Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction.

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.

Nuclear cardiology: present and future.

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.

Alphavbeta3-targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study.

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.

Detection of injury-induced vascular remodeling by targeting activated alphavbeta3 integrin in vivo.

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.

Dobutamine stress test and beta-agonist - a potential concern for nuclear cardiology testing: a case report.

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.

Second Annual Mario S. Verani, MD, Memorial Lecture: Nuclear cardiology, the next 10 years.

The nuclear cardiology of the future will be based on new clinical and biologic targets. It will be driven by modern concepts of molecular and cell biology and molecular genetics. A major effort involves detection of atherosclerosis and vascular vulnerability. Approaches include targeting proliferating smooth muscle cells, angiogenesis, vascular injury, inflammation through a variety of mechanisms, defining cell death and protease activation, and imaging gene expression. Another new clinical target involves imaging stem cells and various progenitor cells. To meet these new objectives, advanced imaging technology is required. This involves the development of micro-single photon emission computed tomography and micro-positron emission tomography systems as well as fusion technology involving radiologic computed tomography imaging together with nuclear imaging. Vascular lesion detection imaging may require intravascular detectors. The future of nuclear cardiology, based on molecular imaging, is extraordinarily exciting. The newly defined biologic targets will allow the answering of many of the key clinical questions that will dominate cardiovascular care in cardiovascular investigation over the next decade.

Pharmacologic stress perfusion imaging with adenosine: role of simultaneous low-level treadmill exercise.

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.

Doxorubicin cardiotoxicity: prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era.

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.