, respectively, P<0.01 for all), and allowed for prediction of LV remodeling on an individual level (area under the curve of 0.85 for strain rate, 0.95 for strain, and 0.90 for regional blood flow, P<0.001 for all). The combined assessment of myocardial perfusion and deformation correctly predicted LV remodeling in four additional patients, compared with each technique separately. CONCLUSION: Contrast echocardiography, strain Doppler imaging, and possibly the combination of both are useful for the prediction of adverse LV remodeling and for the early risk stratification of patients with STEMI.

Evaluation cardioprotective effects of atorvastatin in rats by real time myocardial contrast echocardiography.

BACKGROUND: The ability to assess myocardial perfusion in small animals is important, especially to investigate models of myocardial ischemia. Myocardial perfusion is usually assessed by postmortem techniques, eliminating the possibility of follow-up in intervention studies. The purpose of the study was to examine the feasibility of real time myocardial contrast echocardiography (MCE) to evaluate cardioprotective effects of atorvastatin in a rat model of acute ischemia-reperfusion injury. METHODS: The rats (n=15) underwent 20 minutes of mechanical left descending coronary artery (LAD) occlusion followed by 180 minutes of reperfusion. The animals received either atorvastatin (10 mg/kg), atorvastatin and the nitric oxide synthase (NOS)-inhibitor N-Nitro-L-Argininemethylester (L-NAME) (15 mg/kg), or vehicle. MCE was performed to assess the size of the perfusion defect and the myocardial signal intensities (A(max)) at the baseline, during occlusion, and during reperfusion. For comparison, the infarct size, risk area, and regional myocardial blood flow (MBF) were determined by the standard techniques as well. RESULTS: The dynamics of ischemia-reperfusion injury could be visualized serially by MCE. The infarct size-to-risk area ratio progressively increased during reperfusion and was markedly reduced in the atorvastatin group. Triphenyltetrazolium chloride (TTC) staining confirmed a 23% reduction in the infarct size by atorvastatin. The infarct size by MCE correlated well with the histological methods (r=0.86, P < 0.001). A(max) was reduced in the anterior segments during LAD occlusion (0.08 +/- 0.01 dB) compared to the baseline (2.9 +/- 0.4 dB), approached higher levels post revascularization of LAD (3.22 +/- 0.50 dB), but decreased during 180 minutes of reperfusion (2.32 +/- 0.40 dB). After 180 minutes of reperfusion, A(max) in the risk area was significantly higher in the atorvastain-treated group compared to the vehicle-treated group (2.32 +/- 0.40 dB vs 1.3 +/- 0.4 dB, P

Caught in the act: entrapped embolus through a patent foramen ovale.

A patent foramen ovale (PFO) is detected frequently by transesophageal echocardiography. The diagnosis of paradoxical embolism is usually presumptive when arterial emboli occur in the appropriate clinical setting. Presumably, paradoxical embolism of small thrombi arise in the venous system and pass through the PFO during a transient right-to-left shunt; however, cases demonstrating a thrombus traversing the PFO are relatively few.

Stem cell therapy improves myocardial perfusion and cardiac synchronicity: new application for echocardiography.

OBJECTIVES: Intravenous delivery of mesenchymal stem cell (MSC) is a noninvasive approach for myocardial tissue repair. We aimed to test this strategy in a pig model of myocardial infarction and to examine the usefulness of new echocardiographic applications to monitor cardioprotective effects of stem cell therapy. METHODS: Pigs (n = 8) received autologous or allogeneic MSCs (1 x 10(6)/kg body weight) labeled with fluorescent dye 48 hours after proximal left anterior descending coronary artery occlusion. Infarct size, myocardial function, and perfusion (A x beta) were assessed by myocardial contrast echocardiography and standard histologic methods after 1 month. RESULTS: Morphologic analysis revealed that labeled MSCs migrated in the peri-infarct region resulting in smaller infarct size by myocardial contrast echocardiography (control vs autologous and allogeneic MSC: 38 +/- 10% vs 25 +/- 5% and 28 +/- 6%, P < .01), higher fractional area shortening (23 +/- 3% vs 34.0 +/- 7% and 28 +/- 2%, P < .01), higher cardiac synchrony (167 +/- 36 vs 68 +/- 17 and 85 +/- 26 milliseconds, P < .003), and improved microvascular flow A x beta in the ischemic border zone (0.18 +/- 0.2 vs 0.56 +/- 0.3 and 0.49 +/- 0.2, P < .03). CONCLUSIONS: Systemic delivery of autologous and allogeneic MSCs preserves myocardial viability even in large animals and is, therefore, an attractive approach for tissue repair. Myocardial contrast echocardiography is useful to evaluate microvascular perfusion, which was enhanced by MSCs.

Intravenous delivery of autologous mesenchymal stem cells limits infarct size and improves left ventricular function in the infarcted porcine heart.

Systemic delivery of bone marrow-derived mesenchymal stem cells (MSCs) is a noninvasive approach for myocardial repair. We aimed to test this strategy in a pig model of myocardial infarction. Pigs (n = 8) received autologous MSCs (1 x 10(6)/kg body weight) labeled with fluorescent dye 48 h post proximal left anterior descending artery (LAD) occlusion. Hemodyamics, infarct size, and myocardial function were assessed at baseline and after 1 month. Morphologic analysis revealed that labeled MSCs migrated in the peri-infarct region, resulting in smaller infarct size (32 +/- 7 vs. 19 +/- 7%, p = 0.01), higher fractional area shortening (23 +/- 3 vs. 34.0 +/- 7%, p = 0.001), lower left ventricular end diastolic pressure (18.7 +/- 5 vs. 10.2 +/- 4 mmHg, p = 0.02) and higher +dp/dt (4,570 +/- 540 vs. 6,742 +/- 700 mmHg/s, p = 0.03) during inotropic stimulation. Systemic intravenous delivery of MSCs to pigs limits myocardial infarct size and is an attractive approach for tissue repair.

Quantitative evaluation of myocardial blush to assess tissue level reperfusion in patients with acute ST-elevation myocardial infarction: incremental prognostic value compared with visual assessment.

BACKGROUND: Tissue level reperfusion gauges functional recovery in acute ischemic syndromes. However, its current clinical assessment is based upon visual interpretation of myocardial blush grade (MBG), which is operator dependent. The purpose of the study was to test whether quantification of MBG can enhance the predictive value of visual assessment for functional recovery in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: Myocardial blush grade was assessed in 124 consecutive patients with STEMI visually and quantitatively, analyzing the time course of blush intensity rise. We defined Gmax as the peak gray level intensity and Tmax as the time to peak intensity. Ejection fraction >50% at 4 to 6 months of follow-up was deemed as the primary end point for assessment of successful tissue reperfusion. RESULTS: Ejection fraction >50% at follow-up was predicted by visual MBG with moderate sensitivity (65%) and specificity (64%). However, a cutoff value of Gmax/Tmax = 3.1/s yielded significantly higher sensitivity and specificity (91% and 96%, respectively, for both P < .01). Gmax/Tmax was the most powerful predictor of follow-up ejection fraction >50% (relative risk of 4.6 vs 3.2 for visual MBG). CONCLUSIONS: Quantitative MBG is highly predictive for functional recovery in patients with STEMI and provides incremental prognostic value to visual assessment. Thus, this simple approach may be used to gauge reperfusion strategies in acute ischemic syndromes.

Impact of microbubbles on shock wave-mediated DNA uptake in cells in vitro.

Gas-filled microbubbles have been successfully used as gene delivery reagents in combination with diagnostic ultrasound. Although shock wave exposure has been shown to transfect cells with naked DNA in vitro, it has not been tested whether the addition of microbubbles would augment DNA uptake under those conditions. Therefore, the aim of this study was to test the impact of microbubbles on transgene expression in vitro under shock wave exposure conditions. HEK 293 cells were treated with 60 or 120 pulses of shock waves at varying energy levels. Cells were mixed with either 100 microg/mL luciferase expressing plasmid DNA or with microbubbles that were produced with the same amount of this DNA. Cell death was evaluated after 1 h and transgene expression, after 24 h. In the presence of microbubbles, transgene expression was significantly higher (as much as 29-fold) relative to that obtained without microbubbles. Cells exposed to 120 pulses demonstrated higher transgene expression (as high as 2.7-fold) compared with cells exposed to 60 pulses. The use of microbubbles resulted in greater cell death, varying from 26% (low energy) to 78% (high energy). In conclusion, DNA-loaded microbubbles can significantly increase shock wave mediated gene transfer. However, this effect is associated with increased levels of cell destruction.

Ultrasound-targeted microbubble destruction augments protein delivery into testes.

OBJECTIVES: Gas-filled microbubbles have become an important tool as ultrasound contrast agents. In recent years, ultrasound-targeted microbubble destruction (UTMD) has evolved into a new tool for organ-specific gene and drug delivery. Although many studies have been performed in well-perfused target organs such as the heart or kidney, no study has yet investigated the feasibility of UTMD for delivery of bioactive substances in the testis. Thus, the aim of this study was to determine whether UTMD is a feasible and safe technique to deliver a reporter protein to the testes. METHODS: Different groups of rats received 2 microg of luciferase protein at varying protocols. One group received luciferase-loaded microbubbles infused intravenously while ultrasound was applied to the right testis. Another group received luciferase without microbubbles but with ultrasound applied to the right testis. Protein uptake was quantified by luciferase assay. Also, to rule out UTMD-induced damage, the testes were analyzed histologically. RESULTS: The testes that received ultrasound and luciferase-loaded microbubbles showed about twofold greater luciferase activity compared with testes without ultrasound or without microbubbles. No hemorrhage or microscopic damage was detected. CONCLUSIONS: The results of our study have shown that UTMD is a safe and feasible technique to augment delivery of bioactive substances to the testes.

Immediate and chronic effects of AV-delay optimization in patients with cardiac resynchronization therapy.

BACKGROUND: Acute changes of the AV-delay in CRT patients have a significant impact on hemodynamics. However, the chronic functional effects of AV-delay optimization have not been systematically examined despite of their potential role for chronic functional improvement. METHODS: Therefore, in this study we investigated whether optimization of AV-delay in CRT patients as assessed by echocardiographic measurement of the velocity time integral of the left ventricular outflow tract (LVOT-VTI) chronically changes (1) echocardiographic parameters of systolic and diastolic left ventricular function, (2) walking distance in the 6-min walk test, (3) levels of NT-proBNP and (4) quality of life as assessed by a standard questionnaire. 33 patients underwent optimization of AV-delay 31+/-8 weeks after initiation of CRT. Follow up (FU) was conducted 43+/-5 days later. RESULTS: E/Ea, the ratio of peak E-wave of mitral inflow and of TDI of the mitral annulus, significantly decreased immediately post-optimization (11+/-1 vs. 14+/-1 at baseline, p<0.05) and further decreased at FU (8+/-1, p<0.05 vs. immediately post-optimization) indicating improvement of diastolic function, while traditional parameters of diastolic function derived from pulse wave Doppler remained unchanged. There was a slight increase of LV-ejection fraction as assessed by echocardiography acutely after optimization (baseline: 25+/-2%, optimized: 28+/-1%, p<0.05), while LV-ejection fraction at FU did not differ from baseline. 6-min walk test improved from 449+/-17 m (baseline) to 475+/-17 m at FU (p<0.05). During this period NT-proBNP significantly decreased from 3193+/-765 ng/l to 2593+/-675 ng/l (p<0.05). Quality of life was unchanged at FU. CONCLUSION: This study demonstrates for the first time chronic functional improvement due to AV-delay optimization in patients with CRT.

Prompt resolution of an apical left ventricular thrombus in a patient with takotsubo cardiomyopathy.

This report describes the prompt resolution of an apical left ventricular (LV)-thrombus complicating transient apical ballooning in a 74-year-old woman. The patient was admitted to our emergency department with acute chest pain and ST-elevation on the electrocardiogram. Coronary angiography showed normal coronary arteries and LV-angiography demonstrated the presence of apical ballooning akinesis associated with basal hypercontraction. Echocardiography and MRI studies confirmed the presence of LV-apex akinesis and detected an apical thrombus. Follow-up echocardiography on day 12 before discharge of the patient, revealed a marked improvement of regional contractility of the LV-apex and surprisingly the complete resolution of the LV-apical thrombus. The patient was diagnosed with takotsubo cardiomyopathy.

Evidence of left ventricular contractile asynchrony by echocardiographic phase imaging in patients with type 2 diabetes mellitus and without clinically evident heart disease.

Left ventricular electromechanical asynchrony has been shown to predict cardiac events in patients with heart failure. This study investigated whether left ventricular asynchrony is present in patients with type 2 diabetes mellitus (DM) with no clinically evident heart disease and normal QRS durations. Asynchrony was evaluated in 24 patients with DM, 15 nondiabetic control subjects, and 20 patients with left bundle branch block (LBBB) due to cardiomyopathy serving as positive controls by conventional tissue Doppler imaging and by a novel method, echocardiographic phase imaging. Asynchrony was significantly higher in patients with DM than in controls and significantly lower than in patients with LBBB. This was shown by tissue Doppler imaging: the SD of time to peak myocardial velocity was 13 +/- 10 ms in controls, compared with 30 +/- 19 ms in patients with DM (p <0.01) and 68 +/- 28 ms in those with LBBB (p <0.001). Similar data were obtained using echocardiographic phase imaging: the SD of phase degrees was 25 degrees +/- 8 degrees in controls, compared with 44 degrees +/- 21 degrees in patients with DM (p = 0.02) and 76 degrees +/- 25 degrees in those with LBBB (p <0.001). Tissue Doppler imaging correlated with echocardiographic phase imaging (r = 0.79, p <0.0001) but was more time consuming (15.5 +/- 4.5 vs 4.5 +/- 2.2 min/patient, p <0.05) and showed higher intraobserver variability (5.6% vs 3.2%, p <0.05). In conclusion, this is the first study showing increased left ventricular asynchrony in patients with DM and no clinical evidence of heart disease.

The potential of a new stable ultrasound contrast agent for site-specific targeting. An in vitro experiment.

Microbubble-based ultrasound contrast agents can be used for specific site targeting, but demonstrate time-limited opacification. We have previously demonstrated the potential of gold-bound microtubules to provide a stable ultrasound contrast effect. Aim of the present study was to test the feasibility of gold-bound microtubules specifically to bind to human thrombi and to inflammatory activated human umbilical vein endothelial cells (HUVEC) in vitro. HUVEC were incubated with tumor necrosis factor, to induce expression of adhesion molecules. Human clots and HUVEC were incubated with biotinylated monoclonal antifibrin and anti-E-selectin antibodies, respectively. Probes were incubated with excess avidin followed by biotinylated gold-bound microtubules and by secondary Cy3-anti-beta-tubulin antibody and processed for immune fluorescence microscopy. Clots were transferred in copolymer foils filled with buffer and were ultrasonographically imaged before and after their treatment with the antifibrin antibody and with biotinylated microtubules, using a broadband harmonic transducer, transmitting and receiving at a mean frequency of 1.7 MHz and 3.2 MHz. The feasibility of specific gold-bound microtubules conjugation to antibody treated clots and HUVEC was confirmed using immune fluorescence analysis. Contrast intensities of the clots significantly increased after their treatment with antifibrin antibody and incubation with gold-bound microtubules (39 +/- 2 dB versus 26 +/- 2 dB, p < 0.001) and remained high after 20 min of ultrasound exposure (37 +/- 2 dB versus 39 +/- 2 dB, p = NS). Thus, gold-bound microtubules can specifically bind to human thrombi and to endothelial cells, providing a significant contrast effect which remains stable in the ultrasound field. This may be a promising approach to target thrombi and inflammatory active atherosclerotic plaques.

Ultrasound exposure can increase the membrane permeability of human neutrophil granulocytes containing microbubbles without causing complete cell destruction.

Activated polymorphonuclear neutrophil (PMN) granulocytes can bind and subsequently phagocytose microbubbles used as ultrasound (US) contrast agents. The purpose of the present study was to assess insonation effects on cell membrane integrity and metabolic activity of activated PMN. Furthermore, we investigated whether or not there is an acoustic threshold at which insonation of PMN results in increase of membrane permeability without causing complete cell destruction. PMN isolated from healthy volunteers were activated with phorbol myristate acetate (PMA) for 15 min to allow phagocytosis of albumin and lipid microbubbles and were subsequently exposed to US with a mechanical index between 0.15 and 1.8. Apoptosis, loss of membrane integrity and formation of cell fragments were evaluated by measurement of lactate dehydrogenase leakage and by double staining with annexin V and propidium iodide, using flow cytometry. Neutrophil superoxide anion generation was measured photometrically. Insonation of activated PMN in the presence of microbubbles amplified apoptosis and lactate dehydrogenase leakage and induced loss of membrane integrity and complete cell destruction with increasing acoustic pressures. The bioeffects observed by insonation with high mechanical indices (1.0 to 1.8), and particularly the formation of cell fragments, were significantly more pronounced in the presence of albumin microbubbles. Insonation in the presence of lipid microbubbles increased cell membrane permeability, but caused significantly less cell destruction and left the metabolic activity of activated PMN uninfluenced. Thus, both albumin and lipid microbubbles induce apoptosis and membrane injury during insonation of activated PMN. However, insonation in the presence of lipid microbubbles seems to influence cell viability to a smaller extent. This could be of advantage in the setting of US-guided local drug delivery. In this setting, increase of membrane permeability may allow bioactive substances to enter into cells, which survive the US treatment, and specifically modify their function.

Real-time myocardial perfusion imaging for pharmacologic stress testing: added value to single photon emission computed tomography.

BACKGROUND: Little is known about the incremental value of real-time myocardial contrast echocardiography (MCE) as an adjunct to pharmacologic stress testing. This study was performed to evaluate the diagnostic value of MCE to detect abnormal myocardial perfusion by technetium Tc 99m sestamibi-single photon emission computed tomography (SPECT) and anatomically significant coronary artery disease (CAD) by angiography. METHODS: Myocardial contrast echocardiography was performed at rest and during vasodilator stress in consecutive patients (N = 120) undergoing SPECT imaging for known or suspected CAD. Myocardial opacification, wall motion, and tracer uptake were visually analyzed in 12 myocardial segments by 2 pairs of blinded observers. Concordance between the 2 methods was assessed using the kappa statistic. RESULTS: Of 1356 segments, 1025 (76%) were interpretable by MCE, wall motion, and SPECT. Sensitivity of wall motion was 75%, specificity 83%, and accuracy 81% for detecting abnormal myocardial perfusion by SPECT (kappa = 0.53). Myocardial contrast echocardiography and wall motion together yielded significantly higher sensitivity (85% vs 74%, P < .05), specificity of 83%, and accuracy of 85% (kappa = 0.64) for the detection of abnormal myocardial perfusion. In 89 patients who underwent coronary angiography, MCE and wall motion together yielded higher sensitivity (83% vs 64%, P < .05) and accuracy (77% vs 68%, P < .05) but similar specificity (72%) compared with SPECT for the detection of high-grade, stenotic (> or = 75%) coronary lesions. CONCLUSION: Assessment of myocardial perfusion adds value to conventional stress echocardiography by increasing its sensitivity for the detection of functionally abnormal myocardial perfusion. Myocardial contrast echocardiography and wall motion together provide higher sensitivity and accuracy for detection of CAD compared with SPECT.

Cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 in ischemia-reperfusion injury.

OBJECTIVE: The aims of the study were to visualize the dynamics of ischemia-reperfusion injury by real-time myocardial contrast echocardiography and to investigate the cardioprotective effects of the novel endothelin-A receptor antagonist BSF 461314. BSF 461314 reduced infarct size by 47% and preserved microvascular integrity. Real-time myocardial contrast echocardiography allowed visualization of postischemic microvascular dysfunction and quantification of cardioprotective effects of selective endothelin antagonism. Blood flow index A x beta was reduced in anterior segments during ischemia compared with baseline (0.06 +/- 0.01 vs 0.98 +/- 0.2 dB/s) but was higher in the BSF 461314 group after 120 minutes of reperfusion (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015). Therefore, selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time myocardial contrast echocardiography accurately detected changes in microvascular reflow. BACKGROUND: Endothelin-1 is a potent vasoconstrictor and elevated in myocardial ischemia. The aims of the study were to examine cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 and to visualize changes in the microvasculature by real-time myocardial contrast echocardiography (MCE). METHODS: A total of 16 open-chest pigs underwent 45 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. A total of 1 mg/kg BSF 461314 or vehicle was given intravenously before reperfusion. Serial MCE was performed to assess changes in myocardial blood flow A x beta and perfusion defect size. Myocardial blood flow was measured by fluorescent microspheres and infarct size was measured by triphenyltetrazolium chloride tissue staining. RESULTS: Dynamics of infarct size expansion and tissue perfusion were correctly assessed by MCE. A x beta Was reduced in anterior segments during left anterior descending coronary artery occlusion (0.06 +/- 0.01 dB/s) compared with baseline (0.98 +/- 0.2 dB/s), approached higher levels postrecanalization (1.2 +/- 0.1 dB/s), but gradually decreased during reperfusion (0.3 +/- 0.05 dB/s, P < .01). After 120 minutes of reperfusion A (2.1 +/- 0.5 vs 1.0 +/- 0.6 dB, P < .03), beta (0.36 +/- 0.09/s vs 0.21 +/- 0.09/s, P = .01), and A x beta (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015) in the risk area were higher in the BSF 461314-treated group compared with vehicle indicating preserved myocardial perfusion. Triphenyltetrazolium chloride staining confirmed a 47% reduction in infarct size by BSF 461314. CONCLUSIONS: Selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time MCE allows visual and quantitative evaluation of dynamics of myocardial ischemia-reperfusion injury and monitoring of cardioprotective effects during pharmacologic interventions.