[The prognostic value of preoperative peripheral blood inflammatory biomarkers for intrahepatic cholangiocarcinoma after radical resection].

Objective: To explore the value of preoperative peripheral blood inflammatory biomarkers for predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection. Methods: A total of 124 patients who underwent radical resection for ICC in the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2018 were retrospectively analyzed. Receiver operating characteristic (ROC) curve was conducted to determine the best cut-off values of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), systemic immune inflammatory index (SII), and systemic inflammatory response index (SIRI). Univariate and multivariate analyses of prognostic factors were performed using Cox proportional hazards regression model. Based on the independent prognostic factors screened by multivariate Cox regression analysis, a nomogram model of overall survival prediction for ICC patients after radical resection was established. Results: Among the 124 patients, 87 patients died and 37 patients survived during the follow-up period. The median overall survival time of the whole patients was 21 months. ROC curve analysis showed that the areas under the curve (AUC) of NLR, PLR, LMR, SII and SIRI for predicting the overall survival of ICC patients after radical resection were 57.86%, 64.21%, 60.61%, 67.57% and 66.03%, respectively. Univariate Cox regression analysis showed that the inflammatory biomarkers of NLR, PLR, SII, and SIRI were associated with overall survival of ICC after radical resection (HR=1.787, 95%CI: 1.165-2.741; HR=1.181, 95% CI: 1.224-2.892; HR=2.412, 95% CI: 1.565-3.717; HR=1.648, 95% CI: 1.081-2.513). Multivariate Cox regression analysis showed that the inflammatory biomarker of SII was an independent prognostic factor of ICC after radical resection (HR=1.863, 95% CI: 1.161-2.989). According to the best cut-off value of SII to predict the overall survival of ICC patients after radical resection (709.86×10(9)/L), the patients were divided into low SII group (SII≤709.86×10(9)/L) and high SII group (SII>709.86×10(9)/L). In the high SII group, the proportions of NLR>3.31, PLR>3.31, SIRI>1.30×10(9)/L, carbohydrate antigen 19-9>39.0 U/ml, Child-Pugh liver function (grade B), hemi-hepatic/extended hepatectomy, combined perineural invasion, N1 stage and TNM stage (ⅢB) were higher than those in the low SII group (P<0.05). Based on the independent prognostic factors screened by multivariate Cox regression analysis, a nomogram model of overall survival prediction for ICC after radical resection was established, the C-index values of the training set and testing set were 0.774 and 0.737, respectively. Conclusions: Preoperative peripheral blood inflammatory marker SII is an independent risk factor for the prognosis of intrahepatic cholangiocarcinoma patients after radical resection. The nomogram model of overall survival prediction established that included SII has a good predictive ability and can be used to evaluate the prognosis of intrahepatic cholangiocarcinoma patients after radical resection.

[Analysis of perineural invasion with clinicopathological factors and prognosis for curatively resected gallbladder carcinoma].

Objective: To examine the correlation between perineural invasion and clinicopathological factors and the role of perineural invasion on the prognosis of patients with curatively resected gallbladder carcinoma. Methods: The clinicopathological and follow-up data of 548 patients with gallbladder carcinoma who underwent radical surgery from the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to December 2020 were analyzed retrospectively. There were 173 males and 375 females,with age(M(IQR)) of 62(14)years(range:30 to 88 years). The correlations between perineural invasion and the clinicopathological features were analyzed. The relationship between prognosis and clinicopathological factors were further analyzed. The survival curve was drawn using the Kaplan-Meier method. The univariate analysis and multivariate analysis were done using the Log-rank test and Cox proportional hazard model respectively. Results: Radical resection was performed in 548 cases,including 59 cases(10.8%) with perineural invasion. The results of univariate analysis showed that perineural invasion was related to serum bilirubin level,serum carcinoembryonic antigen(CEA) level,CA19-9 level,T stage,lymph node metastasis,liver invasion,vessel invasion and tumor location(all P<0.05).The results of multivariate analysis showed that jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder were independent risk factors of perineural invasion in gallbladder carcinoma. Survival of 367 patients in T3-T4 stages were analyzed. The prognosis of gallbladder carcinoma patients with perineural invasion was significantly worse than that of patients without perineural invasion(median survival time:12.0 months vs. 34.7 months,P<0.01). Univariate analysis showed that perineural invasion,gallbladder stones,gallbladder polyps,CA125,CEA,CA19-9,serum bilirubin level,tumor location,N stage,liver invasion and pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). The results of Cox proportional hazard model showed that perineural invasion,N stage,liver invasion,gallbladder stones,pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). Conclusions: Jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder are independent risk factors for perineural invasion of gallbladder carcinoma. Perineural invasion is one of the independent risk factors affecting the prognosis of T3-T4 stage gallbladder carcinoma.

[Impact of adjuvant chemotherapy on prognosis in intrahepatic cholangiocarcinoma patients underwent radical resection].

Objectives: To investigate the clinical value of adjuvant chemotherapy(ACT) in patients with intrahepatic cholangiocarcinoma(ICC) who underwent radical resection and to explore the optimal population that can benefit from ACT. Methods: A retrospective cohort study method was adopted. The clinical and pathological data of 685 patients with ICC who underwent curative intent resection in 10 Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected;There were 355 males and 330 females. The age(M(IQR)) was 58(14) years (range: 22 to 83 years). Propensity score matching(PSM) was applied to balance the differences between the adjuvant and non-adjuvant chemotherapy groups. Log-rank test was used to compare the prognosis of the two groups of patients. A Bayesian network recurrence-free survival(RFS) prediction model was constructed using the median RFS time (14 months) as the target variable, and the importance of the relevant prognostic factors was ranked according to the multistate Birnbaum importance calculation. A survival prognostic prediction table was established to analyze the population benefiting from adjuvant chemotherapy. Results: Among 685 patients,214 received ACT and 471 did not receive ACT. A total of 124 pairs of patients were included after PSM, and patients in the ACT group had better overall survival (OS) and RFS than those in the non-ACT group(OS: 32.2 months vs. 18.0 months,P=0.003;RFS:18.0 months vs. 10.0 months,P=0.001). The area under the curve of the Bayesian network RFS prediction model was 0.7124. The results of the prognostic factors in order of importance were microvascular invasion (0.158 2),perineural invasion (0.158 2),N stage (0.155 8),T stage (0.120 9), hepatic envelope invasion (0.090 3),adjuvant chemotherapy (0.072 1), tumor location (0.057 5), age (0.042 3), pathological differentiation (0.034 0), sex (0.029 3), alpha-fetoprotein (0.028 9) and preoperative jaundice (0.008 5). A survival prediction table based on the variables with importance greater than 0.1 (microvascular invasion,perineural invasion,N stage,T staging) and ACT showed that all patients benefited from ACT (increase in the probability of RFS≥14 months from 2.21% to 7.68%), with a more significant increase in the probability of RFS≥14 months after ACT in early-stage patients. Conclusion: ACT after radical resection in patients with ICC significantly prolongs the OS and RFS of patients, and the benefit of ACT is greater in early patients.

[Prognostic value of preoperative peripheral blood neutrophil-to-lymphocyte ratio and γ-glutamyl transpeptidase-to-platelet ratio index in patients with hepatitis B virus related intrahepatic cholangiocarcinoma after radical resection].

Objective: To explore the value of preoperative neutrophil-to-lymphocyte ratio (NLR) and γ-glutamyl transpeptidase-to-platelet ratio index (GPRI) for predicting the prognosis of patients with HBV-related intrahepatic cholangiocarcinoma (ICC) after radical resection. Methods: The data of 79 patients who underwent radical resection for HBV-related ICC in the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2018 were retrospectively analyzed. Among them, 48(60.8%) patients were male and 31 (39.2%) patients were female, (56.9±11.2) years old. X-Tile statistical software was used to determine the best cut-off values of NLR and GPRI. The χ2 test was conducted to analyze the relationship between preoperative NLR and GPRI and the clinicopathological characteristics, and the Cox proportional hazard regression model was conducted for multivariate analysis. A nomogram prognostic prediction model was established based on independent risk factors screened by Cox regression model. Results: The best cut-off values of NLR and GPRI were 3.13 and 1.31 determined by the X-Tile software, respectively. With the best cut-off value, 79 patients were divided into NLR≤3.13 group (45 cases) and NLR>3.13 group (34 cases). GPRI≤1.31 group (54 cases) and GPRI>1.31 group (25 cases). Compared with the preoperative NLR ≤3.13 group, the proportion of patients with liver cirrhosis and atrophy, poor pathological differentiation, tumor diameter>5 cm and late TNM stage was significantly increased in the NLR>3.13 group (all P<0.05); Compared with preoperative GPRI ≤1.31 group, the proportion of patients with liver cirrhosis and atrophy was significantly increased in the GPRI>1.31 group (P=0.025). The postoperative overall survival time of the included patients was 2 to 126 months, with the median survival time being 18 months, and the 1, 3-year overall survival rates were 63.3%, 32.8%, respectively. Multivariate analysis showed that NLR, GPRI, liver cirrhosis and atrophy, and lymphatic metastasis were independent risk factors affecting the overall survival of patients with HBV-related ICC after radical resection (P<0.05). A nomogram prediction model was established based on independent risk factors, with the C-index of 0.750, and the prediction effect was close to the actual survival outcome of the patients. Conclusion: Preoperative peripheral blood NLR and GPRI can be used to predict the prognosis of patients with HBV-related ICC after radical resection.

[Clinical and imaging characteristics of patients with different types of infectious sacroiliitis].

To investigate the clinical manifestations and imaging characteristics of patients with different types of infectious sacroiliitis. Clinical data of 40 patients diagnosed with infectious sacroiliitis were retrospectively analyzed. Among the 40 patients, 16 patients were diagnosed as non-brucellar and non-tuberculous infectious sacroiliitis (ISI), 13 with tuberculous infectious sacroiliitis (TSI), and 11 with brucellar sacroiliitis (BSI). In the ISI and TSI group, female patients accounted for 11/16, 12/13, while the proportion of unilateral involvement was 15/16 and 12/13, respectively. Compared with ISI and TSI group, BSI patients were mainly male (8/11) and presented more bilateral involvement (6/11) (P<0.05). Bone erosion was more common in ISI and TSI groups than in BSI group (6/15, 7/11 and 2/10), as well as abscess formation (3/15, 4/11 and 1/10, respectively). Symptoms in all patients relieved 1-2 weeks after administration of antibiotics or anti-tuberculosis treatment, but the resolution of the magnetic resonance imaging findings delayed about 6 (3-9) months. ISI and TSI patients with infectious sacroiliitis should be differentiated from spondyloarthritis, with a characteristic of more female patients, unilateral sacroiliitis, bone erosion, soft tissue involvement and abscess formation. However, BSI patients are mainly male, more bilateral involvement and less bone destruction and abscess formation. Antibiotic therapy demonstrates significant therapeutic effects, but resolution of the magnetic resonance imaging findings responses late.

[Analysis of related factors for gallstones related gallbladder intraepithelial neoplasia and establishment of prediction models].

Objective: To evaluate the related factors of gallstones related gallbladder intraepithelial neoplasia(GBIN) and establish the prediction models for gallstones related GBIN. Methods: The clinicopathological data of 750 patients who underwent cholecystectomy for gallstones at Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to December 2018 and the postoperative pathological examination showed chronic cholecystitis or GBIN were analyzed retrospectively,including 150 cases of gallstones with GBIN and 600 cases of gallstones with chronic cholecystitis.There were 264 males and 486 females with age of (51.3±14.5) years (range: 18 to 90 years).The related factors for gallstones related GBIN were screened by χ2 test and Logistic regression model,and the prediction models were established based on independent related factors and internal validation was conducted.The original data were randomly divided into a training cohort(526 cases) and a validation cohort(224 cases) at a ratio of 7∶3,and the nomogram and tree augmented naïve Bayes were conducted to establish the prediction model for gallstones related GBIN.The consistency index(C-index),calibration chart,area under the receiver operating characteristic curve(AUC) and confusion matrix were used to evaluate the prediction performance of the two models. Results: Univariate analysis showed that age,gallstones history(years),gallbladder size,whether the gallbladder mucosa smooth or not,whether the gallbladder wall thickened or not,gallstones diameter,and number of gallstones were related factors for the occurrence of gallstones related GBIN (χ²=19.957,8.599,9.724,9.301,8.341,15.288,9.169,all P<0.05).Multivariate analysis showed that age (OR=2.23,95%CI:1.50-3.31,P<0.01),gallbladder size (OR=2.11,95%CI:1.17-3.80,P=0.013),whether the gallbladder mucosa smooth or not (OR=1.80,95%CI=1.13-2.88,P=0.014),gallstones diameter(OR=2.98,95%CI:1.71-5.21,P<0.01),and number of gallstones (OR=2.14,95%CI=1.34-3.42,P<0.01) were independent related factors for the occurrence of gallstones related GBIN; the C-index of the nomogram in training cohort and validation cohort were 0.708 and 0.696,respectively.The AUC of the two models in training cohort were 70.60% and 70.73%,and in validation cohort were 68.14% and 67.47%,respectively.The accuracy of the two models in training cohort were 69.96% and 70.72%,and in validation cohort were 66.96% and 67.41%,respectively. Conclusion: Age,gallbladder size,whether the gallbladder mucosa smooth or not,gallstones diameter and number of gallstones are independent related factors for the occurrence of gallstones related GBIN,and the nomogram and tree augmented naïve Bayes prediction models based on the above factors can be used to predict the occurrence of GBIN.

Intracellular survival of virulence and low-virulence strains of Vibrio parahaemolyticus in Epinephelus awoara macrophages and peripheral leukocytes.

In this study, we examined the virulence factors and pathogenesis of Vibrio parahaemolyticus in Epinephelus awoara. The chemotactic motility of V. parahaemolyticus for phagocytosis and intracellular survival in fish macrophages was determined using virulence strains and low-virulence strains of V. parahaemolyticus. We found that the intracellular mean number of virulence strains of V. parahaemolyticus ranged from 0-180 min after co-incubation with macrophages and peripheral leukocytes, was relatively low, and decreased steadily over the observation period. Low-virulence strains of V. parahaemolyticus were unable to survive in peripheral leukocytes and macrophages. Cell viability in response to V. parahaemolyticus was assessed using the MTT assay. Low-virulence V. parahaemolyticus strains exhibited lower cytotoxicity compared to virulent strains. The average percent of live macrophages and peripheral leukocytes infected by V. parahaemolyticus ranged from 13.50-79.20%. These results indicate that V. parahaemolyticus in E. awoara is a facultative intracellular bacterium that may be involved in virulence.

Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

[Electromechanical mapping of myocardial ischemia in coronary occlusion in the pig]. / Cartographie électromécanique du myocarde ischémique dans un modèle d'occlusion coronaire progressive chez le porc.

The NOGA-Biosense catheter-based mapping technique has been well studied experimentally in infarction model. However, chronic myocardial ischemia with this new device has not been well explored. Thus, the aim of our study was to assess electromechanical changes in a pig aneroid constricor model. To achieved this aim, ten pigs were studied 21 days after the implantation of an aneroid constrictor around the circumflex artery. Coronary reserve assess by intracoronary Doppler flow wire was reduced in the ischemic lateral area (ILA) compared with the nonischemic zone (NIZ) (1.3 +/- 0.1 in the ILA vs. 2.3 +/- 0.2 in the NSZ; p < 0.01). TM echocardiography was used to evaluate myocardial regional contractility under basal condition and after stress induced by rapid atrial pacing. In stress state, the ischemic zone showed an impaired contractility compared with basal state (wall thickening, 32.7 +/- 7.4% vs. 59.7 +/- 8.6%; p < 0.05) whereas the non ischemic zone did not (53.8 +/- 7.6% vs. 60.8 +/- 10.1%; p = ns). Constrast echography showed a decrease in contrast intensity in subendocardium of the ila compared with the niz (46.2 +/- 16.6 vs. 99.2 +/- 35.6; p = 0.03) in pacing. Ventricular mapping quantified unipolar (UV). bipolar (BV) voltage potentials and endocardial local shortening (LLS) in 9 left ventricular regions. In basal state, electrical potentials were preserved in both zones (UV: 9.1 +/- 1.8 mV in the ischemic vs 11.3 +/- 3.6 mV in the non ischemic zone; p = ns; BV: 4.2 +/- 1.1 mV in the ILA vs. 3.9 +/- 1.5 mV; p = ns). In contrast, LLS was significantly lower in the ischemic compared with non ischemic zone (6.4 +/- 5.4% vs. 17.9 +/- 3.0%, p < 0.001). In conclusion, ventricular mapping with the NOGA-Biosense system can identify the ischemic myocardium. In this pig model, the association of a preserved electrical activity and an impaired mechanical activity characterizes the ischemic myocardium. These findings could be interesting in this model in regard of the new developments of the system in particular in the field of angiogenesis.

[Aldosterone and its antagonists in heart failure]. / L'aldostérone et ses antagonistes dans l'insuffisance cardiaque.

THE ROLE OF ALDOSTERONE: Aldosterone is the key hormone in salt-water homeostasis. In heart failure, it participates in the appearance and maintenance of signs of congestion. Predominantly synthesised in the glomerular area of the cortico-adrenal glands, extra adrenal production areas have recently been identified notably in the brain, the heart and the large artery trunks. Aldosterone is activated in the cells by the intracellular mineral corticoid receptor. IN CARDIOVASCULAR-PATHOLOGIES: In chronic heart failure, patients treated with conversion enzyme inhibitor may escape from the renin-angiotensin blockade and this may lead to increased aldosterone plasma levels. This increase can induce not only vascular lesions and myocardial fibrosis but also renal and cerebral lesions. THE EFFECTS OF SPIRONOLACTONE: In patients with NYHA stage III or IV heart failure, addition of spironolactone to the treatment with conversion enzyme inhibitor, diuretic and/or digitalis leads to a reduction in morbidity and mortality, as demonstrated in the RALES study. The mechanisms by which spironolactone has a beneficial effect remain discussed. IN CLINICAL PRACTICE: The prescription of spironolactone is limited by hormonal side effects it provokes. IN THE FUTURE: Eplerenone, a new competitive aldosterone receptor antagonist that appears to be devoid of such side effects and which, at least experimentally may well have the same beneficial effects, is presently under clinical assessment.

Inflammation, cytokines and anti-inflammatory therapies in heart failure.

Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Certain categories in patients with dilated cardiomyopathy have shown the presence of humoral and cellular immunity activation suggesting a possible relation between myocarditis and dilated cardiomyopathy. Recent studies suggest a link between the circulating levels of cytokines (TNF alpha IL-1 et IL-6), the clinical status and prognostic. However, the mechanisms connecting heart failure and cytokine activation are unclear and the sites of cytokines production remain controversial. In the clinical setting, specific measurements of cytokines are not available. As tests of inflammation, erythrocyte sedimentation rate and C-reactive protein concentration appear to have interesting pronostic values. Current conventional therapy i.e. ACE inhibitors, type I angiotensin II antagonist and beta-blockers have shown some anti-cytokine properties. Recently, immunosuppressive therapies have shown their ability to improve symptoms and LV ejection in selected patients with dilated cardiomyopathy and clear sign of myocardium inflammation. Specific anti-cytokine therapy have been developed and showed interesting results in preliminary clinical studies. However large clinical trials testing this new therapy have been stoppel prematurely because of deterious effects.

[Future molecules in heart failure]. / Molécules du futur dans l'insuffisance cardiaque.

TODAY: The management of heart failure (HF) has considerably progressed over the last two decades. Treatment today relies on prevention and treatment of congestion (limited salt intake, diuretics, converting enzyme inhibitors) and limiting neurohormone stimulation (converting enzyme inhibitors +/- aldactone, beta-blockers). IN THE YEARS TO COME: Based on new concepts, several therapeutic strategies are interesting: blocking over vasoconstrictor systems which have not been taking into account; stimulation of vasodilator and natriuretic systems; modulation of cardiac remodelling; modulation of the immune and inflammatory systems; modification in intrinsic contractility; prevention of rhythm disorders. Among these differing strategies and molecules, it is not easy to predict those that will change the HF prognosis. In any event, their efficacy and safety remain to be demonstrated with large cohort randomised studies. THE PRINCIPLES: To reduce the number of drugs administered, two options appear particularly interesting: measurement of hormone levels (BNP) in order to adjust treatment and administration of molecules with greatest efficacy and safety profiles; limit cardiac remodelling by using new imaging techniques to detect it more precisely and select the molecule(s) exerting the required effect. To target the new molecules better, patients should be classified according to their etiology, stage and progressive profile of their disease, cardiac remodelling, expression of principle endocrine systems and pro-inflammatory cytokines, expression of inflammatory and immune systems and inherent genetic characteristics and response to treatment. This would permit the adaptation of treatment to each individual patient with heart failure.

Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs: comparison with B(2) receptor stimulation.

BACKGROUND: Constitutive bradykinin B(1) receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg(9)-bradykinin (a B(1) receptor agonist) and the mechanisms involved. METHODS AND RESULTS: Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg(9)-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg(9)-bradykinin was less potent than bradykinin. Hoe 140 (a B(2) antagonist, 10 microg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg(9)-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg(9)-bradykinin were maintained. Intracoronary lisinopril (0. 75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg(9)-bradykinin responses. Intracoronary N(omega)-nitro-L-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg(9)-bradykinin. The relaxing effect of des-Arg(9)-bradykinin on isolated coronary rings was prevented by des-Arg(9), [Leu(8)]-bradykinin. CONCLUSIONS: In the conscious dog, B(1) receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B(1) receptor stimulation is not as great as that produced by B(2) receptor stimulation.

Increased bradykinin levels accompany the hemodynamic response to acute inhibition of angiotensin-converting enzyme in dogs with heart failure.

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Preserved vasodilator effect of bradykinin in dogs with heart failure.

BACKGROUND: In heart failure (HF), vasoconstrictor systems are activated and endothelium-derived vasodilation is blunted. Bradykinin, a potent vasodilator, may play an important role in this setting. However, it is not known whether its vasodilator effect is modified in HF. METHODS AND RESULTS: Fourteen chronically instrumented dogs were studied in the control state and in pacing-induced HF (250 bpm for 3 weeks). The dose-dependent decrease in mean aortic pressure (MAP) induced by acetylcholine was significantly blunted in HF. In contrast, in both control and HF, bradykinin infusion caused similar dose-dependent decreases in MAP and increases in cardiac output (CO). This vasodilator effect of exogenous bradykinin was potentiated similarly in both states by enalaprilat, which blocks both angiotensin conversion and bradykinin degradation. For evaluating the role of endogenous bradykinin, the effects of enalaprilat were compared with those of ciprokiren, a pure renin inhibitor. In control, ciprokiren did not produce any effect. Enalaprilat, however, produced a significant decrease in MAP and a significant increase in CO, which were attributed to the inhibition of bradykinin degradation, because these effects were absent after pretreatment with Hoe 140 (a bradykinin B2 receptor antagonist). In contrast, in HF, vasodilator effects of ciprokiren were observed, but enalaprilat produced larger changes in MAP and CO, and after Hoe 140, the hemodynamic effects of enalaprilat were significantly decreased, showing the effects of endogenous bradykinin, which were similar to those measured in control. CONCLUSIONS: In this model of HF with a blunted endothelium-derived vasodilation, the vasodilator effects of exogenous and endogenous bradykinin are preserved. These results suggest that bradykinin may play an important role in HF, in which vasoconstriction is present and endothelium-dependent vasodilation is blunted.

[Physiopathological basis of the treatment of heart failure]. / Bases physiopathologiques du traitement de l'insuffisance cardiaque.

Therapeutic advances have changed the mode of presentation of cardiac failure over the last decades: the main cause, nowadays, is myocardial ischaemia. The modern treatment of cardiac failure is based on relatively simple physiopathological mechanisms which take into account the different aspects of cardiac physiology: a pump, a muscle, a coronary circulation supplying oxygen to the myocardium, an automatic contraction. The concept of vasodilatation and the blocking of vasoconstrictive systems introduced during the 70s is the basis of modern treatment of cardiac failure which involves angiotensin converting enzyme inhibitors and, increasingly, betablockers. In the near future, with earlier treatment of cardiac failure, the stimulation of vasodilator systems could become a new therapeutic strategy. Early detection of ischaemia and its complications with the aim of limiting the loss of cardiac myocytes is a priority for slowing the progression of cardiac failure. The prevention of cardiac failure also depends on educating cardiologists to treat rapidly the factors predisposing to or prolonging episodes of even mild cardiac failure.

[Effects of high sodium intake on ventricular remodeling in mice]. / Effets du régime hypersodé sur le remodelage ventriculaire gauche du coeur de souris.

BACKGROUND: Despite extensive research, controversy still exists regarding the role of dietary sodium intake on hypertension and left ventricular (LV) hypertrophy. Echocardiography is a powerful tool to assess LV hypertrophy and recent technical developments allow now its use in small animals. METHODS: We examined the effect of high sodium intake on LV geometry using echocardiography in mice. Three groups of Swiss mice were submitted, for 8 weeks, to different salt diets (0.6, 2 and 4% NaCl; n = 12, n = 8 and n = 12 respectively). LV end-diastolic (ED) septal and posterior wall thicknesses, LV ED diameter were measured at baseline, 4 and 8 weeks. RESULTS: At baseline, heart rate, LV ED septal and posterior wall thicknesses and LV ED diameter were similar between groups. At 8 weeks, for similar heart rate, LV ED posterior wall thickness were not different (0.6%: 0.64 +/- 0.01, 2%: 0.62 +/- 0.08 and 4%: 0.67 +/- 0.03 mm respectively) but LV septal wall thickness ass increased in a salt diet dependent manner (0.6%: 0.63 +/- 0.01, 2%: 0.75 +/- 0.01, 4%: 0.80 +/- 0.02 mm, p < 0.01). This increase was correlated with urinary sodium excretion (r = 0.84, p < 0.01) but occurred in the absence of change in arterial pressure (tail-cuff plethysmography; 0.6%: 135 +/- 6.2%: 127 +/- 4 and 4%: 139 +/- 9 mmHg respectively). The in-vivo interventricular septal remodeling was confirmed in perfused fixed preparations of hearts. CONCLUSION: Echocardiography allows precise measurements of regional LV wall dimensions in mice, and high sodium intake, in the absence of hypertension, induces interventricular septal remodeling.

Bradykinin pathway is involved in acute hemodynamic effects of enalaprilat in dogs with heart failure.

To determine the role of the renin-angiotensin system and the bradykinin pathway in the mechanism of action of angiotensin-converting enzyme inhibitors in heart failure, the acute effects of enalaprilat (1 mg/kg) were compared with those of a renin inhibitor (ciprokiren, 1 mg/kg i.v.) in 10 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (3 wk, 240 beats/min). The effects of enalaprilat and ciprokiren on bradykinin infusion (3, 10, and 30 micrograms/min) and the effects of enalaprilat in the presence of the bradykinin B2 receptor antagonist Hoe-140 (10 micrograms/kg i.v.) were also examined. Both inhibitors significantly decreased mean aortic pressure and increased cardiac output. However, enalaprilat induced significantly greater hemodynamic effects than ciprokiren (mean aortic pressure, -13 +/- 3 vs. -6 +/- 1 mmHg; cardiac output, 0.4 +/- 0.1 vs. 0.15 +/- 0.1 l/min). Bradykinin infusion led to dose-dependent decreases in mean aortic pressure and increases in cardiac output that were not modified by pretreatment with ciprokiren but were potentiated 10-fold by enalaprilat. Hoe-140 significantly reduced the hemodynamic effects of enalaprilat. Thus endogenous bradykinin is involved in the acute hemodynamic effects of enalaprilat in experimental heart failure.

Regional alterations of left ventricular contraction and inotropic reserve in conscious dogs with heart failure.

OBJECTIVE: The goal was to examine left ventricular (LV) regional contraction alterations and especially, regional inotropic reserve changes in tachycardia-induced heart failure (HF). METHODS: Eleven dogs were chronically instrumented to measure LV pressure and its first time derivative (LV dP/dt), left atrial and aortic pressures and to measure antero-apical (AS), -basal (BS) and postero-apical (PS) subendocardial segmental contractions by ultrasonic crystals. Dobutamine (5-15 micrograms/kg per min) and left atrial pacing (150-240 beats/min) were performed in the control state (C) and in HF induced by chronic right ventricular pacing (240 beats/min, 3 weeks). RESULTS: In HF, as compared with in C, LV dP/dt max decreased and LV end-diastolic pressure and end-diastolic segmental lengths increased (Ps < 0.005). The percentage of systolic shortening was more depressed in PS (from 21 +/- 1% to 7 +/- 1%, P < 0.001) than in AS and BS (from 24 +/- 1% to 17 +/- 1% and from 20 +/- 2% to 13 +/- 1% respectively, Ps < 0.05). During dobutamine infusion, in HF as compared with C, the increases in LV dP/dt max were smaller (dobutamine 15 micrograms/kg per min: HF: + 36 +/- 6% vs C: + 68 +/- 11%, P < 0.01) and the increases in the systolic shortening of the three segments were also smaller. However, the responses of the three segments were similar in HF and in C. During left atrial pacing, LV dP/dt max increased less in HF than in C and the poststimulation potentiation of LV dP/dt max was impaired in HF. However, the responses of the systolic shortening during regular left atrial pacing and the increase in the percentage of systolic shortening of the first poststimulation beat were similar in all regions. CONCLUSION: In tachycardia-induced HF, although LV regional contraction is heterogeneously altered, the inotropic reserve appears to be similarly modified in all regions.

Propranolol therapy in experimental heart failure in rabbits improves cardiac response to catecholamines without beta-adrenoceptor up-regulation.

Beta-blockade has been shown to improve cardiac response to catecholamines in heart failure but cellular mechanisms of the improvement are unknown. The effect on left ventricular function of a 14 day propranolol treatment was studied in seven treated and eight non-treated rabbits with experimental heart failure. All animals were subjected to a volume (aortic insufficiency) plus pressure (aortic constriction) overload and were instrumented with a left ventricular catheter and ultrasonic crystals measuring anteroposterior left ventricular diameter. Beta-adrenoceptors were measured using 125I-Cyanopindolol in crude membranes. With isoproterenol, the heart rate was slower in treated rabbits than in non-treated rabbits (p < 0.005) and isoproterenol increased more systolic diameter shortening in treated than in non-treated rabbits (p < 0.05). With norepinephrine, for matched pressures, % delta D increased in the treated group but it did not change in the non-treated group. This improvement of ventricular function was due, in a large part, to an increased diastolic response to norepinephrine: end-diastolic diameter increased in the treated group but not in the non-treated group. In contrast with the improved ventricular response to catecholamines, beta-adrenergic receptor density in the treated group was identical to that of the non-treated group (27.8 fmoles/mg/proteins) and was significantly lower than that of normal rabbits (58.2 fmoles/mg, p < 0.01). The improvement of ventricular response to catecholamines appears to be due to a myocardial protection by propranolol against the toxic effect of catecholamines in heart failure and not, at least in this model, to an up-regulation of beta-adrenoceptors.