Assessing biological safety of metals associated with medical devices.

As human exposure to heavy metals increases, the impact these metals are having on morbidity is a growing concern. Methods of evaluating potential toxicity in medical device materials are discussed.

Semisynthetic fluorohydrolases prepared by chemical modification of ribonuclease.

A process for conformational modification of protein, which we have previously reported, was investigated as a means of generating fluorohydrolase activity in bovine ribonuclease (RNase). The resulting modified RNase had catalytic activity that depended upon the chosen modifier. Bovine pancreatic ribonuclease, modified by addition of hexamethylphosphoramide (HMPA) at pH 3, was derivatized with diimidates of chain lengths from C1 to C8. The derivative with the highest activity was obtained when RNase was crosslinked with dimethyl pimelimidate (C5). This derivative, which was active over a pH range of 6.5 to 8.0 with an optimum pH of 7.4, hydrolyzed phenylmethylsulfonylfluoride (PMSF) and the potent acetylcholinesterase inhibitor, diisopropyl phosphorofluoridate (DFP). The mean fluorohydrolase activity for four preparations using dimethyl pimelimidate was 0.8 +/- 0.2 U mg-1. Gel filtration on G-75 Sephadex and SDS-polyacrylamide gel electrophoresis showed components having a molecular weight of 13,000 and 27,000, with activity restricted to the 27,000 molecular weight fraction. After gel filtration, the specific activity was 9.1 +/- 2.4 U mg-1, resulting in a molecular activity of 125 min-1. The mechanism of this unique transformation of RNase into a fluorohydrolase is not known, nor has the location of the active site been determined.

Advanced time-frequency methods for signal-averaged ECG analysis.

Frequency-domain techniques have been extensively investigated for the analysis of high-resolution electrocardiograms (ECGs), although the merit of frequency-domain analysis is still subject to controversy. Time-frequency analysis methods, which estimate the frequency content of a signal as a function of time, potentially provide even more information for improved ECG analysis. Some researchers report impressive results in predicting the outcome of electrophysiologic studies using the short-time Fourier transform (spectrogram). Other time-frequency representations, such as the Wigner distribution, short-time spectral estimators, and the wavelet transform, have also been investigated. The authors present a unified overview of time-frequency representations, showing that only four classes characterize most time-frequency representations. The authors describe the advantages and drawbacks of the various approaches and speculate on their promise for ECG analysis. Very preliminary experiments in applying some of these techniques to the prediction of the outcome of electrophysiologic studies have suggested some possible new research directions.

Heart rate variability before and after myocardial infarction in conscious dogs at high and low risk of sudden death.

Heart rate variability has been demonstrated both experimentally and clinically to be of prognostic importance in determining mortality after myocardial infarction. However, no paired studies have been reported to examine heart rate variability before and after myocardial infarction. The hypothesis was tested that low values of heart rate variability provided risk assessment both before and after myocardial infarction with use of an established canine model of sudden cardiac death. Risk for sudden death was assessed 1 month after myocardial infarction by a protocol in which exercise and myocardial ischemia were combined; dogs that developed ventricular fibrillation were classified at high risk for sudden death (susceptible) and the survivors were considered low risk (resistant). In resistant dogs, myocardial infarction did not affect any measure of heart rate variability: 1) mean RR interval, 2) standard deviation of the mean RR interval, and 3) the coefficient of variance (standard deviation/RR interval). By contrast, after myocardial infarction, susceptible dogs showed significant decrease in all measures of heart rate variability. Before myocardial infarction, no differences were seen between susceptible and resistant dogs. However, 30 days after infarction, epidemiologic analysis of the coefficient of variance showed high sensitivity and specificity (88% and 80%, respectively), predicting susceptibility. Therefore, results of analysis of 30 min of beat to beat heart period at rest 30 days after myocardial infarction are highly predictive for increased risk of sudden death.

Spectrotemporal analysis of ventricular late potentials.

The authors introduce a new technique for the analysis of ventricular late potentials: spectrotemporal mapping. Spectrotemporal mapping displays a signal in both the time and frequency domains simultaneously, overcoming some of the limitations of single domain analysis. Spectrotemporal analysis of late potentials was developed from a critique of classical spectral analysis methods. Several examples of spectrotemporal analysis of signal-averaged ECG waveforms are presented. These include cases in which spectrotemporal mapping was able to represent late potentials that were not seen after conventional time-domain processing. Spectrotemporal mapping reveals that ventricular late potentials have a time-varying energy spectrum, which theoretically would preclude the use of classical Fourier analysis techniques. Both the vector magnitude and Fourier transformations are a reduced representation of the information available in the signal average. Spectrotemporal mapping combines time and frequency information in a way that is compatible with the basic statistical structure of late potentials.

Continuous-wave Doppler for the noninvasive evaluation of aortic blood velocity and rate of change of velocity: evaluation in dogs.

A new continuous-wave Doppler device is described, which has the capability of measuring peak aortic blood velocity and acceleration noninvasively in the ascending aorta of patients. To test the accuracy of the device, blood velocity and acceleration in the ascending aorta were compared with measurements obtained using an electromagnetic flowmeter in 16 open-chest anesthetized dogs. The Doppler probe was hand held directly on the aorta. Aortic flow was measured with a cuff electromagnetic flow transducer placed at the root of the aorta. Isoproterenol and propranolol, sometimes in combination with lidocaine, were administered intravenously to augment or reduce left ventricular contractile performance. Values of peak velocity, measured with the Doppler, corresponded closely to values measured with the electromagnetic flowmeter (r = 0.95). Values of peak acceleration also corresponded closely with the electromagnetic flow measurements (r = 0.96). The results indicate that valid measurements of blood acceleration in the ascending aorta, as well as blood velocity, can be obtained with continuous-wave Doppler.

Peak aortic blood acceleration reflects the extent of left ventricular ischemic mass at risk.

Peak aortic blood velocity (Vel), peak acceleration (Acc), stroke volume (SV), and left ventricular (LV) ejection fraction (EF) have been used as noninvasive indicators of global LV performance. The purpose of this study was to determine which of these indices of LV performance relates best to the extent of LV ischemic mass at risk. Studies were performed in 24 open-chest anesthetized dogs. Acute ischemia was produced by occlusion of various levels of the left anterior descending and circumflex coronary arteries. LV ischemic mass, measured as a percent of total LV mass, was delineated by injection of Evans blue dye into the nonischemic zone. Acc and Vel were measured with continuous-wave Doppler ultrasound. EF was measured angiographically. All parameters were measured during a control period and within 6 minutes of coronary occlusion. The percent change during ischemia of each parameter relative to control (% delta) was calculated. The correlation coefficient between the percent ischemic mass at risk and % delta Acc was 0.88. It was 0.84 for % delta EF, 0.77 for % delta Vel, and 0.17 for % delta SV. These results indicate that among the various global indices of LV performance that have been used noninvasively, Acc correlates most closely with the extent of LV ischemic mass at risk.

Noninvasive evaluation of left ventricular performance based on peak aortic blood acceleration measured with a continuous-wave Doppler velocity meter.

Peak aortic blood acceleration is recognized to be a sensitive index of global left ventricular performance. In the present study peak acceleration was assessed noninvasively in patients with a continuous-wave Doppler velocity meter. Peak aortic blood velocity and peak blood acceleration were measured by placing the ultrasonic transducer at the suprasternal notch. Measurements were obtained in 36 patients undergoing diagnostic cardiac catheterization. Peak velocity and acceleration were measured at rest just before left ventriculography. In patients with ejection fractions greater than 60%, peak acceleration was 19 +/- 5 m/sec/sec. In patients with ejection fractions of 41% to 60%, peak acceleration was lower, at 12 +/- 2 m/sec/sec (p less than .001). In patients with ejection fractions of 40% or less, peak acceleration (8 +/- 2 m/sec/sec) was markedly lower than in patients with ejection fractions greater than 60% (p less than .001). Peak acceleration showed a good linear correlation with ejection fraction (r = .90), and a better power fit (r = .93). These results indicate that peak acceleration, measured noninvasively with a continuous-wave Doppler velocity meter, is a useful indicator of global left ventricular performance.

Comparative rates of resolution of QRS changes after operative and nonoperative acute myocardial infarcts.

An independently developed and previously validated QRS scoring system for estimating myocardial infarct size has been used to compare the development and regression of changes associated with myocardial infarcts occurring in 2 different clinical settings. It is known that QRS changes suggesting myocardial infarction occur after coronary artery bypass grafting. This study compares the magnitudes and time courses of these QRS changes in 40 patients with the QRS changes observed in a control group of 46 patients with nonoperative acute myocardial infarcts. Only patients in both groups who had a baseline electrocardiogram (ECG) with no evidence of previous myocardial infarcts, ventricular hypertrophy, or bundle branch block were included. Both groups attained similar peak QRS scores during the acute phase but different rates of resolution of scores were observed. During the subsequent 2 months, regression of QRS changes occurred more rapidly in the perioperative group than in the control group (43 versus 19%). Rates of regression were similar in both groups during the remainder of the follow-up period, attaining total decreases of 62% in the operative group and 37% in the nonoperative group by 18 months. These results could mean either that factors other than acute infarction are responsible for the perioperative QRS changes or that the infarct healing process in the 2 clinical settings are quite different.