[Long-term outcome of EVAHEART I implantable ventricular assist device for the treatment of end stage heart failure: clinical 3-year follow-up results of 15 cases].

Objective: To evaluate the long-term efficacy and safety of the implantable ventricular assist system EVAHEART I in clinical use. Methods: Fifteen consecutive patients with end-stage heart failure who received left ventricular assist device therapy in Fuwai Hospital from January 2018 to December 2021 were enrolled in this study, their clinical data were retrospectively analyzed. Cardiac function, liver and kidney function, New York Heart Association (NYHA) classification, 6-minute walk distance and quality of life were evaluated before implantation and at 1, 6, 12, 24 and 36 months after device implantation. Drive cable infection, hemolysis, cerebrovascular events, mechanical failure, abnormally high-power consumption and abnormal pump flow were recorded during follow up. Results: All 15 patients were male, mean average age was (43.0±7.5) years, including 11 cases of dilated cardiomyopathy, 2 cases of ischemic cardiomyopathy, and 2 cases of valvular heart disease. All patients were hemodynamically stable on more than one intravenous vasoactive drugs, and 3 patients were supported by preoperative intra aortic balloon pump (IABP). Compared with before device implantation, left ventricular end-diastolic dimension (LVEDD) was significantly decreased ((80.93±6.69) mm vs. (63.73±6.31) mm, P<0.05), brain natriuretic peptide (BNP), total bilirubin and creatinine were also significantly decreased ((3 544.85±1 723.77) ng/L vs. (770.80±406.39) ng/L; (21.28±10.51) µmol/L vs. (17.39±7.68) µmol/L; (95.82±34.88) µmol/L vs. (77.32±43.81) µmol/L; P<0.05) at 1 week after device implantation. All patients in this group were in NYHA class Ⅳ before implantation, and 9 patients could recover to NYHA class Ⅲ, 3 to class Ⅱ, and 3 to class Ⅰ at 1 month after operation. All patients recovered to class Ⅰ-Ⅱ at 6 months after operation. The 6-minute walk distance, total quality of life and visual analogue scale were significantly increased and improved at 1 month after implantation compared with those before operation (P<0.05). All patients were implanted with EVAHEART I at speeds between 1 700-1 950 rpm, flow rates between 3.2-4.5 L/min, power consumption of 3-9 W. The 1-year, 2-year, and 3-year survival rates were 100%, 87%, and 80%, respectively. Three patients died of multiple organ failure at 412, 610, and 872 d after surgery, respectively. During long-term device carrying, 3 patients developed drive cable infection on 170, 220, and 475 d after surgery, respectively, and were cured by dressing change. One patient underwent heart transplantation at 155 d after surgery due to bacteremia. Three patients developed transient ischemic attack and 1 patient developed hemorrhagic stroke events, all cured without sequelae. Conclusion: EVAHEART I implantable left heart assist system can effectively treat critically ill patients with end-stage heart failure, can be carried for long-term life and significantly improve the survival rate, with clear clinical efficacy.

[Clinical application of modified minimally cardiopulmonary bypass: compared with conventional cardiopulmonary bypass].

OBJECTIVE: To evaluate the safety and effects on blood transfusion of modified minimally cardiopulmonary bypass (CPB). METHODS: From April 2013 to February 2016, 1 103 elective cardiac surgery cases in National Center for Cardiovascular Diseases China, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were prospectively enrolled in the study. Patients undergoing modified minimally CPB were assigned to mini-CPB group (n=553), the others undergoing conventional CPB were assigned to conventional group (n=550). In mini-CPB group, oxygenator with integrated arterial filter, modified minimized circuit, mini-cardioplegia and vacuum assisted venous drainage(VAVD) were used. In conventional group, conventional CPB was composed with conventional oxygenator from the same manufactory, conventional circuit and 1∶4 blood cardioplegia. Analysis was performed with t test, t' test, Wilcoxon rank-sum test, χ(2) test, and Fisher exact test. RESULTS: No CPB accidents and peri-operative stroke were observed. There was no statistical difference in postoperative mechanical ventilation time, length of ICU stay, postoperative complications and mortality between the two groups. The incidence of erythrocyte transfusion (13.7% vs. 27.6%, χ(2)=32.458, P=0.000) and the incidence of ultrafilter (11.0% vs. 33.7%, χ(2)=76.019, P=0.000) were lower in the mini-CPB group. Postoperative hematocrit (M(QR): 32.9 (5.7) vs. 32.2 (5.7), Z=3.403, P=0.001) and 12-hour chest drainage ((228±154) ml vs.(260±197) ml, t'=3.004, P=0.003) of mini-CPB were imporved compared with conventional group. CONCLUSIONS: Modified minimally CPB is safe. It might reduce erythrocyte transfusion for adult cardiac surgery, warranting widely adoption.

Nitroreduction of 4-nitropyrene is primarily responsible for DNA adduct formation in the mammary gland of female CD rats.

We determined whether DNA adducts derived from 4-nitropyrene (4-NP) are formed via nitroreduction or ring oxidation. DNA adduct markers derived from both pathways were prepared and, consequently, were compared with those obtained in vivo in rats treated with 4-NP. Following in vitro reaction of 9,10-epoxy-9,10-dihydro-4-nitropyrene (4-NP-9,10-epoxide), an intermediate metabolite derived from ring oxidation of 4-NP, with calf thymus DNA (average level of binding in two determinations was 8.5 nmol/mg of DNA), DNA was enzymatically hydrolyzed to deoxyribonucleosides and the DNA hydrolysates were analyzed by HPLC. Electrospray mass and 1H NMR spectra of the major products indicated that these adducts are deoxyguanosine (dG) derivatives that resulted from N2-dG substitution at the 9- or 10-position of the pyrene nucleus. However, these adducts were not detected in vivo in the rat mammary gland and liver following the administration of 4-NP. Nitroreduction of 4-NP catalyzed by xanthine oxidase in the presence of DNA resulted in three major putative DNA adducts (level of binding of 12.0 +/- 1.1 nmol/mg of DNA, n = 4) designated as peak 1 (46%), peak 2 (25%), and peak 3 (17%). Although peak 1 was further resolved into peaks 1a and 1b, both were unstable and gradually decomposed to peak 2, and the latter was unequivocally identified as pyrene-4,5-dione. On the basis of electrospray mass spectral analysis, peak 3 was tentatively identified as a deoxyinosine-derived 4-aminopyrene adduct. None of the adducts derived from nitroreduction of 4-NP catalyzed by xanthine oxidase coeluted with the synthetic standard N-(deoxyguanosin-8-yl)-4-aminopyrene prepared by reacting dG with N-acetoxy-4-aminopyrene. Nevertheless, HPLC analysis of the hydrolysates of liver and mammary DNA obtained from rats treated with [3H]-4-NP yielded four radioactive peaks, all of which coeluted with the markers derived from the nitroreduction pathway. These results indicate that nitroreduction is primarily responsible for DNA adduct formation in the liver and, especially, in the mammary gland which is the organ susceptible to carcinogenesis by this environmental agent.

Evaluation of benzyl selenocyanate glutathione conjugate for potential chemopreventive properties in colon carcinogenesis.

Observational, clinical and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. Since toxicity and chemopreventive efficacy of selenium compounds depend to a large extent, on the form of selenium the development of efficacious organoselenium compounds with low toxicity is being pursued in our laboratory. We have assessed the chemopreventive properties of a newly synthesized organoselenium compound, benzyl selenocyanate glutathione conjugate (BSeSG), and of benzyl selenocyanate (BSC), as a positive control, using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 10 or 20 ppm BSeSG (1.7 and 3.4 ppm as Se, respectively), or 10 ppm BSC (4.1 ppm as Se). One week later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg of body weight, once weekly for 2 weeks). All animals were sacrificed 7 weeks after the last AOM injection, and the ACF, levels of prostaglandin E2 (PGE2), cyclooxygenase protein expression (COX-1 and -2), and glutathione S-transferase type mu (GST-mu) were determined in the colon. As expected, dietary administration of BSC suppressed ACF development by about 37%. In rats administered 10 or 20 ppm BSeSG, the frequencies of AOM-induced colonic ACF were significantly decreased compared to those of rats given AOM and control diet by about 41% (P<0.01) and 61% (P<0.001), respectively. Administration of BSeSG inhibited PGE2 production (81-88% inhibition) via COX-2 synthesis in the colonic mucosa (18-60% inhibition). Also, BSeSG increased GST-mu protein activity in colonic mucosa (30-32% increase). These data suggest that a newly synthesized organoselenium compound, BSeSG might be a promising chemopreventive agent against colon carcinogenesis.

Comparative metabolism and DNA binding of 1-, 2-, and 4-nitropyrene in rats.

The metabolism and DNA binding studies of mono-NP isomers under identical conditions were conducted, as an initial investigation, in order to provide an understanding for the higher carcinogenic activity of 4-NP in the rat mammary gland. Urinary and fecal excretion patterns of 4-NP and 1-NP 24 h following administration to female CD rats (i.p.; 24 mg/kg body weight; 1.55 mCi/rat) were similar but higher than those of 2-NP. The identified metabolites were formed via nitroreduction and ring oxidation pathways. Neither the excretion patterns nor the nature of the metabolites readily explained why the mammary tumorigenic activity of these three isomers varied. Although overall levels of mono-NP bound to liver DNA did not account for the observed differences in the biological activity, further HPLC analysis of the liver DNA hydrolysates showed that only 4-NP had yielded putative multiple DNA adducts; none were detected in the case of 1-NP and 2-NP. 1-, 2-, and 4-NP were found to bind to mammary DNA at levels of 0.6, 0.3, and 2.1 pmol/mg DNA, respectively. The structure of DNA adducts in the mammary gland and in the liver of female CD rats following the i.p. administration of 4-NP has not been identified. Collectively, the results of this preliminary study indicate that the difference in levels of DNA binding in the mammary gland in vivo may reflect why 4-NP has higher carcinogenic activity.

Lack of tumorigenicity of cholesterol epoxides and estrone-3,4-quinone in the rat mammary gland.

The purpose of this study is to test the long-standing hypothesis that endogenous agents found in human breast fluid and in plasma are potential initiators of breast cancer. Therefore, we evaluated the tumorigenicity in the mammary glands of female CD rats of cholestan-5 alpha,6 alpha-epoxy-3 beta-ol (cholesterol-alpha-epoxide), cholestan-5 beta,6 beta-epoxy-3 beta-ol (cholesterol-beta-epoxide), and 1,5(10)estradiene-3,14,17-trione (estrone-3,4-quinone). As a positive control, trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthren e (BcPDE) was used. Rats were fed a high-fat AIN-76A diet (23.5% corn oil) to mimic the Western dietary composition. Because literature data suggest that the endogenous agents tested in this study are weak electrophiles, the total doses of cholesterol epoxides (12.3 mumol/rat) and of estrone-3,4-quinone (30 mumol/rat)were 10- and 25- fold higher, respectively, than that of BcPDE (1.2 mumol/rat). Each agent was dissolved in DMSO, and one-sixth of the total dose was injected under each of six nipples on the right side. The thoracic glands of the rat were treated at 30 days of age, and those located in the inguinal area were treated on the following day. The experiment was terminated at 44 weeks after treatment. Consistent with our previous study, BcPDE was a strong mammary carcinogen. However, there were no differences between rats treated with DMSO alone or those receiving DMSO containing cholesterol-alpha-epoxide, cholesterol-beta-epoxide, or estrone-3,4-quinone. The results of this study clearly indicate, for the first time, that metabolites derived from cholesterol and estrone lack tumorigenic activity in the rat mammary gland, at least under the conditions of the present protocol.