Angela M. Sharkey

A Novel Site-Targeted Ultrasonic Contrast Agent With Broad Biomedical Application

BACKGROUND In this work, we report a novel targetable ultrasonic contrast agent with the potential to noninvasively define and localize myriad pathological tissues for diagnosis or therapy. The agent is a biotinylated, lipid-coated, perfluorocarbon emulsion that has low inherent echogenicity unless bound to a surface or itself. METHODS AND RESULTS In study 1, emulsions with and without biotin were suspended in buffered saline and imaged with a 7.5-MHz linear-array transducer. Neither emulsion manifested significant ultrasonic backscatter until avidin was added. Avidin-induced aggregation produced a marked enhancement in backscatter from the biotinylated but not from the control emulsion. In study 2, porcine fibrin clots in vitro were pretargeted with biotinylated antifibrin monoclonal antibodies and then exposed to avidin and then to biotinylated or control perfluorocarbon emulsions. The basal acoustic reflectivity of clots imaged with a 7.5-MHz linear-array transducer was uniformly low and was increased substantially by exposure to the targeted biotinylated emulsion. In study 3, partially occlusive arterial thrombi were created in dogs and then exposed to antifibrin antibodies and avidin in situ. Biotinylated or control emulsion was administered either in situ or systemically. At baseline, all thrombi were undetectable with a 7.5-MHz linear-array transducer. Thrombi exposed to antifibrin-targeted contrast exhibited increased echogenicity (P < .05); control thrombi remained acoustically undetectable. CONCLUSIONS These data provide the first in vivo demonstration of a site-specific ultrasonic contrast agent and have potential for improved sensitivity and specificity for noninvasive diagnosis of thrombi and other pathological diseases.

Doppler echocardiography of fetal ductus arteriosus constriction versus increased right ventricular output

A prospective longitudinal study from 121 examinations of 41 normal pregnant women showed that fetal ductal flow velocities increased with gestational age. These normal data were compared with data in three groups of fetuses with altered ductal flow velocities: 22 fetuses (mean gestational age 31.3 weeks) had ductal constriction due to maternal indomethacin treatment; 10 fetuses (mean gestational age 27.9 weeks) had been exposed to terbutaline, a positive inotropic agent and 14 fetuses (mean gestational age 33.3 weeks) had hypoplastic left heart syndrome. In normal fetuses maximal systolic, mean and end-diastolic ductal flow velocities increased linearly (p less than 0.0001). The pulsatility index did not change (mean +/- 2 SD: 2.46 +/- 0.52). Fetuses with ductal constriction had higher maximal, mean and end-diastolic flow velocities and a significantly lower pulsatility index than did normal fetuses (1.25 +/- 0.76; p less than 0.0005). Six of 10 fetuses of the terbutaline group and 8 of 14 fetuses with hypoplastic left heart syndrome had increased maximal flow velocity, but normal or only mildly elevated mean flow velocity. The pulsatility index in fetuses during terbutaline therapy and with hypoplastic left heart syndrome was significantly higher than in normal fetuses (3.11 +/- 0.46 and 3.09 +/- 0.7, respectively, vs. 2.46 +/- 0.52; p less than 0.0005). Fetal ductal waveform analysis was necessary to distinguish fetal ductal constriction from increased right ventricular output. These measurements may be helpful in the diagnosis of left-sided outflow obstruction and assessment of fetal hemodynamic data.

Cardiac rehabilitation after cancer therapy in children and young adults

Abstract Approximately two thirds of 6,000 children diagnosed with cancer in the United States each year are treated successfully. 1 With increasing cure rates and longer disease-free survival, the long-term outcome of cancer therapy has become important. Both anthracyclines and cardiac irradiation have acute and chronic cardiotoxicity. Previous studies showed that surviving patients of childhood cancer who were treated with these modalities have abnormal exercise tests, echocardiograms and Holter recordings. 2–4 The effects of deconditioning on these findings is unknown. To separate the effects of deconditioning secondary to chronic illness from long-term cardiotoxic effects secondary to anthracyclines, we used exercise testing to study surviving patients of childhood cancer before and after a 12-week aerobic conditioning program.

Contractile proteins in myocardial cells are regulated by factor(s) released by blood vessels.

The importance of perfusion of the coronary vasculature in the regulation of ATPase activity of myosin in rat myocardial cells has been studied. Quantitative histochemistry was used to determine the activity of the enzyme among cells in tissues that had been either perfused through the coronary system or superfused over the surface of the tissue. Enzymatic activity was measured in cryostatic sections from three different preparations: 1) hearts frozen immediately after removal from the animal; 2) isolated hearts frozen after they had been perfused through the coronary circulation; and 3) isolated papillary muscles or trabeculae that had been superfused after dissection and then frozen. ATPase activity was measured in the isolated tissues at different times after dissection. Both calcium- and actin-activated myosin ATPase activities were uniform among cells in both the ventricles of the hearts frozen immediately after dissection and those that had been perfused through the coronary system. In the superfused tissues, although calcium-activated myosin ATPase activity was uniform, actin-activated ATPase activity was not uniform for about 90 minutes after the dissection, the period required for stabilization of the contraction. The pattern of nonuniformity was complex. In all bundles the lowest enzymatic activity was found in the most superficial cells. In very thin bundles, the cells in the center had the highest activity. In the medium and thicker bundles, there were three concentric zones of actin-activated ATPase activity, the superficial zone with the lowest activity, an intermediate zone with high activity, and a central zone with lower activity. Within each zone, the activity was often greatest in myocardial cells immediately next to blood vessels even though the blood vessels had not been perfused. The transverse distribution of ATPase activity of myosin could be explained by a mechanism in which cells in blood vessels (presumably endothelium) release a substance that upregulates myosin ATPase activity, with the rate of release being related to the local oxygen tension. A downregulating substance may also be produced. The period of stabilization of the contraction coincides with the time during which the pattern of actomyosin ATPase activity is nonuniform. These data suggest that the contractile proteins are regulated by a substance produced by blood vessels in proportion to the local PO2, and possibly in relation to shear force on the vascular endothelium.

Common Complaints with Cardiac Implications in Children

Chest pain, palpitations, and dizziness are not infrequent complaints in the office of a primary care physician. Historical events and physical findings can lead to a more accurate determination of cardiac causes of these symptoms. Electrocardiogram and chest radiographs are two additional tests most often helpful in determining cardiac causes of symptoms.

THE SPECTRUM OF AORTIC DISEASE IN LOEYS-DIETZ SYNDROME

Results: Patients ranged from age 9-55 years, with 10 males and 16 females. 19/26 underwent aortic surgery at ages 14-43 years. 4 adults suffered aortic dissection: 3 as the initial presentation. Aortic root size was 3.9 cm at the time of dissection in one patient. One patient died from an aortic arch dissection months after prophylactic root replacement and at the time of dissection the arch measured 3.5 cm. Patients with aortic dissection required multiple subsequent aortic operations. 4 patients underwent total aortic replacement. Branch vessel involvement requiring repair included aneurysms of the brachiocephalic and subclavian arteries. 11 patients underwent valve-sparing (VS) aortic root replacement and 8 patients underwent composite aortic valve and root replacement (CVG). Of the 11 patients with VS root replacement, one required reoperation due to failed Ross procedure in a patient previously diagnosed as bicuspid aortic valve disease alone. Two others who underwent a Yacoub-type “remodeling” VS procedure developed early splaying of the remaining aortic sinus tissue with progressive enlargement of the aorta. Patients who have had a David “reimplantation” VS procedure or CVG have had stable repairs. Other cardiac procedures have included repair of an atrial septal defect, patent ductus arteriosus and replacement of the mitral valve.