Human Peritoneal Adhesions Show Evidence of Tissue Remodeling and Markers of Angiogenesis

Purpose This study was designed to investigate the vascular structure and angiogenic activity of human peritoneal adhesions. Methods Adhesions were collected from patients undergoing laparotomy (n = 32). Histologic features were documented and the distribution of mature and immature vascular markers were determined by immunolocalization and quantified by image analysis. The three-dimensional organization of blood vessels was investigated by confocal microscopy. Expression of vascular endothelial growth factor A, its receptor flk-1, and proliferating cell nuclear antigen were assessed by immunohistochemistry as indicators of angiogenic activity. Results Adhesions were found to be vascularized structures comprising bundles of collagen, interspersed with varying amounts of adipose tissue. Functional blood vessels expressed recognized vascular markers (vWF, CD34, α-SMA, and CD105) and formed a branching network similar to that of the peritoneum. Those adhesions expressing vascular endothelial growth factor A and its receptor showed significantly higher numbers of immature vessels as defined by expression of CD105. Omental adhesions (n = 16) contained significantly more adipose tissue (P < 0.05) and displayed a higher microvessel density (P < 0.01) but lower cellularity (P < 0.05) compared with nonomental adhesions (n = 16). Conclusions All adhesions contained functional blood vessels and most showed evidence of cell proliferation. The presence of vascular endothelial growth factor A and its receptor in human adhesions suggests ongoing angiogenic activity. This study demonstrates that adhesions are vascular structures with evidence of tissue remodeling and suggests potential for new prevention strategies involving antiangiogenic therapies. Presented in part at the Tripartite Colorectal Meeting, Dublin, Ireland, July 5 to 7, 2005. Supported by the Royal College of Surgeons of England, Shire Pharmaceuticals, Medical Research Council, and Christie Hospital Surgical Research Fund.     

Reverse Myocardial Remodeling Following Valve Repair in Patients With Chronic Severe Primary Degenerative Mitral Regurgitation

ObjectivesThe aims of this study were to quantify preoperative myocardial fibrosis using late gadolinium enhancement (LGE), extracellular volume fraction (ECV%), and indexed extracellular volume (iECV) on cardiac magnetic resonance; determine whether this varies following surgery; and examine the impact on postoperative outcomes.BackgroundMyocardial fibrosis complicates chronic severe primary mitral regurgitation and is associated with left ventricular dilatation and dysfunction. It is not known if this nonischemic fibrosis is reversible following surgery or if it affects ventricular remodeling and patient outcomes.MethodsA multicenter prospective study was conducted among 104 subjects with primary mitral regurgitation undergoing mitral valve repair. Cardiac magnetic resonance and cardiopulmonary exercise stress testing were performed preoperatively and ≥6 months after surgery. Symptoms were assessed using the Minnesota Living With Heart Failure Questionnaire.ResultsMitral valve repair was performed for Class 2a indications in 65 patients and Class 1 indications in 39 patients. Ninety-three patients were followed up at 8.8 months (IQR: 7.4 months-10.6 months). Following surgery, there were significant reductions in both ECV% (from 27.4% to 26.6%; P = 0.027) and iECV (from 17.9 to 15.4 mL/m²; P < 0.001), but the incidence of LGE was unchanged. Neither preoperative ECV% nor LGE affected postoperative function, but iECV predicted left ventricular end-systolic volume index (β = 1.04; 95% CI: 0.49 to 1.58; P < 0.001) and left ventricular ejection fraction (β = ?0.61; 95% CI: ?1.05 to ?0.18; P = 0.006). Patients with above-median iECV of ≥17.6 mL/m² had significantly larger postoperative values of left ventricular end-systolic volume index (30.5 ± 12.7 mL/m² vs 23.9 ± 8.0 mL/m²; P = 0.003), an association that remained significant in subcohort analyses of patients in New York Heart Association functional class I.ConclusionsMitral valve surgery results in reductions in ECV% and iECV, which are surrogates of diffuse myocardial fibrosis, and preoperative iECV predicts the degree of postoperative remodeling irrespective of symptoms. (The Role of Myocardial Fibrosis in Degenerative Mitral Regurgitation; NCT02355418)     

Minimal Clinically Important Differences in 6-Minute Walk Test in Patients With HFrEF and Iron Deficiency

BackgroundThe 6-minute walk test (6MWT) is widely used to measure exercise capacity; however, the magnitude of change that is clinically meaningful for individuals is not well established in heart failure with reduced ejection fraction (HFrEF).ObjectiveTo calculate the minimal clinically important difference (MCID) for change in exercise capacity in the 6MWT in iron-deficient populations with HFrEF.MethodsIn this pooled secondary analysis of the FAIR-HF and CONFIRM-HF trials, mean changes in the 6MWT from baseline to weeks 12 and 24 were calculated and calibrated against the Patient Global Assessment (PGA) tool (clinical anchor) to derive MCIDs in improvement and deterioration.ResultsOf 760 patients included in the 2 trials, 6MWT and PGA data were available for 680 (89%) and 656 (86%) patients at weeks 12 and 24, respectively. The mean 6MWT distance at baseline was 281 ± 103 meters. There was a modest correlation between changes in 6MWT and PGA from baseline to week 12 (r = 0.31; P < 0.0001) and week 24 (r = 0.43; P < 0.0001). Respective estimates (95% confidence intervals) of MCID in 6MWT at weeks 12 and 24 were 14 meters (5;23) and 15 meters (3;27) for a “little improvement” (vs no change), 20 meters (10;30) and 24 meters (12;36) for moderate improvement vs a “little improvement,”, -11 meters (-32;9.2) and -31 meters (-53;-8) for a “little deterioration” (vs no change), and -84 meters (-144;-24) and -69 meters (-118;-20) for “moderate deterioration” vs a “little deterioration”.ConclusionsThe MCID for improvement in exercise capacity in the 6MWT was 14 meters–15 meters in patients with HFrEF and iron deficiency. These MCIDs can aid clinical interpretation of study data.     

Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure

BackgroundWe sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF).MethodsWe measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF).ResultsHigher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73–4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11–2.79) for VEGFR1; and HR 4.04 (95% CI 2.19–7.44) for HGF).ConclusionsProteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.     

Effects of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFrEF

Background

Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by sacubitril/valsartan in comparison to enalapril.

心房颤动患者离子通道蛋白质重构的研究

目的 :研究心房颤动 (房颤 )患者心房组织电重构相关离子通道蛋白质表达变化及意义。方法 :以窦性心律患者为窦性心律组 (n =19) ,应用免疫组化和免疫电镜检测风湿性心脏病伴阵发性房颤 (阵发性房颤组 ,n =4)和慢性房颤≤ 6个月 (慢性房颤≤ 6个月组 ,n =6 )及慢性房颤 >6个月 (慢性房颤 >6个月组 ,n =12 )患者心房组织L 型电压依赖钙通道α1c亚基 (LVDCCα1c)、电压依赖KV4 3钾通道α亚基 (VDKV4 3α)和电压依赖钠通道α亚基 (VDSCα)抗原的表达 ,用图像分析系统对免疫组化抗原表达进行半定量分析。结果 :窦性心律组内先天性心脏病和风湿性心脏病间 3种离子通道亚基蛋白质表达均无明显差别。LVDCCα1c蛋白质在慢性房颤≤ 6个月组和慢性房颤 >6个月组中表达较窦性心律组均明显下降 ,有显著性差异 (P <0 0 5 ) ,在阵发性房颤组中的表达则无显著改变 ;VDKV4 3α在阵发性房颤组、慢性房颤≤ 6个月组和慢性房颤 >6个月组患者中的表达较窦性心律组均明显降低 ,有显著性差异 (P <0 0 5～ 0 0 1)。VDSCα在各组患者的中的表达则无明显差别。左、右心耳间 3种离子通道亚基的表达亦无差异。结论 :慢性房颤伴LVDCCα1c、VDKV4 3α蛋白表达下调 ,可能是其L型钙流 (ICaL)和短暂外向型钾流 (Ito1)下调的分子基础。     

Serum Iron Markers in Patients With Chronic Hepatitis C Infection

Background

Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury.

Objectives

The aim of this study was to investigate the possible correlations between iron metabolism serum markers, HCV viral load, and liver disease severity in treatment-naive patients with chronic hepatitis C infection.

Patients and Methods

Eighty five patients with untreated hepatitis C chronic infection were investigated.

Results

Twenty one patients (24.7%) had elevated serum iron levels, and 29 subjects (34.1%) had severe liver fibrosis. Significantly elevated levels of serum iron (P < 0.05) and ferritin (P < 0.001), associated with lower levels of TIBC (P < 0.05) were detected in patients with severe fibrosis compared to no/mild fibrosis. Severe necroinflammatory activity was also significantly correlated with serum iron (P < 0.001), TIBC (P < 0.05), and ferritin levels (P < 0.001). Using multiple linear regression analysis, serum levels of ferritin and transferrin were the independent variables selected as being good predictors for advanced fibrosis and severe necroinflammatory activity. No significant correlations were detected between HCV viral load and iron markers.

Conclusions

This study revealed that serum iron markers (especially ferritin and transferrin) might be used as surrogate markers for both liver fibrosis and necroinflammatory activity.Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury.     

Sex-Associated Differences in Cardiac Reverse Remodeling in Patients Supported by Contemporary Left Ventricular Assist Devices

BackgroundWomen differ from men in their left ventricular (LV) structure, function and remodeling with age and diseases. The LV assist device (LVAD) unloads the LV and reversely remodels the heart. We sought to define the effects of sex on longitudinal reverse remodeling after LVAD implantation.Methods and ResultsCardiac structure and function were assessed by serial echocardiograms. Mixed effect regression models were constructed to assess the independent contribution of sex to longitudinal changes in cardiac structure and function. A total of 355 consecutive patients with advanced heart failure received continuous flow LVADs between 2006 and 2016. The average age was 56 ± 13 years, 73% were men, and 67% were black. Early (within 3 months) after LVAD implantation, women had a greater reduction in LV dimensions and a greater increase in LV ejection fraction compared with men. These differences were independent of age, body surface area, device type, or ischemic etiology of heart failure. At long-term follow-up, LV dimensions increased slightly over time in women compared with men, but overall, earlier changes were maintained.ConclusionWomen had significantly more favorable longitudinal changes in cardiac structure and function in response to LV unloading compared with men. Understanding the cause of sex difference in reverse remodeling after LVAD may help to devise novel therapeutic strategies for women with advanced heart failure.     

Endothelial Markers in Schistosomiasis Patients With or Without Portal Hypertension

Purpose To evaluate the serum levels of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelin-3 (ET-3) in patients with the isolated, inactive form of Schistosomiasis mansoni. Patients were classified into two groups: 10 patients without (SM group) and 18 with (PH group) portal hypertension. Results Serum albumin, VEGF, and vWF levels did not differ between the two groups (P > 0.05). The prothrombin time (INR), number of platelets, spleen size, splenic vein diameter, and endothelin levels differentiated the PH group, which showed decreased ET-1 (SM = 22.4 ± 2.4 pg/ml and PH = 16.4 ± 1.5 pg/ml; P = 0.034) and increased ET-3 (SM = 2.1 ± 0.1 ng/ml and PH = 3.2 ± 0.1 ng/ml; P = 0.000) levels. Conclusions In patients with schistosomiasis and portal hypertension (presinusoidal type), the levels of VEGF and ET-1 differ from those reported in patients with cirrhosis.     

胺碘酮逆转阵发性特发性心房纤颤患者左心房重塑的研究

目的 探讨胺碘酮对阵发性特发性心房纤颤（房颤）的复律及逆转左房重塑的作用。方法将150例阵发性特发性房颤患者随机分为胺碘酮组50例、倍他乐克组50例、对照组50例。计算3组治疗后3、6、12个月的窦性心律维持率和治疗前、治疗后3、6、12个月的左心房内径（LAD）、E峰、A峰以及E／A比值。结果胺碘酮组治疗后3、6、12个月较治疗前左室舒张功能明显改善,左房内径明显缩小,差异有统计学意义（P〈0．05）。倍他乐克组和对照组治疗后3、6、12个月左室舒张功能和左房内径与治疗前比较,差异均无统计学意义（P〉0．05）。随访12个月后,胺碘酮组窦性心律的维持率为87．8％,倍他乐克组为58．14％,对照组无1例复律。3组间比较差异有统计学意义（P〈0．05）。结论胺碘酮维持阵发性特芡性房颤窦性心律的疗效和逆转左房重塑优于倍他乐克及对照组。     

原发性高血压病人颈动脉重构与收缩期血流峰值关系的探讨

目的 :探讨原发性高血压病人颈动脉结构、功能、收缩期血流峰值改变及其三者之间的相互关系。　　方法 :选取原发性高血压病人 (原发性高血压组 ) 80例 ,正常对照组 2 5例。应用高分辨率超声测定颈动脉结构、功能及收缩期血流峰值。　　结果 :2级、 3级高血压颈动脉内膜—中层厚度 (IMT)较正常对照组显著增厚 (P <0 0 5 ) ,有显著性差异 ,1级高血压IMT与正常对照组间无显著差异 ,原发性高血压组颈动脉内径与正常对照组无差异 ,颈动脉IMT与内径显著正相关(γ =0 418,P <0 0 1)。原发性高血压组较正常对照组颈动脉扩张性显著降低 (P <0 0 5 ) ,僵硬度显著增高 (P <0 0 5 ) ,颈动脉扩张性、僵硬度与颈动脉IMT、内径显著相关 (P <0 0 1) ,均有显著性差异。 1级、 2级高血压与正常对照组颈动脉收缩期血流峰值无显著差异 ,3级高血压收缩期血流峰值较正常对照组显著降低 (P <0 0 5 ) ,颈动脉收缩期血流峰值与颈动脉IMT、内径显著相关 (P <0 0 5 ) ,而颈动脉收缩期血流峰值与扩张性、僵硬度无关。　　结论 :原发性高血压病人颈动脉IMT增厚 ,并与高血压分级有关。原发性高血压病人颈动脉弹性降低 ,并与颈动脉IMT增厚、内径扩大显著相关。随着高血压分级的增高 ,颈动脉收缩期血流峰值降低 ,并与颈动脉结构     

心室重塑患者瘦素抵抗与胰岛素抵抗及其相关性研究

目的:探讨不同基础病因的心室重塑患者血浆瘦素、可溶性瘦素受体水平的改变及其与胰岛素抵抗的关系.方法:选择心室重塑患者(心室重塑组,η=180)和体检正常者(对照组,η=60)采用酶联免疫吸附法测定血浆瘦素及可溶性瘦素受体、空腹胰岛素的浓度,同时常规测空腹血糖、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、体重指数、腰臀比等指标.采用彩色多普勒超声诊断仪测量心室重塑患者左心室舒张末期间隔厚度、左心室后壁厚度、左心室舒张末期内径及左心室射血分数值,计算左心室质量指数.结果:心室重塑组血浆瘦素、空腹胰岛素均高于对照组[(12.22±6.10)ng/ml vs(8.89±5.27)ng/ml,P<0.01];[(14.37±7.19)ng/ml vs(10.48±5.17)ng/ml,P<0.01],可溶性瘦素受体水平低于对照组[(124.08±62.12)ng/ml v8(164.23±69.60)ng/ml,P<0.01],差异均有统计学显著意义;其中缺血性心肌病患者血浆瘦素和空腹胰岛素水平最高,较高血压性心脏病和扩张型心肌病患者差异有统计学显著意义(P<0.01).可溶性瘦素受体呈现相反的变化,以对照组最高,其次为扩张型心肌病、高血压性心脏病和缺血性心肌病患者.结论:心室重塑患者存在高胰岛素血症和胰岛素抵抗.瘦素抵抗和胰岛素抵抗与心室重塑密切相关.     

应用蛋白芯片联合检测急性冠状动脉综合征患者循环血中蛋白标志物

目的:同步联检急性冠状动脉(冠脉)综合征患者循环血中10种蛋白标志物浓度并探讨其临床意义。方法:运用蛋白芯片技术联检经冠脉造影及临床表现证实为急性冠脉综合征患者104例(分为急性心肌梗死组54例、不稳定性心绞痛组50例)及正常对照组50例血清或血浆中10种蛋白标志物水平,选择其中3种蛋白标志物与经典的酶联免疫双抗体夹心吸附实验(ELISA法)对照。结果:急性心肌梗死组和不稳定性心绞痛组血清中基质金属蛋白酶-9(MMP-9)、可溶性CD40L(sCD40L)、肌钙蛋白I(cTnI)、C反应蛋白(CRP)、心脏型脂肪酸结合蛋白(H-FABP)、白细胞介素-6(IL-6)及血浆中内皮素-1(ET-1)浓度,与正常对照组比较,差异有显著性(P＜0.01);急性心肌梗死组血清中H-FABP、cTnI含量明显高于不稳定性心绞痛组,差异有显著性(P＜0.01)。CRP与IL-6和sCD40L与可溶性血管细胞粘附分子-1(sVCAM-1)、MMP-9之间的直线相关分析结果发现,CRP与IL-6显著正相关(r=0.961,P＜0.01);sCD40L与sVCAM-1显著正相关(r=0.644,P＜0.01), sCD40L与MMP-9无相关性(r=0.158,P＞0.05)。采用蛋白芯片法与ELISA法检测急性冠状动脉综合征患者血中的3种蛋白标志物,结果显示H-FABP、sCD401的含量,差异无显著性(P＞0.05),而MMP-9差异有显著性(P＜0.01)。结论:心血管蛋白芯片技术不失为一种综合评估急性冠脉综合征蛋白标志物的有力工具。急性冠脉综合征患者循环中10种蛋白标志物水平异常,可作为急性冠脉综合征发生、发展过程中分子水平的标志物群。     

Exposure to Elevated Nitrogen Dioxide Concentrations and Cardiac Remodeling in Patients With Dilated Cardiomyopathy

BackgroundEmpirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalizations, and mortality, but the biological basis of this remains unclear. We sought to determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy.Methods and ResultsWe undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009–2015, n = 716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO₂) and particulate matter with diameter of 2.5 µm or less (PM_2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO₂ was associated with higher indexed left ventricular (LV) mass (4.3 g/m² increase per interquartile range increase in NO₂, 95% confidence interval 1.9–7.0 g/m²) and lower LV ejection fraction (–1.5% decrease per interquartile range increase in NO₂, 95% confidence interval –2.7% to –0.2%), independent of age, sex, socioeconomic status, and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on LV mass was greatest in women. These effects were specific to NO₂ exposure.ConclusionsExposure to air pollution is associated with raised LV mass and lower LV ejection fraction, with the strongest effect in women. Although epidemiological associations between air pollution and heart failure have been established and supported by preclinical studies, our findings provide novel empirical evidence of cardiac remodeling and exposure to air pollution with important clinical and public health implications.