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Introduction: Chest pain with ST-segment elevation is a rare clinical problem during dobutamine stress testing. Although beta-agonists treatment prior to dobutamine stress testing has been shown to reduce the duration and amount of dobutamine infusion and atropine requirement, there is insufficient information about potential complications of this pharmacologic combination., Case Presentation: We present a 67-year-old patient with dobutamine stress testing -induced chest pain and ST elevation who received albuterol for clinical treatment of bronchospastic disease prior to the test. She developed persistent chest pain and ST elevation despite medical management. Urgent cardiac catheterization showed no significant obstructive coronary artery disease. Thus coronary artery spasm was likely responsible for the chest pain and electrocardiogram abnormality in our patient as a result of beta-agonist and dobutamine combination., Conclusions: Beta-agonists pre-treatment with dobutamine stress testing may induce coronary spasm in association with chest pain and ST elevation. Clinicians and nuclear cardiologist should be aware of this potential side effect of beta-agonists treatment with dobutamine stress testing, particularly since dobutamine stress testing in nuclear cardiology is done in patient with chronic obstructive lung disease.

Nuclear cardiology has made significant advances since the first reports of planar scintigraphy for the evaluation of left ventricular perfusion and function. While the current "state of the art" of gated myocardial perfusion single-photon emission computed tomographic (SPECT) imaging offers invaluable diagnostic and prognostic information for the evaluation of patients with suspected or known coronary artery disease (CAD), advances in the cellular and molecular biology of the cardiovascular system have helped to usher in a new modality in nuclear cardiology, namely, molecular imaging. In this review, we will discuss the current state of the art in nuclear cardiology, which includes SPECT and positron emission tomographic evaluation of myocardial perfusion, evaluation of left ventricular function by gated myocardial perfusion SPECT and gated blood pool SPECT, and the evaluation of myocardial viability with PET and SPECT methods. In addition, we will discuss the future of nuclear cardiology and the role that molecular imaging will play in the early detection of CAD at the level of the vulnerable plaque, the evaluation of cardiac remodeling, and monitoring of important new therapies including gene therapy and stem cell therapy.

Graft arteriopathy (GA), characterized by diffuse concentric narrowing of coronary arteries, is the major cause of late graft failure in cardiac transplantation. alphavbeta3 Integrin is up-regulated in proliferating vascular cells and may constitute an appropriate target for imaging GA. We used a human/mouse chimeric model of GA, in which segments of human coronary artery were transplanted to severe combined immunodeficiency mice, followed by reconstitution with allogeneic human peripheral blood mononuclear cells (PBMC). This led to vascular remodeling characterized by neointima formation over a period of 4 wk. alphavbeta3 expression in the graft was minimal in animals without PBMC, considerably increased by 2 wk, and decreased toward baseline by 4 wk after PBMC reconstitution. Cell proliferation was maximal at 2 wk, correlating with peak alphavbeta3 expression. RP748, an 111In-labeled alphavbeta3 (active conformation)-targeted radiotracer was injected into groups of 5 recipients at 0, 2, and 4 wk after PBMC reconstitution. Relative uptakes, defined as autoradiographic intensity in the graft/native aortas closely tracked the proliferative process. Specificity of uptake was demonstrated using excess nonlabeled tracer. In conclusion, alphavbeta3 integrin is transiently up-regulated (and activated) in GA and may be targeted by RP748 for detection of the proliferative process in early GA.

Background: The alpha(v)beta3 integrin plays a critical role in cell proliferation and migration. We hypothesized that vascular cell proliferation, a hallmark of injury-induced remodeling, can be tracked by targeting alpha(v)beta3 integrin expression in vivo., Methods and Results: RP748, a novel 111In-labeled alpha(v)beta3-specific radiotracer, was evaluated for its cell-binding characteristics and ability to track injury-induced vascular proliferation in vivo. Three groups of experiments were performed. In cultured endothelial cells (ECs), TA145, a cy3-labeled homologue of RP748, localized to alpha(v)beta3 at focal contacts. Activation of alpha(v)beta3 by Mn2+ led to increased EC binding of TA145. Left common carotid artery wire injury in apolipoprotein E-/- mice led to vascular wall expansion over a period of 4 weeks. RP748 (7.4 MBq) was injected into groups of 9 mice at 1, 3, or 4 weeks after left carotid injury, and carotids were harvested for autoradiography. Relative autographic intensity, defined as counts/pixel of the injured left carotid area divided by counts/pixel of the uninjured right carotid area, was higher at 1 and 3 weeks (1.8+/-0.1 and 1.9+/-0.2, respectively) and decreased significantly by 4 weeks after injury (1.4+/-0.1, P<0.05). Carotid alpha(v) and beta3 integrin expression was maximal at 1 week and decreased by 4 weeks after injury. The proliferation index, as determined by Ki67 staining, followed a temporal pattern similar to that of RP748 uptake. Dynamic gamma imaging demonstrated rapid renal clearance of RP748., Conclusions: RP748 has preferential binding to activated alpha(v)beta3 integrin and can track the injury-induced vascular proliferative process in vivo.

Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.

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., (Copyright 2004 Elsevier Inc.)

Background: Congestive heart failure (CHF) is among the most serious toxicities of doxorubicin, a potent cancer chemotherapeutic agent. Serial left ventricular ejection fraction (LVEF) monitoring during doxorubicin therapy for preventing CHF was proposed over 20 years ago. The current utility and cost-effectiveness of this approach in the present era are not known., Methods and Results: Clinical and follow-up data of 265 patients with cancer (age, 53 +/- 14 years; 76% women) undergoing doxorubicin chemotherapy with serial equilibrium radionuclide angiocardiography (ERNA) monitoring (> or =2 studies) were analyzed retrospectively. Patients with a normal baseline LVEF (> or =50%) and a 10% or greater point fall in LVEF to a final value of less than 50% during doxorubicin therapy were considered "at risk" for CHF (n = 41). Over 679 +/- 426 days of follow-up, 7 patients (2.6%) had CHF develop and 90 (34%) died (all cancer-related deaths, with none due to CHF). A comparison of "at-risk" (n = 41 [15%]) and "low-risk" (n = 224 [85%]) groups showed a higher incidence of CHF (12% vs 0.9%, P <.0001), lower baseline LVEF (58% +/- 8% vs 64% +/- 8%, P <.0001), lower value for the lowest LVEF (42% +/- 8% vs 57% +/- 7%, P <.0001), and higher rate of cancer-related deaths (59% vs 29%, P =.0003) in the former despite similar cumulative doxorubicin dose (304 +/- 124 mg/m(2) vs 284 +/- 110 mg/m(2), P = not significant). There were no differences in age, gender, cancer type, and co-morbidity. Cost analysis showed the overall cost of ERNA studies to be lower than the 1-year cost of caring for additional cases of CHF that would potentially be prevented by routine LVEF monitoring., Conclusions: An incipient fall in LVEF detected on serial ERNA during doxorubicin therapy provides an appropriate and cost-effective approach for predicting and preventing impending CHF. Use of this approach was associated with a low incidence of CHF (2.6%) and no CHF-related mortality in this study.

Background: Adenosine is commonly used for pharmacologic stress myocardial perfusion imaging (MPI). However, it frequently results in adverse effects, and the subdiaphragmatic tracer uptake may interfere with the image interpretation. Our aim was to determine the feasibility of combining low-level treadmill exercise with adenosine MPI and its impact on adverse effects, image quality, and myocardial ischemia., Methods and Results: Forty-one patients underwent technetium 99m sestamibi single photon emission computed tomography following adenosine and adenosine with low-level exercise (adenosine-Ex) on separate occasions and rest MPI. A comparison was made of symptoms, hemodynamic response, electrocardiographic changes, image quality, and image interpretation between the 2 protocols. With adenosine-Ex, fewer patients had one or more adverse effects (61% vs 90%; P =.006), more patients had ischemic electrocardiographic changes (34% vs 15%; P =.03), a higher percentage had excellent- or fair-quality images (88% vs 61%; P =.003), and they had higher heart-liver ratios (1.0 +/- 0.37 vs 0.84 +/- 0.29; P =.002) compared with adenosine alone. Four adenosine MPI studies, but only 2 adenosine-Ex studies, were uninterpretable because of excessive subdiaphragmatic radiotracer activity. Of the 39 patients with at least 1 interpretable stress study, interpretation was discordant in 11 (28%): 7 showed greater ischemia with adenosine-Ex, 2 uninterpretable adenosine studies were interpretable with adenosine-Ex, and 2 studies interpreted as abnormal with adenosine were normal by adenosine-Ex (both had normal coronary angiograms)., Conclusions: Simultaneous low-level treadmill exercise with adenosine Tc-99m sestamibi imaging is safe and feasible, significantly reduces unfavorable side effects, enhances image quality, and may result in greater ischemia detection compared with adenosine alone.

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.

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.

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.

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., (Copyright 1999 The European Society of Cardiology.)

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.