Daunorubicin cardiotoxicity: evidence for the importance of the quinone moiety in a free-radical-independent mechanism.

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98+/-6% at 1 Hz, and 73+/-8 and 67+/-8% for 30 and 60 sec PRP, respectively, and 73+/-3 and 63 +/-3% at 2 and 3 Hz, respectively, for 88 microM Daun (P<0.05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force-frequency relationship or PRP contractions. Additional studies in Ca(2+)-loaded SR microsomes indicated that both Daun and 5-ID opened Ca(2+) release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca(2+) release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.

Insensitivity of color Doppler flow imaging for detection of acute calf deep venous thrombosis in asymptomatic postoperative patients.

PURPOSE: Although color Doppler flow imaging (CDFI) has been shown to accurately depict calf vein thrombosis in symptomatic patients, this technique has not been proved accurate for detection of calf vein thrombosis in a population restricted to asymptomatic postoperative patients. PATIENTS AND METHODS: To evaluate the accuracy of CDFI in asymptomatic postoperative patients, both CDFI and contrast venography were performed on 78 limbs of 76 patients without symptoms of deep venous thrombosis (DVT) who had undergone either hip or knee replacement. CDFI and venographic examination were interpreted blindly with respect to the results of the other modality or clinical findings. Venography was the standard for comparison of results. RESULTS: Fifty-six percent of CDFI examinations of the calf vein were technically adequate. The remaining studies were compromised technically by limb swelling and/or obesity. For the technically adequate CDFI studies, calf vein thrombosis was detected in eight of 10 patients. Calculated sensitivity in this cohort was 80%, and specificity was 97%. The sensitivity of CDFI for acute calf DVT in all patients, regardless of image quality, was 42%. CONCLUSION: These observations suggest that state-of-the-art CDFI is not an accurate examination for acute calf vein DVT in asymptomatic postoperative patients. CDFI is associated with a high rate of technically compromised studies and relatively low sensitivity in studies that are deemed technically satisfactory. These observations do not preclude the use of CDFI in postoperative patients for detection of thrombus extension into the popliteal vein or for detecting thrombosis of more proximal lower extremity veins.

Techniques for color flow sonography of the lower extremity.

Color flow sonography permits noninvasive examination of the deep venous system in the lower extremity. In many patients, the modality is sufficiently accurate to serve as the sole diagnostic procedure for suspected deep venous thrombosis. Over 1,500 color flow sonographic examinations of the lower extremity have been performed at our institutions with various scanning techniques. For the inexperienced sonographer, we describe our current technique, which is easy, quick, accurate, and well tolerated by patients.

Symptomatic lower extremity deep venous thrombosis: accuracy, limitations, and role of color duplex flow imaging in diagnosis.

Color duplex flow imaging (CDFI) permits pain- and risk-free direct imaging of the deep venous system of the lower extremities. To prospectively ascertain the accuracy and limitations of this technique, CDFI was performed in 75 lower limbs of 69 consecutive patients referred for venographic evaluation of clinically suspected lower extremity deep venous thrombosis (DVT). The CDFI study was obtained within 24 hours of the contrast venogram. Both studies were interpreted without knowledge of the patient's clinical findings or the results of the other test. Contrast venography was regarded as the standard for diagnosis of DVT. Accuracy was 99% for detection of DVT above the knee and 81% below the knee. Sonographic evaluation of the calf veins was technically adequate in 60% of limbs; accuracy was 98% in this group. In the 40% of limbs with technically limited CDFI studies of the calf, accuracy decreased to 57%. Although small nonocclusive thrombi occurred infrequently in this series of symptomatic patients, CDFI missed three of four such thrombi. It is concluded that CDFI, when not technically compromised, is sufficiently accurate to definitively diagnose symptomatic lower extremity DVT.