Piotr Abramczyk

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.

Tonic activity of carotid body chemoreceptors contributes to the increased sympathetic drive in essential hypertension

Carotid chemoreceptors provoke an increase in muscle sympathetic nerve activation (MSNA) in response to hypoxia; they are also tonically active during normoxic breathing. The contribution of peripheral chemoreceptors to sympathetic activation in hypertension is incompletely understood. The aim of our study was to investigate the effect of chemoreceptor deactivation on sympathetic activity in untreated patients with hypertension. A total of 12 untreated hypertensive males and 11 male controls participated in this randomized, crossover, placebo-controlled study. MSNA, systolic blood pressure(BP), diastolic BP, heart rate (HR), electrocardiogram, hemoglobin oxygen saturation (Sat%) and respiratory movements were measured during repeated 10-min periods of respiration with 100% oxygen or 21% oxygen in a blinded fashion. Compared with controls, hypertensives had higher resting MSNA (38±10 vs. 29±0.9 burst per min, P<0.05), systolic BP (150±12 vs. 124±10 mm Hg, P< 0.001) and diastolic BP (92±10 vs. 77±9 mm Hg, P<0.005). Breathing 100% oxygen caused significant decrease in MSNA in hypertensive patients (38±10 vs. 26±8 burst per min and 100±0 vs. 90±10 arbitrary units, P<0.05) and no change in controls (29±9 vs. 27±7 burst per min and 100±0 vs. 96±11 arbitrary units). BP, respiratory frequency and end tidal CO2 did not change during chemoreceptor deactivation with hyperoxia. HR decreased and Sat% increased in both the study groups. These results confirm the role of tonic chemoreceptor drive in the development of sympathetic overactivity in hypertension.

Sexual behavior in male rats after nitric oxide synthesis inhibition

The influence of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on the copulatory behavior of sexually experienced male Wistar rats was investigated. L-NAME was injected i.p. 10 min before the onset of a session using a dose of 30 mg/kg (L-NAME 30 group), or 60 mg/kg (L-NAME 60 group). The copulatory sessions were terminated after the third ejaculation in the control group or after 1500 s in the L-NAME 30 and L-NAME 60 groups. L-NAME administration reduced the number of rats that achieved ejaculation by 43% and 86% in the L-NAME 30 and 60 groups, respectively. In both experimental groups only a few intromissions and an increased number of mountings were observed. An increase in the number of ultrasonic vocalizations in the 50 kHz band, a dose-dependent effect, was observed. The level of sexual motivation evaluated by mount latency was not influenced by inhibition of NO synthesis.

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7±10 years). In this randomized, placebo-controlled, double-blinded study, patients were treated with simvastatin (40 mg day−1; n=15) or placebo (n=16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R–R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5±5 to 27.8±6 bursts per min, P=0.001), heart rate (from 77±6.7 to 71±6.1 beats per min, P=0.01) and both total and low-density lipoprotein cholesterol (from 249±30.6 to 184±28.3 mg dl−1, P=0.001 and from 169±30.6 to 117±31.2 mg dl−1, P=0.01, respectively). Simvastatin also improved BRS (from 10.3±4.1 to 17.1±4.3 ms per mm Hg, P=0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r=−0.94, P<0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

Deactivation of carotid body chemoreceptors by hyperoxia decreases blood pressure in hypertensive patients

Previous studies have shown that hyperoxia-induced deactivation of carotid body chemoreceptors reduces sympathetic activity in hypertensive patients but it does not affect blood pressure. The maintenance of blood pressure can be explained by the direct, vasoconstrictive effect of hyperoxia, which offsets diminished sympathetic activity. This study compares the effect of acute hyperoxia on hemodynamic parameters between hypertensive and normotensive subjects. Twelve males with hypertension (age 39.4±2.4 years; body mass index 27.4±1.1 kg m−2) and 11 normotensive males (age 39.9±2.7 years; body mass index 25.4±0.7 kg m−2) received, via non-rebreathing mask ventilation, ambient air, followed by 100% oxygen for 20 min. The stroke volume, heart rate, cardiac output, blood pressure, total peripheral resistance, respiratory rate, baroreceptor control of heart rate and oxygen saturation were recorded continuously. Several 30 s periods were analyzed before, during and after inducing hyperoxia. At baseline, the hypertensive subject’s blood pressure was higher and their baroreflex control of heart rate was lower when compared with the normotensive control group. After the first 30 s of hyperoxia, systolic, diastolic and mean blood pressures, as well as the total peripheral resistance, decreased significantly in hypertensives but not in normotensives. After 20 min of 100% oxygen ventilation, systolic and mean blood pressures and total peripheral resistance was increased in hypertensive patients, and the cardiac output and stroke volume had decreased in both groups. The results of this study confirm that deactivation of carotid body chemoreceptors can acutely decrease blood pressure in humans.

KIDNEY DENERVATION COMBINED WITH ELIMINATION OF ADRENAL–RENAL PORTAL CIRCULATION PREVENTS THE DEVELOPMENT OF HYPERTENSION IN SPONTANEOUSLY HYPERTENSIVE RATS

1. Kidney denervation in spontaneously hypertensive rats (SHR) during the prehypertensive stage delays and attenuates the development of hypertension. The same results have been obtained after elimination of the adrenal–renal portal circulation (ARPC). The aim of the present study was to investigate the influence of concomitant kidney denervation and elimination of ARPC on hypertension in SHR.

The effect of enalapril and telmisartan on clinical and biochemical indices of sympathetic activity in hypertensive patients.

Objective. To compare the effect of ARB and ACE inhibitor on sympathetic activity in 32 hypertensives. Design and Methods. After a four-week wash-out period, patients were randomized to four weeks of therapy with enalapril or telmisrtan, with crossover to another drug for another four weeks. Blood pressure (BP), NPY, and catecholamine levels and HRV (frequency analysis) were measured during wash-out, in basal condition, and after postural stimulation test (PST). Results. Both drugs significantly reduced BP and NPY as compared to initial values, while no differences in BP and NPY between drugs were observed. Increase in NPY during PST was significantly higher in the enalapril than in the telmisartan group and during the wash-out period. No differences between enalapril and telmisartan in plasma catecholamines were observed. Telmisartan decreased low frequency/high frequency ratio as compared to initial values and enalapril values. Conclusions. Despite similar BP control, telmisartan attenuated autonomic balance more effectively than enalapril.

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.

INTERNAL JUGULAR VEIN VALVE INSUFFICIENCY IN COUGH SYNCOPE

A 53-year-old man with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea was admitted to the hospital for the evaluation of recurrent syncopal episodes induced by paroxysmal cough. Loss of consciousness was brief, and preceded by the sensation of “fullness in the head.” Syncope was provoked also by prolonged expiration during spirometry, which revealed severe bronchial obstruction. However, oxygen saturation on room air and blood gases were within normal limits. To reproduce reported symptoms, the Valsalva maneuver (VM) was performed with the patient in the supine position with noninvasive, continuous blood pressure monitoring (Finapres, Ohmeda) and finger pulse oximetry. This resulted in a brief loss of consciousness, although no desaturation, decrease in blood pressure, or bradycardia was noted. Transthoracic echocardiography revealed normal left and right ventricular function, mild tricuspid insufficiency, and no evidence of pulmonary hypertension. There was no right-to-left shunt detected on the bubble-contrast study. Neurologic assessment, MRI of the brain, and EEG were unremarkable. Duplex-Doppler examination of extracranial carotid and vertebral arteries showed no stenosis. However, evaluation of the internal jugular veins (IJVs) with the use of color Doppler revealed right internal jugular valve insufficiency with flow reversal during inspiration (figure …

Occlusion of the adrenal vein leads to an increase in renal vascular resistance in the ipsilateral kidney.

1. The aim of the present study was to investigate the effect of an acute increase in blood flow through the adrenal‐renal vascular connection (ARVC), due to occlusion of the adrenal vein, on renal blood flow (RBF) and renal vascular resistance (RVR).