Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.

Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.

Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study - the importance of comprehensive clinical evaluation.

BACKGROUND: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. METHODS: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. RESULTS: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). CONCLUSION: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.

Why Not Dipyridamole: a Review of Current Guidelines and Re-evaluation of Utility in the Modern Era.

Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in coronary artery disease (CAD) has fallen out of practice in the modern era with the advent of new anti-platelet agents, and most modern guidelines on the management of CAD either neglect to comment on its utility or outright recommend against it. The majority of the studies used in these guidelines are outdated and took place in an era when high doses of aspirin were used and statins were not widely utilized. There is growing evidence in rat models of dipyridamole's synergy with statins through adenosine modulation resulting in significant myocardial protection against ischemia-reperfusion injury and limitation of infract size. The data in human studies are limited but show a similar potential synergy between dipyridamole and statins. It would thus be prudent to reconsider the recommendations against the use of dipyridamole in CAD and to re-evaluate its possible role and potential benefits through well-designed randomized trials combining it with statins, low-dose aspirin, and/or other anti-platelet agents.

Pentraxin 3 in primary percutaneous coronary intervention for ST elevation myocardial infarction is associated with early irreversible myocardial damage : Kinetic profile, relationship to interleukin 6 and infarct size.

BACKGROUND: The inflammatory marker long pentraxin 3 (PTX3) has been shown to be a strong predictor of 30-day and one-year mortality after acute myocardial infarction. The aim of this study was to evaluate the kinetic profile of PTX3 and its relationship with interleukin 6 (IL-6), high-sensitive C-reactive protein (hs-CRP) and infarct size. METHODS: PTX3, IL-6 and hs-CRP were measured at predefined time points, at baseline (before percutaneous coronary intervention (PCI)), at 12 and 72 hours after PCI in 161 patients with first-time ST elevation myocardial infarction (STEMI). RESULTS: PTX3 and IL-6 levels increased in the early phase, followed by a gradual decrease between 12 and 72 hours. There were statistically significant correlations between PTX3 and IL-6 in general, for all time points and for changes over time (0-72 hours). In a linear mixed model, PTX3 predicted IL-6 (p < 0.001). PTX3 is also correlated with hs-CRP in general, and at each time point post PCI, except at baseline. PTX3, IL-6 and hs-CRP were all significantly correlated with infarct size in general, and at the peak time point for maximum troponin I. In addition, there was a modest correlation between IL-6 levels at baseline and infarct size at 72 hours after PCI (ρ = 0.23, p = 0.006). CONCLUSIONS: PTX3 had a similar kinetic profile to IL-6, with an early increase and decline, and was statistically significantly correlated with markers of infarct size in STEMI patients post primary PCI. Baseline levels of IL-6 only predicted infarct size at 72 hours post PCI.

A key requirement for CD300f in innate immune responses of eosinophils in colitis.

Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill-defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f-/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f-/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell-specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases.

A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair.

Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.

Interleukin-33 requires CMRF35-like molecule-1 expression for induction of myeloid cell activation.

BACKGROUND: IL-33 is a potent activator of various cells involved in allergic inflammation, including eosinophils and mast cells. Despite its critical role in Th2 disease settings, endogenous molecular mechanisms that may regulate IL-33-induced responses remain to be defined. We have recently shown that eosinophils express CMRF35-like molecule (CLM)-1. Yet, the role of CLM-1 in regulating eosinophil functions is still elusive. METHODS: CLM-1 and CLM-8 expression and cellular localization were assessed in murine bone marrow-derived and/or peritoneal cells at baseline and following IL-33 stimulation (flow cytometry, western blot). IL-33-induced mediator release and signaling were assessed in wild-type (wt) and Clm1(-/-) cells and mice. RESULTS: BM-derived eosinophils express high levels of glycosylated CLM-1. IL-33 induced a rapid, specific, concentration- and time-dependent upregulation of CLM-1 in eosinophils (in vitro and in vivo). Clm1(-/-) eosinophils secreted less IL-33-induced mediators than wt eosinophils. CLM-1 co-localized to ST2 following IL-33 stimulation and was required for IL-33-induced NFκB and p38 phosphorylation. Th2 cytokine (e.g., IL-5, IL-13) and chemokine (e.g., eotaxins, CCL2) secretion was markedly attenuated in IL-33-treated Clm1(-/-) mice. Subsequently, IL-33-challenged mice displayed reduced infiltration of mast cells, macrophages, neutrophils, and B cells. Despite the markedly impaired IL-33-induced eotaxin expression in Clm1(-/-) mice, eosinophil accumulation was similar in wt and Clm1(-/-) mice, due to hyperchemotactic responses of Clm1(-/-) eosinophils. CONCLUSIONS: CLM-1 is a novel regulator of IL-33-induced eosinophil activation. These data contribute to the understanding of endogenous molecular mechanisms regulating IL-33-induced responses and may ultimately lead to receptor-based tools for future therapeutic intervention in IL-33-associated diseases.

Diuretic use in heart failure and outcomes.

Diuretics are frequently administered to relieve congestive symptoms in patients with heart failure (HF). Despite their widespread use, prospective data on the potential of diuretics to modulate HF-related morbidity and mortality are scarce. Diuretic efficacy may be limited by adverse neurohormonal activation and by "congestion-like" symptoms that may occur in the absence of fluid overload. Herein, we review the current knowledge on diuretic use and outcomes in HF.

Osteoprotegerin concentrations and prognosis in acute ischaemic stroke.

AIM: Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited. METHODS AND RESULTS: In 244 patients with acute ischaemic stroke (age: 69 +/- 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause mortality as the sole end-point. Multivariable predictors of OPG values at presentation included haemoglobin (T = -2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow-up 72 patients (29%) had died. Patients with OPG < or =2945 pg mL(-1) at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time-points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long-term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024). CONCLUSION: Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long-term mortality.

Dyspnoea after antiplatelet agents: the AZD6140 controversy.

Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug.

[Trends and characteristics of diabetes-related lower limb amputations in the Negev, 1996-1999].

BACKGROUND: The loss of a lower limb because of diabetic foot problems such as infections is an important complication of diabetes mellitus. The goals of this study were: (1) to examine trends in incidence of diabetic-related lower limb amputations in the Negev, (2) to describe the clinical characteristics of patients who underwent amputations in the Soroka University Medical Center and (3) to estimate in-hospital mortality and its predictors. METHODS: This study included all diabetic patients who underwent non-traumatic lower limb amputation in the Soroka Hospital during the period 1996-1999. The computerized hospitalization files and surgery logs during the study period were reviewed for ICD-9 diagnoses of diabetes and amputations. For each patient, hospitalization records were abstracted and data on socio-demographic and clinical characteristics were collected. RESULTS: During the study period 411 amputations were performed on 250 diabetic patients (1.6 amputation/person). The estimated mean annual incidence rate of lower limb amputations in the Negev was 5 per 1000 diabetic patients, 27.3 per 100,000 total population, and 45 per 100,000 adults above 18 years of age. The mean age was 68 (SD +/- 11.4) years. The most frequent types of surgery were standard below-knee amputation. Fourteen percent of patients died during hospitalization. Systolic blood pressure, white blood count and serum creatinine at admission were independent predictors of in-hospital mortality. CONCLUSIONS: The incidence of lower limb amputation in the Negev is similar to that reported in other countries. Interventions directed to early detection of diabetic foot problems may have an impact on the reduction of lower limb amputations and related mortality.

Cardiac troponin I is modified in the myocardium of bypass patients.

BACKGROUND: Selective proteolysis of cardiac troponin I (cTnI) is a proposed mechanism of contractile dysfunction in stunned myocardium, and the presence of cTnI degradation products in serum may reflect the functional state of the remaining viable myocardium. However, recent swine and canine studies have not demonstrated stunning-dependent cTnI degradation. METHODS AND RESULTS: To address the universality of cTnI modification, myocardial biopsy samples were obtained from coronary artery bypass patients (n=37) before and 10 minutes after removal of cross-clamp. Analysis of biopsy samples for cTnI by Western blotting revealed a spectrum of modified cTnI products in myocardium both before and after cross-clamp, including degradation products (7 products resulting from differential N- and C-terminal processing) and covalent complexes (3 products). In particular, a 22-kDa cTnI degradation product with C-terminal proteolysis was identified, which may represent an initial ischemia-dependent cTnI modification, similar to cTnI(1-193) observed in stunned rat myocardium. Although no systematic change in amount of modified cTnI was observed, subgroups of patients displayed an increase (n=10, 85+/-5% of cTnI remaining intact before cross-clamp versus 75+/-5% after) or a decrease (n=12, 67+/-5% before versus 78+/-5% after). Electron microscopy demonstrated normal ultrastructure in biopsy samples, which suggests no necrosis was present. In addition, cTnI modification products were observed in serum through a modified SDS-PAGE methodology. CONCLUSIONS: cTnI modification, in particular proteolysis, occurs in myocardium of bypass patients and may play a key role in stunning in some bypass patients.

Effect of coronary thrombolysis on the plasma concentration of osteonectin (SPARC, BM40) in patients with acute myocardial infarction.

Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet alpha-granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447. 7+/-20.6 ng/ml) and AMI patients (425.7+/-43.3 ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4+/-26.9 ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this alpha-granule constituent, challenge the postulate of uniform platelet activation in AMI patients.

Congenital pseudoarthrosis of the tibia.

Congenital pseudoarthrosis of the tibia remains one of the most difficult conditions to treat in orthopedic surgery. Seven cases were treated in our hospital by different methods. Three out of seven patients were healed, two of these refractured. At follow-up, the success rate was 14% (one out of seven cases). It is our recommendation that early primary amputation with an appropriate prosthesis should be considered, and that the final evaluation should not be based on obtaining bone union, but on the level of function of the lower extremity.

Reduced concentrations of soluble adhesion molecules after antioxidant supplementation in postmenopausal women with high cardiovascular risk profiles--a randomized double-blind study.

BACKGROUND: One of the suggested mechanisms of increased cardiovascular risk in postmenopause is a loss of the antioxidant effects of estrogens. It has been shown that classical cardiovascular risk factors increase oxidative stress on the arterial wall, and that endothelial cells react to this insult by increased expression of cellular adhesion molecules (CAM), which in turn are markers of arterial wall inflammation. METHODS: A randomized, placebo-controlled, double-blind study was performed in 60 postmenopausal women with high cardiovascular risk profiles, but free from clinical atherosclerotic disease. Patients were randomized to either antioxidant supplementation (using a combination of natural antioxidants; n = 30) or placebo (n = 30), and followed for 12 weeks. The concentrations of the adhesion molecules sVCAM-1 and sICAM-1 were measured by ELISA at baseline and at the end of the study, as well as total cholesterol, LDL, HDL, triglycerides and blood pressure. RESULTS: 27 women in the antioxidant supplementation group and 29 on placebo completed the study. At baseline, there were no significant differences in measured parameters between the groups: sICAM-1 concentrations were 341.8 +/- 116.9 vs. 349.9 +/- 104.6 ng/ml (active treatment vs. placebo; p = n.s.) and sVCAM-1 concentrations were 780.5 +/- 325.8 vs. 761.0 +/- 333.7 ng/ml (p = n.s.). In contrast, at the end of the study, sICAM-1 concentrations were 301.6 +/- 56.0 vs. 356.0 +/- 134.8 ng/ml (active treatment vs. placebo; p = 0.053) and sVCAM-1 concentrations were 656.0 +/- 326.5 vs. 818.5 +/- 381.0 ng/ml (p = 0.04). There were no significant differences between or changes within the groups in measured cholesterol and blood pressure. CONCLUSION: Antioxidant supplementation reduces serum concentrations of endothelium-derived adhesion molecules sICAM-1 and sVCAM-1 in postmenopausal women with high cardiovascular risk profiles.

Comparison of methods of fractional area change for detection of regional left ventricular dysfunction.

Three methods for assessment of fractional area change (FAC) and conventional versus cross-sectional segmentation were compared under conditions known to occur frequently during stress echocardiography. Quantitative analysis of 80 echocardiograms obtained from healthy subjects, patients with left ventricular (LV) dysfunction and after coronary artery bypass grafting included segmental and cross-sectional FACs by the centroid method with fixed and floating reference and a method with floating external reference. All segmental and cross-sectional FACs were equally sensitive to LV dysfunction, and segmental FACs failed to accurately predict the location of coronary lesions. The centroid method with floating reference and cross-sectional FACs were the least affected by surgery induced intrathoracic heart motion. In moderate to severe LV dysfunction FAC by the centroid method with floating reference and cross sections were rarely within normal limits. Cross-sectional FACs may prove to be useful in stress echocardiography. For viability studies segmental FAC by fixed reference appears to be the method of choice.

Results of complete soft tissue clubfoot release combined with calcaneocuboid fusion in the 4-year to 8-year age group following failed clubfoot release.

A subset of postoperative recurrent clubfeet was isolated in a group of patients 4 to 8 years old. Twenty-seven consecutive patients who underwent redo surgery consisting of complete soft tissue clubfoot release combined with a calcaneocuboid fusion were reviewed for this study. Twenty-six feet of 27 feet in 20 patients had a long-term good result, suggesting that this procedure is the one of choice for this age group.

Increased soluble platelet/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy.

BACKGROUND: Platelet-endothelial interactions modulated by adhesion molecules, may play an important role in the pathogenesis of congestive heart failure (CHF). Soluble levels of these molecules and platelet-derived substances are reportedly elevated in patients with CHF. However, no data are available on the plasma levels of Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1), and platelet-derived osteonectin in this growing population. METHODS AND RESULTS: Soluble levels by ELISA were prospectively determined in patients with severe CHF (n = 37) and correlated to etiology and antecedent aspirin use, and compared with 14 healthy control subjects. Left ventricular dysfunction was attributed to idiopathic dilated cardiomyopathy in 18 and coronary artery disease in 19 patients. Twenty-one patients were aspirin-free and 16 patients were using aspirin (81-500 mg daily). Elevated soluble PECAM-1 (51.31+/-2.44 ng/ml, P = 0.0001), and osteonectin (826.27+/-22.37 ng/ml, P = 0.0001) were observed in patients with CHF, as compared to healthy controls (32.56+/-1.21 ng/ml, and 478.02+/-31.32 ng/ml, respectively). Neither etiology of CHF, nor antecedent aspirin therapy significantly affects the levels of PECAM-1 or osteonectin. CONCLUSIONS: Despite long-term aspirin therapy and independently of the etiology of the disease, soluble PECAM-1 and osteonectin were elevated in the majority of patients with severe CHF, suggesting platelet-endothelial activation. The present data provide additional evidence that more potent anti-platelet and endothelial preservation regimens deserve further study in the heart failure population.

Dobutamine stress echocardiography to detect inducible demand ischemia in anesthetized patients with coronary artery disease.

BACKGROUND: A cardiac risk stratification test that can be performed during operation would be expected to give valuable information for the therapeutic management of patients who need urgent noncardiac surgery. This study was designed to evaluate the feasibility and safety of a dobutamine-atropine stress protocol to detect inducible demand ischemia in anesthetized patients. METHODS: A standard dobutamine-atropine stress protocol was performed in 80 patients with severe coronary artery disease during fentanyl-isoflurane anesthesia. Biplane transesophageal echocardiography and 12-lead electrocardiography were used to detect induced ischemia. After dobutamine testing, esmolol, nitroglycerin, or both were used to revert ischemia and any hemodynamic changes, as appropriate. RESULTS: The protocol detected inducible ischemia or achieved the target heart rate in 75 of the 80 (94%) patients. None of the prospectively defined adverse outcomes, such as cardiovascular collapse, severe ventricular arrhythmia, persistent (> or =5 min) ischemia, or hemodynamic instability, occurred in any of the patients. Ischemia was induced and detected in 73 of the 80 (91%) patients. CONCLUSION: Dobutamine stress echocardiography is feasible in anesthetized patients with severe coronary artery disease. The lack of serious complications and the high sensitivity to detect inducible ischemia in this patient population provide the basis for further evaluation of the safety and diagnostic value of dobutamine stress echocardiography during general anesthesia in larger studies of patients at risk for coronary artery disease undergoing noncardiac surgery.