Vascular cell adhesion molecule-1-targeted detection of endothelial activation in human microvasculature.

The hallmark of endothelial activation, an early and critical step in many alloimmune and inflammatory responses, is the transcriptional induction and expression of endothelial adhesion molecules (eg, vascular cell adhesion molecule-1 [VCAM-1]). We assessed the feasibility of VCAM-1-targeted in vivo detection of endothelial activation using I-125-labeled-F(ab')2 fragments of E1/6, a monoclonal antibody against human but not murine VCAM-1. The Kd and Bmax, determined by saturation binding in tumor necrosis factor (TNF)-activated human endothelial cells (ECs), were 3.2 +/- 0.6 nmol/L and 5600 +/- 300 binding sites per EC, respectively. Biodistribution and in vivo binding characteristics of I-125-E1/6 F(ab')2 were assessed in a novel chimeric human/mouse model, in which human skin (as a source of human microvasculature) is grafted onto SCID/beige mice. I-125-E1/6 F(ab')2 localized to TNF-activated human skin grafts as detected by autoradiography and gamma well-counting. Relative uptakes (uptake in human skin graft/uptake in the surrounding mouse skin) were, respectively, 2.6 +/- 0.8 (n = 14) and 1.6 +/- 0.3 (n = 12) for E1/6 and MOPC-21, an isotype-matched control antibody (P < .01). The preferential uptake in human skin graft was not due to differences in tissue vascularity assessed by Tc-99m-labeled murine red blood cells. In conclusion, the chimeric human/mouse model is a novel experimental tool for in vivo evaluation of human endothelial cell-specific radiopharmaceuticals. Although I-125-E1/6 F(ab')2 localized to human skin grafts, the limited number of VCAM-1 molecules/endothelial cell adversely affects its suitability as a target for in vivo imaging of endothelial activation.

The Connecticut Cardiovascular Consortium: a unique, state-wide research collaboration to advance clinical outcomes in patients with heart disease.

The establishment of "best clinical practices" founded upon evidence-based medicine has become an increasingly important priority. Frequently, management guidelines are derived from published research data and disseminated among practitioners to help optimize patient care. The ultimate clinical impact of these guidelines in the "real world," however, is often clouded by an incomplete assessment of patient outcomes throughout the continuum of health-care delivery models. In order to address this gap in clinical outcome assessment, we propose to establish the Connecticut Cardiovascular Consortium. The Consortium will consist of a collaborative partnership among all 31 Connecticut hospitals working in concert with Connecticut Office of Health Care Access (OHCA). The primary objective of the Consortium will be to assess, compare, and optimize clinical outcomes among Connecticut residents with cardiovascular disease. As an initial goal for the Consortium, we further propose to undertake a prospective, observational study of Connecticut residents who present with ST Segment Elevation Acute Myocardial Infarction (STEMI). Recent advances in pharmacologic and mechanical reperfusion for STEMI have resulted in a need to define the optimal use of these therapies in the community at large. The primary purpose of this study will be to determine the relative merits of different treatment patterns for STEMI with regard to the use of fibrinolytic therapy and percutaneous coronary intervention (PCI). Particular emphasis will be placed on assessing the relative benefits of urgent mechanical revascularization performed at the state's seven tertiary facilities with PCI capability compared to all other treatment modalities. Successful completion of this unique collaborative endeavor is expected to have significant impact on improved patient care and on current health-care policy for medical resource allocation. Moreover, continued collaboration of health-care providers within the Connecticut Cardiovascular Consortium infrastructure should serve as a useful mechanism for ongoing improvements in evidence-based cardiovascular medicine and clinical research in the state of Connecticut.

Day-to-day reproducibility of mental stress-induced abnormal left ventricular function response in patients with coronary artery disease and its relationship to autonomic activation.

BACKGROUND: Mental stress (MS) results in left ventricular (LV) dysfunction in approximately half of the patients with symptomatic coronary artery disease (CAD) and is an adverse prognostic sign. The reproducibility of various MS tasks in inducing LV dysfunction and its relationship to autonomic activation in patients with CAD are not known. We studied the reproducibility on different days of 3 commonly used MS tasks on LV ejection fraction (LVEF), heart rate, blood pressure, and rate-pressure product and the relationship of reproducibility to autonomic activation as determined by heart rate variability in patients with chronic stable angina. METHODS AND RESULTS: Ten patients with CAD and exercise-induced ischemia who had abnormal LVEF responses to at least one MS task from a battery of MS tasks (mental arithmetic, anger recall, and color Stroop test) while undergoing continuous ambulatory Holter and LV function monitoring underwent a second MS testing 4 to 8 weeks later, with no change in clinical status or cardiac medications in the interim. Autonomic tone was determined from indexes of heart rate variability (high frequency [HF] for parasympathetic activity and low frequency [LF] and low frequency/high frequency ratio [LF/HF] for sympathetic activity). MS tasks resulted in a small increase in heart rate (P <.0001), a modest increase in systolic blood pressure (P <.0001) and the rate-pressure product (P <.0001), and a small but statistically significant increase in LF (P <.002) and LF/HF (P <.0001), but no change in HF compared with baseline. These changes were highly reproducible over the 2 studies. With a fall in LVEF of 5% or greater considered as indicative of an MS-positive task, anger recall was the most effective and reproducible MS task in inducing LV dysfunction. MS-positive tasks were associated with a greater increase in systolic blood pressure (P =.005). Anger recall resulted in a trend toward a higher increase in systolic blood pressure (P =.08) than the other MS tasks. In MS tasks with inconsistent LVEF responses in the 2 studies (LV dysfunction present in one study but not in the other), there was significant parasympathetic withdrawal (P =.02) in MS-negative tasks but no difference in sympathetic activation. On the other hand, in MS tasks with consistent LV dysfunction on both occasions, there was no difference in parasympathetic or sympathetic activation. MS-positive tasks were not accompanied by chest pain or ST depression. CONCLUSIONS: Of the commonly used MS tasks, anger recall produces LV dysfunction with the highest frequency and is the most reproducible task when retested 4 to 8 weeks later in patients with CAD. These data are relevant for planning studies of the effects of therapeutic interventions on MS-induced LV dysfunction.

Myocardial blood-flow response during mental stress in patients with coronary artery disease.

Positron emission tomography was used to quantify changes in myocardial blood flow during mental stress in patients with and without coronary artery disease. Blunted augmentation of myocardial blood flow during mental stress was observed in regions without significant epicardial stenosis.

Quantification of regional myocardial wall thickening on electrocardiogram-gated SPECT imaging.

BACKGROUND: Current assessment of regional left ventricular function with electrocardiogram (ECG)-gated single photon emission computed tomography (SPECT) imaging is generally performed by visual inspection. The objective of this study was to develop and validate a new computer algorithm for quantifying regional left ventricular wall thickening on ECG-gated SPECT images. METHODS: Regional wall thickening was measured from count density changes during the cardiac cycle observed in 24-sector circumferential count distribution profiles generated from each of 8 frames of an ECG-gated SPECT study. Wall thickening was expressed as the percent count increase during systole relative to end diastole. The program was tested in a phantom simulation and in patient studies consisting of a pilot study (n = 40) and a validation study (n = 33). In the phantom study varying degrees of wall thickening were simulated. The pilot study included 20 normal subjects with low likelihood (<3%) of coronary disease and 20 patients with prior myocardial infarction. Mean wall thickening - 2 standard deviations, measured in normal subjects, defined the lower limit of normal wall thickening. This criterion was tested in the validation study in 13 normal subjects and 20 patients with prior myocardial infarction. Abnormal wall thickening was characterized by extent (percent of circumferential profile) and severity (minimal thickening). RESULTS: The phantom study showed excellent linear correlation between wall thickening computed by the new software and actual wall thickening (r = 0.98). Interobserver and intraobserver reproducibility of quantitative assessment of minimal wall thickening were excellent (r = 0.98 and 0.99, P < .001). Regional wall thickening varied considerably from apex to base in the same ventricle among normal subjects. The average lower limit of normal wall thickening was 25% to 30% at the apex, 19% to 24% in the mid-ventricle, and 13% to 20% at the base of the left ventricle. In the validation study 11 of 13 normal subjects had wall thickening profiles within the pre-defined normal range. All 20 patients with prior myocardial infarction had abnormal regional wall thickening. Minimal regional wall thickening in the infarct areas was 5.4% +/- 5.5%, compared with 30.1% +/- 9.1% wall thickening in comparable anatomic areas in normal subjects (P < .001). CONCLUSION: Regional wall thickening can be quantified reliably from regional count density changes during the cardiac cycle on ECG-gated SPECT images. The new software measured the extent and severity of abnormal regional wall thickening relative to normal files. The method is highly reproducible. Clinical validation showed good differentiation between normal subjects and patients with prior infarction. Quantification of regional wall thickening may enhance diagnostic accuracy and reproducibility of interpretation of gated SPECT imaging.

Factors associated with failure of medical therapy in patients with unstable angina and non-Q wave myocardial infarction. A TIMI-IIIB database study.

CONTEXT: Current management of patients with unstable angina and non-Q wave myocardial infarction generally consists of intensive medical therapy, with angiography and revascularization sometimes limited to those who fail such therapy. AIM: To determine if certain baseline characteristics are predictive of patients who fail medical therapy, since such patients could then be expeditiously directed to a more invasive strategy in a cost-effective manner. METHODS: The study cohort consisted of the 733 patients in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB study who were randomized to conservative strategy. Patients were to be treated with bedrest, anti-ischaemic medications, aspirin, and heparin, and were to undergo risk-stratifying tests, consisting of an exercise test with ECG and thallium scintigraphy, scheduled to be performed within 3 days prior to, or 5 days after, hospital discharge and 24 h Holter monitoring scheduled to begin 2-5 days after randomization. Baseline clinical and ECG characteristics were compared between patients who 'failed' medical therapy and those who did not 'fail'. Failure was defined using clinical end-points (death, myocardial infarction, or spontaneous ischaemia by 6 weeks after randomization) or a strongly positive risk-stratifying test. For each test an ordered failure profile of results was calculated and consisted of death, myocardial infarction, or rest ischaemia occurring prior to performance of the test, a markedly abnormal test result, and no abnormality. RESULTS: Clinical end-points occurred in 241 (33%) patients and were more likely to occur in patients who at presentation were older, had ST-segment depression on the qualifying ECG, or were being treated with heparin or aspirin. Characteristics independently predictive of developing a clinical event or an abnormal exercise treadmill test included: ST-segment depression on the qualifying ECG, history of prior angina, family history of premature coronary disease (i.e. onset <55 years of age), prior use of heparin or aspirin, and increasing age. By combining these baseline risk characteristics for each outcome the incidence of developing a clinical event ranged from 8% if none was present to 63% if all six were present, and of developing a markedly abnormal risk stratifying test from 8-21% if none were present to approximately 90% if all six were present. CONCLUSIONS: Baseline characteristics associated with developing a clinical event or a markedly abnormal risk stratifying test were similar: rest anginal episode accompanied by ST-segment depression and occurring despite treatment with aspirin and heparin, a history of angina, older age, and family history of coronary disease. Patients with these characteristics are appropriate candidates for expeditious cardiac catheterization and consideration for revascularization, while patients without them may be suitable for medical management alone.

Quantification of SPECT myocardial perfusion images: methodology and validation of the Yale-CQ method.

BACKGROUND: Quantification of single photon emission computed tomography (SPECT) images is important for reproducible and accurate image interpretation. In addition, SPECT quantification provides important prognostic information. The purpose of this study was to validate the Yale circumferential quantification (Yale-CQ) method in phantom studies. METHODS: Myocardial perfusion defects of varying extent and severities were simulated in a cardiac phantom with fillable defect inserts. Forty-five different phantom configurations simulated 45 different myocardial perfusion defect sizes, ranging from 1.6% to 32% of the cardiac phantom volume. Automatic processing was compared with manual processing in the phantom SPECT studies. RESULTS: The automatic Yale-CQ algorithm performed well in all phantom studies. Compared with manual processing, the mean absolute error for automatically determined center of short axis slices was 0.27 pixel in the x direction, 0.45 pixel in the y direction, and 0.15 pixel in radius. Quantification of phantom defects with the Yale-CQ method correlated well with actual defect sizes (R = 0.99), but there was a systematic underestimation (mean error = -7.9%). With derived correction factors the overall correlation between 45 phantom defects and actual defect sizes was excellent, and the estimation error was significantly improved (R = 0.98, mean error = -0.82% for manual method and -0.95% for automatic method). CONCLUSION: The automatic processing algorithm performs well for the phantom studies. Myocardial perfusion abnormalities can be quantified accurately by use of the Yale-CQ method. Quantified SPECT defect size can be expressed as a percentage of the left ventricle.