Cardiotoxicity of the anticancer therapeutic agent bortezomib.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

Descending aortic Doppler flow pattern in patients with proximal peripheral artery disease.

Midsystolic deceleration (notch) in pulmonary pulse-wave (PW) Doppler flow is a common finding in patients with pulmonary embolism. The possible mechanism involves early reflection of pressure wave from proximal embolic sites. The aim of this study was to evaluate with PW Doppler whether occlusion or significant stenosis in the distal aorta or iliac arteries might produce a similar midsystolic notch in descending aortic flow. Echocardiography was performed in 97 consecutive patients with severe peripheral artery disease (PAD) admitted for vascular surgery and in 41 controls. PW Doppler assessment of flow in the proximal descending aorta was recorded from the suprasternal window. After exclusion of 13 patients due to inadequate visualization, atrial fibrillation, or aortic aneurysm, 84 patients were analyzed. Diagnosis of midsystolic notch was made by an experienced echocardiographer blinded to the vascular status of patients. A midsystolic notch in the descending aorta was present in 43 of 49 patients (87.7%) with occlusion or with >70% stenosis in the aortoiliac segment, 6 of 35 (17.1%) patients with occlusion or significant stenosis distal to the external iliac artery, and 0 patient from the control group. Sensitivity of the midsystolic notch in the detection of aortoiliac disease in patients with PAD was 87.7% and specificity was 82.8%. In conclusion, midsystolic deceleration (notch) in the descending aortic Doppler waveform is characteristic for patients with significant proximal PAD. The possible mechanism involves arterial pressure wave reflection from the occlusion or significant stenosis in the aortoiliac segment.