Cardiotoxicity in signal transduction therapeutics: erbB2 antibodies and the heart.

Cardiotoxicity is a common and potentially devastating side effect of antineoplastic drug therapy. This empiric observation is seen as paradoxical given that the cardiomyocyte is considered to be a terminally differentiated cell. Despite the fact that these cells do not divide after birth, adult cardiomyocytes may become "innocent bystander" targets of anticancer drugs designed to interfere with cell signaling pathways in rapidly proliferating cells. In breast cancer clinical trials, treatment with the erbB2 receptor antibody trastuzumab combined with anthracyclines has been associated with an increased risk for the development of cardiac pump failure. Trastuzumab/anthracycline cardiomyopathy may be the first clinically significant cardiotoxicity to emerge from signal transduction therapeutics. The erbB2 receptor tyrosine kinase is known to have a critical role in cardiac development. In addition, erbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes as part of a signaling network that involves neuregulins and the neuregulin receptor erbB4. However, erbB2 levels in the adult heart are low when compared with the levels found in erbB2-overexpressing breast cancer cells that are the intended targets of trastuzumab therapy. Thus, trastuzumab-associated cardiotoxicity must be explained by some alternative mechanism. After confirming that trastuzumab is capable of inducing tyrosine phosphorylation of the human cardiomyocyte erbB2 protein, a novel system for culturing human myocardium was developed in our laboratory. We used this system to study the effects of trastuzumab on human cardiomyocytes in vitro and observed trastuzumab-induced structural and functional changes in human cardiomyocytes that were at least partially reversible with the addition of recombinant neuregulins. The results obtained in these experiments support a direct action of trastuzumab on human cardiomyocytes. In addition, these data provide insight regarding potential molecular mechanisms. Most importantly, these data draw attention to the inherent risk of cardiotoxicity associated with a newly emerging class of antineoplastic drugs that interfere with signal transduction pathways.

Myocardial perfusion scintigraphy: effect on diagnostic and clinical management algorithms.

UNLABELLED: Research has demonstrated that myocardial perfusion imaging increases the sensitivity and specificity of stress electrocardiography. However, the additional effect of the perfusion component of a stress study on clinical management algorithms remains poorly defined. METHODS: We prospectively assessed the decision-making process in 518 patients, from 191 clinicians, undergoing stress myocardial perfusion imaging in our departments. Each clinician was asked, by telephone interview, to define the probability of reversible myocardial ischemia and their management plan (i.e., no antianginal treatment, medical therapy or an invasive intervention) in three stages: pretest, after the stress data was made available and after completion of the perfusion study. RESULTS: The results of the stress data alone influenced the estimate of the probability of reversible ischemia in 149 of 518 patients, and management strategy in 50 of 518 patients. The data from the perfusion component in isolation changed probability of reversible disease in 219 of 518 patients and altered clinical management in 77 of 518 patients. Of 103 patients in whom an invasive procedure was planned after the stress data, the availability of the perfusion data led to deferral of catheterization in 48 cases (46.6%). Conversely, of the 415 patients triaged to a noninvasive plan after stress data, only 29 (7.0%) were changed to an invasive strategy. Of note, only 2.3% of women changed from a conservative strategy as a consequence of the perfusion data, compared to 9.1% of men. CONCLUSION: The perfusion component of a stress study has a significant effect on both estimation of clinical probability and the definition of patient management strategy. Myocardial perfusion imaging reduced the number of catheterizations in patients initially triaged to an invasive management strategy. Conversely, the effect of stress and perfusion data in patients triaged to conservative management on clinical grounds, especially women, remains less well defined.

Demonstration of viable, stunned myocardium with technetium-99m-sestamibi.

Delayed improvement of left ventricular contractile function in the setting of acute ischemia followed by reperfusion ("stunned myocardium") has been observed in a number of clinical scenarios, and may have important clinical implications. At present, there are no widely accepted techniques available to demonstrate its presence. We report a case in which a rest 99mTc-sestamibi scan performed 12 hr after thrombolytic therapy in the setting of acute myocardial infarction demonstrated viable myocardium in a region that was akinetic by contrast ventriculography. After surgical revascularization, follow-up 99mTc-sestamibi images showed normal perfusion and radionuclide ventriculography demonstrated normal left ventricular function. Demonstration of preserved 99mTc-sestamibi myocardial uptake in the infarct zone despite an extensive region of akinesis by contrast ventriculography predicted the recovery of left ventricular function after revascularization in this case. This suggests that perfusion imaging with 99mTc-sestamibi early after myocardial reperfusion can detect stunned myocardium and thus facilitate the decision-making process regarding management of such patients.

Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging.

BACKGROUND: The identification of ischemic but viable myocardium by thallium exercise scintigraphy is often imprecise, since many of the perfusion defects that develop in ischemic myocardium during exercise do not "fill in" on subsequent redistribution images. We hypothesized that a second injection of thallium given after the redistribution images were taken might improve the detection of ischemic but viable myocardium. METHODS: We studied 100 patients with coronary artery disease, using thallium exercise tomographic imaging and radionuclide angiography. Patients received 2 mCi of thallium intravenously during exercise, redistribution imaging was performed three to four hours later, and a second dose of 1 mCi of thallium was injected at rest immediately thereafter. The three sets of images (stress, redistribution, and reinjection) were then analyzed. RESULTS: Ninety-two of the 100 patients had exercise-induced perfusion defects. Of the 260 abnormal myocardial regions identified by stress imaging, 85 (33 percent) appeared to be irreversible on redistribution imaging three to four hours later. However, 42 of these apparently irreversible defects (49 percent) demonstrated improved or normal thallium uptake after the second injection of thallium, with an increase in mean regional uptake from 56 +/- 12 percent on redistribution studies to 64 +/- 10 percent on reinjection imaging (P less than 0.001). Twenty patients were restudied three to six months after coronary angioplasty. Of the 15 myocardial regions with defects on redistribution studies that were identified as viable by reinjection studies before angioplasty, 13 (87 percent) had normal thallium uptake and improved regional wall motion after angioplasty. In contrast, all eight regions with persistent defects on reinjection imaging before angioplasty had abnormal thallium uptake and abnormal regional wall motion after angioplasty. CONCLUSIONS: These data indicate that the reinjection of thallium improves the detection of ischemic myocardium and that myocardial regions with improved thallium uptake on reinjection imaging represent viable but jeopardized myocardium.

Evaluation of left ventricular diastolic function using an ambulatory radionuclide monitor: relationship to left ventricular systolic performance.

Abnormalities of left ventricular (LV) filling may occur prior to systolic dysfunction in patients with both coronary and noncoronary heart disease. To determine the incidence of diastolic dysfunction and to assess the relationship of such dysfunction to systolic performance, we measured systolic and diastolic function at rest in a series of healthy volunteers (n = 10) and in patients with cardiovascular disease (n = 42). Twenty patients had coronary artery disease (CAD) with prior myocardial infarction, six patients had CAD without myocardial infarction, and the remaining 16 patients had a variety of noncoronary heart diseases, including valvular heart disease, dilated cardiomyopathy, and hypertensive disease. The 42 patients manifested a wide variation in LV systolic function (ejection fractions ranged from 6% to 65%). Patients with reduced LV ejection fraction (EF) manifested a reduction in cardiac output and peak ejection rate proportionate to the reduction in EF. Diastolic function showed a fall in LV peak (PFR) and average (AFR) filling rates; these were reduced in proportion to the fall in EF. Heart rate was an insensitive index of the magnitude of impairment of LV systolic function. These data suggest that measurements of diastolic function do not provide additional information in patients with impaired systolic function.

Comparison of thallium redistribution with rest "reinjection" imaging for the detection of viable myocardium.

To determine the incidence of incomplete redistribution on conventional delayed thallium images, 41 patients with persistent perfusion defects on myocardial images recorded 3 to 4 hours after thallium injection during exercise were studied. At the conclusion of their delayed images the patients were reinjected at rest with approximately 1 mCi of thallium-201 and a third set of images was recorded. The images were presented at random in pairs (initial:delayed, initial:reinjection) to 2 experienced observers for qualitative scoring of 9 segments/patient. Of the 360 segments analyzed, concordance between the delayed and reinjected images occurred in 307 (85%). Of 141 segments that demonstrated a persistent perfusion abnormality on 3- to 4-hour delayed images, 44 (31%) were reassigned to a redistribution score after reinjection. In 9 patients, reinjection images provided the only evidence of ischemia from the scintigraphic data. In 13 of 14 vascular territories that demonstrated redistribution after reinjection, intact perfusion (either anterograde or via collaterals) was detected at coronary angiography. These data suggest that rest reinjection imaging may provide a means of detecting viable myocardium in segments that demonstrate a fixed perfusion abnormality on conventional 3- to 4-hour delayed thallium images.

Acute pulmonary edema following removal of a spinal orthosis: an unusual complication of a halo vest.

The halo vest is a commonly used spinal orthosis that provides stability to the cervical spine. Known complications include loss of spinal reduction, local pin tract infection, skin breakdown over the scapulae, and, rarely, brachial plexus and cranial nerve palsies. The use of the halo vest has not been associated with significant respiratory compromise. Cardiopulmonary complications associated with halo vests have not been reported. We report a case of pulmonary edema associated with removal of a halo vest in a patient with occult mitral stenosis. We speculate that removal of the orthosis resulted in rapid redistribution of peripheral blood volume sufficient in magnitude to provide the hemodynamic substrate for acute pulmonary edema.

Cardiac blood-pool imaging. II: Applications in noncoronary heart disease.

The role of radionuclide ventriculography in the initial evaluation, periodic assessment, and therapeutic follow-up of patients with valvular disease, hypertensive heart disease, lung disease, and cardiomyopathy is discussed.

Technetium-99m isonitrile myocardial uptake at rest. I. Relation to severity of coronary artery stenosis.

To determine the potential of planar technetium-99m methoxybutyl isonitrile myocardial imaging as a method of detecting totally occluded or severely stenosed coronary arteries, the regional distribution of technetium-99m isonitrile at rest was compared with the coronary anatomy in 38 patients with prior myocardial infarction who underwent coronary arteriography. Left ventricular technetium-99m isonitrile tracer uptake at rest was assessed in the three major coronary vascular territories. When qualitative rest technetium-99m isonitrile uptake was markedly reduced or absent (grade 0), there was a 91% probability of finding a totally occluded or severely stenosed coronary artery. When qualitative tracer uptake was reduced (grade 1) or normal (grade 2), it excluded all territories supplied by a totally occluded vessel with poor collateral flow. Quantitative technetium-99m isonitrile uptake (mean +/- 1 standard deviation) in territories supplied by an occluded coronary artery with poor collateral flow (42 +/- 21%) was lower than in territories supplied by a vessel with less than 50% stenosis (87 +/- 10%) and 50 to 99% stenosis (74 +/- 19%) (p less than 0.001). Furthermore, technetium-99m isonitrile uptake in areas supplied by an occluded coronary artery with good collateral flow (61 +/- 23%) was lower than in areas supplied by a vessel with less than 50% stenosis (87 +/- 10%) (p less than 0.001). Because rest technetium-99m isonitrile imaging detects coronary occlusion with poor collateral flow, this method may be useful in assessing patients with acute myocardial infarction.

Technetium-99m isonitrile myocardial uptake at rest. II. Relation to clinical markers of potential viability.

To determine the utility of rest-injected technetium-99m methoxybutyl isonitrile (Tc-99m isonitrile) uptake as a marker of myocardial viability, the regional uptake of this agent was compared with regional wall motion by equilibrium gated blood pool scan in 26 patients with previous myocardial infarction and with postrevascularization uptake in 8 patients after coronary bypass surgery. Rest left ventricular Tc-99m isonitrile uptake was assessed qualitatively in three coronary vascular territories as grade 0 (markedly reduced) to grade 2 (normal), and quantitatively by circumferential profile analysis. Wall motion was scored qualitatively in corresponding vascular territories as normal, hypokinetic or akinetic/dyskinetic. There was an overall relation between qualitative Tc-99m isonitrile uptake and wall motion. Abnormal wall motion occurred in 74% of vascular territories with perfusion grade 0, in 61% of those with grade 1 and in 30% of those with grade 2; however, 26% of territories with grade 0 uptake had normal wall motion. In the territories visually assigned perfusion grade 0, quantitative isonitrile uptake (mean value +/- SD) was higher when corresponding wall motion was normal or hypokinetic (62 +/- 15%) than when akinesia was detected by gated blood pool scan (39 +/- 16%, p less than 0.02). Qualitative Tc-99m isonitrile uptake improved after coronary bypass surgery in 12 of 13 territories with reduced uptake preoperatively; this included all 5 territories with a preoperative Tc-99m isonitrile score of 0. Quantitative uptake in these regions increased from 55 +/- 18% to 73 +/- 21% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of ventricular function in patients with coronary artery disease.

The recent expansion of interventional cardiovascular technologies has stimulated a concomitant expansion of noninvasive cardiac studies, both to assist in diagnosis and to evaluate treatment outcomes. Radionuclide ventricular function studies provide a reliable, reproducible means to quantify global left ventricular systolic performance, a critical determinant of prognosis in patients with cardiovascular disease. In addition, the ability to evaluate regional left ventricular wall motion and to assess ventricular performance during exercise have secured a fundamental role for such studies in the screening and treatment of patients with coronary artery disease. Radionuclide techniques have been extended to the evaluation of left ventricular relaxation/filling events, left ventricular systolic/diastolic function in the ambulatory setting, and with appropriate technical modifications, to the assessment of right ventricular performance at rest and with exercise. As a complement to radionuclide perfusion studies, cardiac blood-pool imaging allows for thorough noninvasive description of cardiac physiology and function in both normal subjects and in patients with a broad range of cardiovascular diseases.