G551D CF mice display an abnormal host response and have impaired clearance of Pseudomonas lung disease

Several cystic fibrosis (CF) mouse models demonstrate an increased susceptibility to Pseudomonas aeruginosa lung infection, characterized by excessive inflammation and high rates of mortality. Here we developed a model of chronic P. aeruginosa lung disease in mice homozygous for the murine CF transmembrane conductance regulator G551D mutation that provides an excellent model for CF lung disease. After 3 days of infection with mucoid P. aeruginosa entrapped in agar beads, the G551D animals lost substantially more body weight than non-CF control animals and were less able to control the infection, harboring over 40-fold more bacteria in the lung. The airways of infected G551D animals contained altered concentrations of the inflammatory mediators tumor necrosis factor-alpha, KC/N51, and macrophage inflammatory protein-2 during the first 2 days of infection, suggesting that an ineffective inflammatory response is partly responsible for the clearance defect.

Clopidogrel: A CURE in acute coronary syndromes? (A Key Paper Evaluation)

The standard approach to preventing acute coronary syndromes (ACSs)has been to inhibit platelet aggregation with aspirin and to inhibit blood coagulation with low molecular-weight heparin (LMWH). Even with this combination there is still a substantial short and long-term cardiovascular risk. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [1] compared clopidogrel plus aspirin against aspirin alone in patients with ACSs. The clopidogrel regimen was a loading dose of 300 mg p.o. followed by 75 mg/day and the recommended dose of aspirin was 75 - 325 mg/day. The first primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke and this occurred significantly less often in the clopidogrel than the placebo group (9.3 vs. 11.4%). Although there were more clopidogrel patients with life-threatening bleeding (clopidogrel 2.2%, placebo 1.8%), this represented GI haemorrhages and bleeding at sites of arterial puncture rather than fatal bleeding. This trial suggests a role for clopidogrel in the long-term treatment of ACSs

Determinants of tissue Doppler measures of regional diastolic function during dobutamine stress echocardiography

Background Diastolic dysfunction induced by ischemia may alter transmitral blood flow, but this reflects global ventricular function, and pseudonormalization may occur with increased preload. Tissue Doppler may assess regional diastolic function and is relatively load-independent, but limited data exist regarding its application to stress testing. We sought to examine the stress response of regional diastolic parameters to dobutomine echocardiography (DbE). Methods Sixty-three patients underwent study with DbE: 20 with low probability of coronary artery disease (CAD) and 43 with CAD who underwent angiography. A standard DbE protocol was used, and segments were categorized as ischemic, scar, or normal. Color tissue Doppler was acquired at baseline and peak stress, and waveforms in the basal and mid segments were used to measure early filling (Em), late filling (Am), and E deceleration time. Significant CAD was defined by stenoses >50% vessel diameter. Results Diastolic parameters had limited feasibility because of merging of Em and Am waves at high heart rates and limited reproducibility. Nonetheless, compared with normal segments, segments subtended with significant stenoses showed a lower Em velocity at rest (6.2 +/- 2.6 cm/s vs 4.8 +/- 2.2 cm/s, P < .0001) and peak (7.5 +/- 4.2 cm/s vs 5.1 +/- 3.6 cm/s, P < .0001), Abnormal segments also showed a shorter E deceleration time (51 +/- 27 ms vs 41 +/- 27 ms, P = .0001) at base and peak. No changes were documented in Am. The same pattern was seen with segments identified as ischemic with wall motion score. However, in the absence of ischemia, segments of patients with left ventricular hypertrophy showed a lower Em velocity, with blunted Em responses to stress. Conclusion Regional diastolic function is sensitive to ischemia. However, a number of practical limitations limit the applicability of diastolic parameters for the quantification of stress echocardiography.

Development of a fully quantitative approach to the interpretation of stress echocardiography using radial and longitudinal myocardial velocities

Background: Tissue Doppler may be used to quantify regional left ventricular function but is limited by segmental variation of longitudinal velocity from base to apex and free to septal walls. We sought to overcome this by developing a composite of longitudinal and radial velocities. Methods and Results. We examined 82 unselected patients undergoing a standard dobutamine echocardiogram. Longitudinal velocity was obtained in the basal and mid segments of each wall using tissue Doppler in the apical views. Radial velocities were derived in the same segments using an automated border detection system and centerline method with regional chords grouped according to segment location and temporally averaged. In 25 patients at low probability of coronary disease, the pattern of regional variation in longitudinal velocity (higher in the septum) was the opposite of radial velocity (higher in the free wall) and the combination was homogenous. In 57 patients undergoing angiography, velocity in abnormal segments was less than normal segments using longitudinal (6.0 +/- 3.6 vs 9.0 +/- 2.2 cm/s, P = .01) and radial velocity (6.0 +/- 4.0 vs 8.0 +/- 3.9 cm/s, P = .02). However, the composite velocity permitted better separation of abnormal and normal segments (13.3 +/- 5.6 vs 17.5 +/- 4.2 cm/s, P = .001). There was no significant difference between the accuracy of this quantitative approach and expert visual wall motion analysis (81% vs 84%, P = .56). Conclusion: Regional variation of uni-dimensional myocardial velocities necessitates site-specific normal ranges, probably because of different fiber directions. Combined analysis of longitudinal and radial velocities allows the derivation of a composite velocity, which is homogenous in all segments and may allow better separation of normal and abnormal myocardium.

Use of stress echocardiography to predict mortality in patients with diabetes and known or suspected coronary artery disease

OBJECTIVE - This study sought to determine whether stress echocardiography using exercise (when feasible) or dobutamine echo could be used to predict mortality in patients with diabetes. RESEARCH DESIGN AND METHODS - Stress echo was performed in 937 patients with diabetes (aged 59 +/- 13 years, 529 men) for symptom evaluation (42%) and follow-up of known coronary artery disease (CAD) (58%). Stress echocardiography using exercise was performed in 333 patients able to exercise maximally, and dobutamine echo using a standard dobutamine stress was used in 604 patients. Patients were followed for less than or equal to9 years (mean 3.9 +/- 2.3) for all-cause mortality. RESULTS - Normal studies were obtained in 567 (60%) patients; 29% had resting left ventricular (LV) dysfunction, and 25% had ischemia. Abnormalities were confined to one territory in 183 (20%) patients and to multiple territories in 187 (20%) patients. Death (in 275 [29%] patients) was predicted by referral for pharmacologic stress (hazard ratio [HR] 3.94, P < 0.0001), ischemia (1.77, P <0.0001), age (1.02, P = 0.002), and heart failure (1.54, P = 0.01). The risk of death in patients With a normal scan was 4% per year, and this was associated with age and selection for pharmacologic stress testing. In stepwise models replicating the sequence of clinical evaluation, the predictive power of independent clinical predictors (age, selection for pharmacologic stress, previous infarction, and heart failure; model chi(2) = 104.8) was significantly enhanced by addition of stress echo data (model chi(2) = 122.9). CONCLUSIONS - The results of stress echo are independent predictors of death in diabetic patients with known or suspected CAD.. Ischemia adds risk that is incremental to clinical risks and LV dysfunction.

Prediction of outcomes in hypertensive patients with suspected coronary disease

Stress echocardiography has been shown to improve the diagnosis of coronary artery disease in the presence of hypertension, but its value in prognostic evaluation is unclear. We sought to determine whether stress echocardiography could be used to predict mortality in 2363 patients with hypertension, who were followed for up to 10 years (mean 4.0+/-1.8) for death and revascularization. Stress echocardiograms were normal in 1483 patients (63%), 16% had resting left ventricular (LV) dysfunction alone, and 21% had ischemia. Abnormalities were confined to one territory in 489 patients (21%) and to multiple territories in 365 patients (15%). Cardiac death was less frequent among the patients able to exercise than among those undergoing dobutamine echocardiography (4% versus 7%, P<0.001). The risk of death in patients with a negative stress echocardiogram was <1% per year. Ischemia identified by stress echocardiography was an independent predictor of mortality in those able to exercise (hazard ratio 2.21, 95% confidence intervals 1.10 to 4.43, P=0.0001) as well as those undergoing dobutamine echo (hazard ratio 2.39, 95% confidence intervals 1.53 to 3.75, P=0.0001); other predictors were age, heart failure, resting LV dysfunction, and the Duke treadmill score. In stepwise models replicating the sequence of clinical evaluation, the results of stress echocardiography added prognostic power to models based on clinical and stress-testing variables. Thus, the results of stress echocardiography are an independent predictor of cardiac death in hypertensive patients with known or suspected coronary artery disease, incremental to clinical risks and exercise results.

Quality of care of patients hospitalized with acute coronary syndromes

Background: Measurement and improvement of quality of care is a priority issue in health care. Patients hospitalized with acute coronary syndromes (ACS) constitute a high-risk population whose care, if shown to be suboptimal on the basis of available research evidence, may benefit from quality improvement interventions. Aim: To evaluate the quality of in-hospital care for patients with ACS, using explicit quality indicators. Methods: Retrospective case note review was undertaken of 397 patients admitted to three teaching hospitals in Brisbane, Queensland, Australia, between 1 October 2000 and 17 April 2001. The main out-come measures were 12 process-of-care quality indicators, calculated as either: (i) the proportion of all patients who received specific interventions or (ii) the proportion of ideal patients who received -specific interventions (i.e. patients with clear indi-cations and lacking contraindications). Results: Quality indicators with values above 80% included: (i) patient selection for thrombolysis (100%) and discharge prescription of beta-blockers (84%), (ii) antiplatelet agents (94%) and (iii) lipid-lowering agents (82%). Indicators with values between 50% and 80% included: (i) timely per-formance of electrocardiogram (ECG) on admission (61%), (ii) early coronary angiography (75%), (iii) measurement of serum lipids (71%) and (iv) discharge prescription of angiotensin-converting-enzyme (ACE) inhibitors (73%). Indicators with values <50% included: (i) timely administration of thrombolysis (35%), (ii) non-invasive risk assessment (23%) and (ii) formal in-hospital and post-hospital cardiac rehabilitation (47% and 7%, respectively). Conclusion: There were delays in performing ECG and administering thrombolysis to patients who presented to emergency departments with ACS. Improvement is warranted in use of non-invasive procedures for identifying high-risk patients who may benefit from coronary revascularization as well as use of serum lipid measurements, ACE inhibitors and cardiac rehabilitation.

Refinements in stress echocardiographic techniques improve inter-institutional agreement in interpretation of dobutamine stress echocardiograms

Aims To determine the degree of inter-institutional agreement in the assessment of dobutamine stress echocardiograms using modern stress echo cardiographic technology in combination with standardized data acquisition and assessment criteria. Method and Results Among six experienced institutions, 150 dobutamine stress echocardiograms (dobutamine up to 40 mug.kg(-1) min(-1) and atropine up to I mg) were performed on patients with suspected coronary artery disease using fundamental and harmonic imaging following a consistent digital acquisition protocol. Each dobutamine stress echocardiogram was assessed at every institution regarding endocardial visibility and left ventricular wall motion without knowledge of any other data using standardized reading criteria. No patients were excluded due to poor image quality or inadequate stress level. Coronary angiography was performed within 4 weeks. Coronary angiography demonstrated significant coronary artery disease (less than or equal to50% diameter stenosis) in 87 patients. Using harmonic imaging an average of 5.2+/-0.9 institutions agreed on dobutamine stress echocardiogram results as being normal or abnormal (mean kappa 0.55; 95% CI 0.50-0.60). Agreement was higher in patients with no (equal assessment of dobutamine stress echocardiogram results by 5.5 +/- 0.8 institutions) or three-vessel coronary artery disease (5.4 +/- 0.8 institutions) and lower in one- or two- vessel disease (5.0 +/- 0.9 and 5.2 +/- 1.0 institutions, respectively-, P=0.041). Disagreement on test results was greater in only minor wall motion abnormalities. Agreement on dobutamine stress echocardiogram results was lower using fundamental imaging (mean kappa 0.49; 95% CI 0.44-0.54; P

Myocardial infarction and type II diabetes - preferential treatment for high risk patients?

Objectives: To compare variability of blood glucose concentration in patients with type II diabetes with (cases) and without (controls) myocardial infarction. A secondary objective was identification of predictive factors for higher blood glucose on discharge from hospital. Design: A retrospective matched case-control study. Participants: Medical notes of 101 type II diabetic patients admitted with a myocardial infarction (MI) and 101 type II diabetic patients (controls) matched on gender and age with no MI were reviewed. Blood glucose concentrations over two consecutive 48-h periods were collected. Demographic data and therapy on admission/discharge were also collected. Results: Patient characteristics were comparable on recruitment excluding family history of cardiovascular disease (P =0.003), dyslipidaemia (P =0.004) and previous history of MI (P =0.007). Variability of blood glucose in cases was greater over the first 48 h compared with the second 48 h (P =0.03), and greater when compared with controls over the first 48 h (P =0.01). Cases with blood glucose on discharge >8.2 mmol / L (n =45) were less likely to have a history of previous MI (P =0.04), ischaemic heart disease (P =0.03) or hypertension (P =0.02). Conclusions: Type II diabetics with an MI have higher and more variable blood glucose concentrations during the first 48 h of admission. Only cardiovascular 'high risk' patients had target blood glucose set on discharge. The desirability of all MI patients with diabetes, having standardized-glucose infusions to reduce variability of blood glucose, should be evaluated in a randomized controlled trial.

Macrophages, myofibroblasts and neointimal hyperplasia after coronary artery injury and repair

Macrophages participate in the restenosis process through the release of cytokines, metalloproteinases and growth factors. Studies of peritoneal granulation tissue suggest that macrophages may be precursors of myofibroblasts. This study examined the contribution of monocyte/macrophage lineage cells to neointimal cellular mass in a porcine model of thermal vascular injury. Thermal coronary artery injury caused medial smooth muscle cell necrosis and transformation of the media into an extracellular matrix barrier. The neointimal hyperplasia that developed over the injury sites was evaluated by light microscopy, electron microscopy and immunohistochemistry. At day 3, blood monocytes were adhered to the vessel wall and infiltrated the fibrotic media. At day 14, 42 +/- 3.9% of neointimal cells had a monocytic nuclear morphology and expressed macrophage-specific antigen SWC3 (identified by monoclonal antibody DH59B). Moreover, 9.2+/-1.8% of neointimal cells co-expressed SWC3 and alpha-smooth muscle actin and had ultrastructural characteristics intermediate between macrophages and myofibroblasts. At day 28, 10.5 +/- 3.5%, of cells expressed SWC3 and 5.2+/-1.8% of cells co-expressed SWC3 and alpha-smooth muscle actin. This study indicates that hematopoietic cells of monocyte/macrophage lineage abundantly populate the neointima in the process of lesion formation and may be precursors of neointimal myofibroblasts after thermal vascular injury. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.