Barry L. Zaret

Serial Assessment of Doxorubicin Cardiotoxicity with Quantitative Radionuclide Angiocardiography

We measured cardiac performance sequentially, using quantitative radionuclide angiocardiography to estimate left ventricular ejection fraction in 55 patients receiving doxorubicin for treatment of cancer. With final doxorubicin dosages greater than 350 mg per square meter, the lowest ejection fraction measured was significantly less than the initial determination. Five patients had severe cardiotoxicity (congestive heart failure). All had an ejection fraction of less than 30 per cent at the time of heart failure, and demonstrated moderate cardiotoxicity (a decline in ejection fraction by at least 15 per cent to a final value of less than 45 per cent) before clinical manifestations. Six patients with moderate toxicity in whom doxorubicin was discontinued did not have heart failure or a further decline in ejection fraction during the follow-up period. Moderate toxicity was continued, but mild toxicity (decline of ejection fraction by greater than 10 per cent, noted in 11 patients) was not well predicted. The assessment of radionuclide left ventricular ejection fraction during doxorubicin therapy may make it possible to avoid congestive heart failure.

Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: Seven-year experience using serial radionuclide angiocardiography

To impact on the development of clinical congestive heart failure as a complication of doxorubicin therapy, left ventricular ejection fraction was monitored with serial resting radionuclide angiocardiography in 1,487 patients with cancer over a seven-year period in both university and community hospital environments. A high-risk subset of 282 patients was selected for retrospective analysis of their clinical outcome. High-risk patients were identified by one or two of the following three criteria: decline of 10 percent or more in absolute left ventricular ejection fraction from a normal baseline to 50 percent or less; high cumulative dose of doxorubicin (more than 450 mg/m2); abnormal baseline left ventricular ejection fraction (less than 50 percent). Clinical congestive heart failure occurred in 46 (16 percent) during the treatment period, and in an additional three patients (1.3 percent) at last follow-up examination 11.8 +/- 14.2 months following discontinuation of doxorubicin. Total cumulative dosages of doxorubicin that precipitated congestive heart failure (75 to 1,095 mg/m2) and those that did not (30 to 880 mg/m2) varied widely. Decline of 10 percent or more in absolute left ventricular ejection fraction to a value of 50 percent or less preceded administration of the final dose of doxorubicin that precipitated clinical congestive heart failure in the majority of patients in whom congestive heart failure developed. Clinical congestive heart failure improved in 87 percent given routine therapy with digitalis, diuretics, and/or vasodilators. Criteria for monitoring left ventricular ejection fraction and discontinuing doxorubicin were formulated. The occurrence of clinical congestive heart failure was compared in those patients whose management was concordant with proposed criteria (Group A) and in those whose management was not (Group B). Group A had a lower incidence of congestive heart failure compared with Group B (2.9 percent versus 20.8 percent, p less than 0.001) and had only mild congestive heart failure that resolved with treatment (n = 2) and no deaths due to congestive heart failure. Multivariate analysis with proportional-hazards regression (Coxs model) demonstrated a fourfold reduction in the incidence of congestive heart failure independent of other clinical predictor variables in those patients whose management was concordant with proposed guideline criteria. The incidence, persistence, late development, predictability, and reversibility of clinical congestive heart failure were comparable in university and community hospital settings.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Functional left ventricular aneurysm formation after acute anterior transmural myocardial infarction: incidence, natural history and prognostic implications

To assess the clinical and prognostic importance of the early appearance of a functional left ventricular aneurysm after myocardial infarction, we used equilibrium radionuclide angiocardiography to study 51 patients with an initial anterior infarction. A functional aneurysm was defined as an area of systolic akinesis or dyskinesis with a distinct diastolic deformity and preserved adjacent wall motion. Functional aneurysms developed in 18 patients (Group 1). Left ventricular ejection fraction was comparable in this group and in the 33 patients without aneurysm (Group 2) (27.3 +/- 10 vs. 31.4 +/- 12 per cent). One-year mortality was markedly different, with 11 deaths (61 per cent) in Group 1 and 3 (9 per cent) in Group 2 (P less than 0.001). Six (55 per cent) of the deaths in Group 1 were sudden. Patients with a functional aneurysm appearing within 48 hours had the highest risk of dying (8 of 10). Thus, early formation of a functional aneurysm occurs frequently after anterior myocardial infarction and carries a high risk of death within one year that is independent of ejection fraction. In addition, the absence of a functional aneurysm identifies a large group with a low one-year mortality despite a markedly impaired ejection fraction.

Myocardial imaging with thallium-201: A multicenter study in patients with angina pectoris or acute myocardial infarction

A multicenter study of rest and exercise thallium-201 myocardial imaging in 190 patients from five centers was performed. Exercise images were obtained after graded treadmill or bicycle stress with use of five different gamma camera models and were interpreted by the originating investigator without knowledge of other clinical data. Of 42 patients with less than 50 percent coronary stenosis, 4 (10 percent) had a resting image defect, 1 (2 percent) a new exercise defect and 5 (12 percent) either a resting or an exercise image defect, or both. Of 148 patients with coronary stenosis of 50 percent or greater, 64, (45 percent) had an image defect in the study at rest, 90 (61 percent) had new or increased defects after exercise, and 115 (78 percent) had resting or exercise defects, or both. New exercise image defects were more common than exercise S-T depression (90 of 148 [61 percent] versus 62 of 148[42 percent]; P less than 0.01). In a second group of 111 patients with acute myocardial infarction studied at three centers, 90 patients (81 percent) had image defects compared with 71 (64 percent) two had new electrocardiographic Q waves (P less than 0.01). Smaller infractions, as assessed with serum enzyme values, and diaphragmatic infarctions were less commonly detected than larger or anterior infarctions. These findings suggest that myocardial imaging complements the electrocardiographic identification of acute myocardial infarction of exericse-induced myocardial ischemia.

Sequential radionuclide assessment of left and right ventricular performance after acute transmural myocardial infarction.

Ventricular performance was evaluated sequentially in 31 patients with uncomplicated acute transmural myocardial infarction (13 anterior and 18 inferior). Left ventricular ejection fraction, ejection rate, regional wall motion, and right ventricular ejection fraction were ascertained using first-pass radionuclide angiocardiography on four occasions during hospitalization. Inferior infarction resulted in a greater reduction in right ventricular ejection fraction than anterior infarction (mean +/- SEM; 48 +/- 2 versus 56 +/- 2%, P less than 0.01). In contrast, in anterior infarction there was greater depression of left ventricular ejection fraction than in inferior infarction (34 +/- 3 versus 50 +/- 3%, P less than 0.01). From initial to discharge studies, there was no significant change in global performance or regional wall motion in either group. These data show that the location of transmural infarction has a profound effect upon the magnitude of right and left ventricular dysfunction. In addition, ventricular systolic performance remains relatively stable during the hospital phase of uncomplicated transmural myocardial infarction.

Effects of aminophylline upon right and left ventricular performance in chronic obstructive pulmonary disease: Noninvasive assessment by radionuclide angiocardiography

Abstract Although aminophylline is a widely used bronchodilator in chronic obstructive pulmonary disease (COPD), its effects upon cardiac performance have not been fully established. The effect of aminophylline upon right ventricular and left ventricular ejection fraction and the left ventricular ejection rate was evaluated by first-pass quantitative radionuclide angiocardiography in 15 patients with COPD, including four with cor pulmonale, and in five control subjects without cardiopulmonary disease. Aminophylline infusion (9 mg/kg) significantly increased the right ventricular ejection fraction (45 to 52 per cent), left ventricular ejection fraction (60 to 67 per cent) and left ventricular ejection rate (3.4 to 4.1 sec −1 ) in patients with COPD (all parameters, p −1 ) (p 1 ) and forced vital capacity (FVC) increased significantly in patients with COPD but not in control subjects. Arterial carbon dioxide tension decreased significantly in both groups (p These data indicate that aminophylline acutely enhances biventricular performance in COPD. Since comparable cardiovascular changes are induced in normal subjects in whom ventilatory function was not altered, the beneficial effects of aminophylline upon global ventricular performance appear to be independent of the degree of pulmonary compromise.

Detection of Injury-Induced Vascular Remodeling by Targeting Activated αvβ3 Integrin In Vivo

Background—The &agr;vβ3 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 &agr;vβ3 integrin expression in vivo. Methods and Results—RP748, a novel 111In-labeled &agr;vβ3-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 &agr;vβ3 at focal contacts. Activation of&agr;vβ3 by Mn 2+ 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 &agr;v and β3 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 &agr;vβ3 integrin and can track the injury-induced vascular proliferative process in vivo.

Regional cardiac prostaglandin release during myocardial ischemia in anesthetized dogs.

Cardiac prostaglandin release was studied in closed-chest dogs during acute coronary occlusion. Aortic and coronary sinus blood was obtained before, and at intervals after, balloon occlusion of the left anterior descending artery in seven dogs. Samples were assayed for prostaglandins F, E, and A by radioim-munoassay. All dogs demonstrated prostaglandin F release. Mean ± se postocclusion aortic levels were 0.26 ± 0.01 ng /ml; coronary sinus levels were 0.67 ± 0.01 ng/ml [P < 0.001). In six dogs, prostaglandin E also was released. Mean postocclusion aortic levels were 0.24 ± 0.01 ng/ml; coronary sinus, 0.44 ± 0.01 ng/ml (P < 0.001). There was no release of prostaglandin A. To examine the site of prostaglandin release, simultaneous samples from the aorta, the coronary sinus, and the great cardiac vein were obtained before and after left circumflex artery occlusion in six additional studies. The great cardiac vein drained effluent from nonischemic myocardium, whereas the coronary sinus drainage included blood from both ischemic and nonischemic zones. All six dogs demonstrated prostaglandin F release from the ischemic region. Mean postocclusion aortic prostaglandin F was 0.32 ± 0.01 ng/ml. Coronary sinus prostaglandin F was 1.69 ± 0.03 ng/ml (P < 0.001), whereas the great cardiac vein level remained at 0.34 ± 0.01 ng/ml (P > 0.05). Prostaglandin E was released from both ischemic and nonischemic regions. Mean aortic prostaglandin E was 0.21 ± 0.01 ng/ml; great cardiac vein, 0.55 ± 0.02 ng/ml (P < 0.001); and coronary sinus, 1.07 ± 0.04 ng/ml (P < 0.001). These results have led us to conclude that the different local availability of prostaglandins E and F may influence the cardiac response to ischemia.

Frequency and significance of right ventricular dysfunction during inferior wall left ventricular myocardial infarction treated with thrombolytic therapy (results from the Thrombolysis in Myocardial Infarction [TIMI] II trial)☆

To determine the effect of thrombolytic therapy on the frequency of right ventricular (RV) dysfunction, and whether RV dysfunction is a risk factor for morbidity and mortality after discharge from the hospital, 1,110 patients in the Thrombolysis in Myocardial Infarction (TIMI) II trial with acute inferior wall left ventricular myocardial infarction were studied. RV dysfunction was defined as an RV wall motion abnormality on equilibrium radionuclide ventriculography performed a mean of 9 days after admission to the hospital. Fifty-eight patients (5%) had RV dysfunction. Baseline clinical characteristics among patients with and without RV dysfunction were similar. However, patients with RV dysfunction had a lower mean left ventricular ejection fraction (51.2 +/- 1.2% vs 55.5 +/- 0.3%; p < 0.001) and a greater frequency of in-hospital complications. Angiographic data from patients undergoing protocol catheterization 18 to 48 hours after hospital admission show that the infarct-related artery was more likely to be occluded in those with RV dysfunction (48% [15 of 31] vs 14% [68 of 495]; p < 0.001). There was no difference in the frequency of multivessel disease between the 2 groups. In patients with RV dysfunction in whom radionuclide ventriculography was repeated 6 weeks after hospital discharge, RV wall motion abnormalities persisted in only 18% (8 of 45). Mortality in the year after discharge was 3.5% (2 of 58) among patients with RV dysfunction compared with 1.7% (18 of 1,052; p = NS) among those without RV dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)