Abstract N-Nitrosamines are a class of compounds that includes the potent mutagenicity and carcinogenicity of many of its members and is distributed widely throughout the human environment. DNA alkylation by their diazonium ions formed metabolically acts as a molecular initiating event (MIE) that links molecular chemistry to mutagenicity. However, the regiochemistry for diazonium ions reacting with DNA bases is still under debate. Hence, density functional theory calculations involving SN2 alkylation of guanine (Gua) by 14 diverse diazonium ions are presented, the results of which showed the mutagenicity-related shift from GuaN7- to GuaO6-alkylation proceeds by increasing complexity of the alkylating agents, along with a greater proportion of SN1 characteristic in SN2 transition states. Hence, “high oxyphilic” and “low oxyphilic” alkylating agents may instead be “SN1” and “SN2” species, respectively. As the degree of MIE selectivity for hard−hard interactions can be quantified by hard and soft acids and bases theory, quantitative relationships were modeled between the nucleophilic index (ω-) and hydrophobicity (log P) of diazonium ions and their carcinogenic potency. Therefore, the mechanistic link from MIE to target toxicity can be bridged by computational chemistry.
Objective: To investigate the peripheral small airway dysfunction differences between idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Impulse oscillmetory system testing (IOS) and pulmonary function testing (PFT) were performed in IPAH and CTEPH patients and 30 healthy control group. We also carried out a subgroup analysis depending on their medical history of airway diseases. Results: We included 42 IPAH and 47 CTEPH patients (with or without airways disease: 8 vs. 34 and 17 vs. 34, respectively). Compared with CTEPH patients, IPAH patients were younger but had more serious pulmonary vessel resistance and mean pulmonary arterial resistance. Compared with IPAH patients, CTEPH patients had significant impaired peripheral small airway dysfunction with decreased of MEF(50) (% pred), MMEF(75/25) evaluated by PFT and R5-R20, Δ R5-R20 and AX measured by IOS [10.6(2.0, 33.0) vs. 2.5(-5.0, 16.5); 22.1(14.0, 32.6) vs. 15.5 (7.0, 23.2); 7.64(4, 18.6) vs. 6(3, 11) respectively, all P<0.05]. Subgroup analysis revealed there were no significant peripheral small dysfunction differences in IPAH patients with or without airway diseases. CTEPH patients had a higher proportion of airway diseases and more serious peripheral dysfunction than IPAH patients with airway diseases. Compared with control healthy group, peripheral airway dysfunction was more obvious even in IPAH and CTEPH patients without airway diseases. Conclusion: Compared with IPAH, CTEPH patients were older, but had better hemodynamics and a higher proportion of airway diseases. The peripheral airway dysfunction were more serious in CTEPH patients without airway diseases than IPAH patients without airway diseases and healthy controls group.目的： 比较特发性肺动脉高压（IPAH）及慢性血栓栓塞性肺动脉高压（CTEPH）患者的小气道功能差异。 方法： 回顾性纳入2015年11月至2017年11月上海市肺科医院肺循环科确诊为肺动脉高压的患者89例，其中IPAH患者42例（IPAH组），其中男18例，女29例，年龄26~73岁，平均（46±16）岁；CTEPH患者47例（CTEPH组），其中男13例，女29例，年龄22~80岁，平均（61±13）岁；同期30名健康体检者作为对照组，其中男12名，女18名，年龄24~59岁，平均（54±6）岁。所有患者均进行常规肺功能及脉冲振荡肺功能（IOS）检查，分析IPAH与CTEPH患者肺功能小气道变化特点，并比较合并其他气道疾病对小气道功能的影响。 结果： 与IPAH组比较，CTEPH组患者小气道功能受累更严重，肺功能呼出50%肺活量时最大呼气流量占预计值%（MEF(50)占预计值%）在IPAH组和CTEPH组分别为（74±22）%和（59±27）%。IOS检查CTEPH组振荡频率为5和20 Hz时气道阻力差值（R(5)-R(20)）为10.6（2.0, 33.0），R(5)-R(20)与振荡频率为20 Hz时的气道阻力比值（ΔR(5)-R(20)）为22.1（14.0, 32.6），电抗面积为7.6（4.0, 18.6），均高于IPAH组[2.5（-5.0, 16.5）、15.5（7.0, 23.2）、6.0（3.0, 11.0），均P<0.05]。IPAH组中合并其他气道病变的患者与不合并气道病变的患者相比，小气道功能无明显统计学差异（P>0.05）；合并气道疾病的CTEPH患者小气道功能比合并气道疾病的IPAH患者更差；不合并气道疾病的CTEPH患者小气道功能比不合并气道疾病的IPAH患者及对照组差。 结论： 与IPAH患者相比，CTEPH患者平均确诊年龄高，确诊时血流动力学参数较好，合并气道疾病比例高，小气道功能受损更明显；不合并气道疾病的CTEPH患者的小气道功能差于不合并气道疾病的IPAH患者及健康人群。.
Abstract Background The importance of multidisciplinary team (MDT) centered on pregnant women with pulmonary hypertension (PH) has been highlighted. However, rare studies have explored the its effects on pregnancy outcomes. This study seeks to investigate whether and how the MDT has an effect on the treatment and outcomes of PH pregnant women. Methods A pre- and post-intervention study was conducted based on an interrupted time series design to compare the treatment and outcomes of patients with PH before (pre-MDT) and after (post-MDT) implementation of the MDT. PH was defined as pulmonary artery systolic pressure (sPAP) ≥ 40 mmHg measured by echocardiography or right heart catheterization and sPAP at 40–60mmHg and over 60mmHg was defined as mild and severe PH, respectively. All results were analyzed by T-tests, Chi square tests or Fisher exact test and two-sided p-value < 0.05 was set to be statistically significant. Results 149 pregnancies were found in 143 women with PH. Overall, 46 pregnancies were elective abortions, remaining 49 and 54 pregnancies completing delivery in the pre-MDT group and post-MDT group, respectively. Five (10.2%) mother and seven (8.6%) neonatal died in the former, while no maternal deaths but 1.9% neonatal death occurred in the latter. In subgroup analysis, maternal and fetal/neonatal complications were higher in patients with severe PH and New York Heart Association (NYHA) functional class III/IV and all maternal deaths occurred in class III/IV women. In pre-MDT and post-MDT groups, there were 8 and 22 pregnant women receiving the pulmonary-specific therapy and completing delivery, respectively. The percentage of heart failure and urgent cesarean of pre-MDT group was higher than the post-MDT group (30.6% vs. 12.9%, p = 0.02; 40.8% vs. 14.8%, p = 0.01, respectively). Conclusion Implementing the MDT decreased the rate of urgent cesarean section and heart failure in patients with PH and no maternal death occurred in the post-MDT group. Pregnant women with severe PH and NYHA FC III/IV might have poor prognosis, whereas the use of pulmonary-specific therapy might improve outcomes of pregnancy in PH.
Background: Idiopathic pulmonary arterial hypertension (PAH) is a potentially fatal pulmonary vascular disease with an extremely poor natural course. The limitations of current treatment and the unclear etiology and pathogenesis of idiopathic PAH require new targets and avenues of exploration involved in the pathogenesis of PAH. tRNA-derived small RNAs (tsRNAs), a new type of small non-coding RNAs, have a significant part in the progress of diverse diseases. However, the potential functions behind tsRNAs in idiopathic PAH remain unknown. Methods: Small RNA microarray was implemented on three pairs of plasma of idiopathic PAH patients and healthy controls to investigate and compare tsRNAs expression profiles. Validation samples were used for real-time polymerase chain reaction (Real-time PCR) to verify several dysregulated tsRNAs. Bioinformatic analysis was adopted to determine potential target genes and mechanisms of the validated tsRNAs in PAH. Results: Microarray detected 816 statistically significantly dysregulated tsRNAs, of which 243 tsRNAs were upregulated and 573 were downregulated in PAH. Eight validated tsRNAs in the results of Real-time PCR were concordant with the small RNA microarray: four upregulated (tRF3a-AspGTC-9, 5'tiRNA-31-GluCTC-16, i-tRF-31:54-Val-CAC-1 and tRF3b-TyrGTA-4) and four downregulated (5'tiRNA-33-LysTTT-4, i-tRF-8:32-Val-AAC-2, i-tRF-2:30-His-GTG-1, and i-tRF-15:31-Lys-CTT-1). The Gene Ontology analysis has shown that the verified tsRNAs are related to cellular macromolecule metabolic process, regulation of cellular process, and regulation of cellular metabolic process. It is disclosed that potential target genes of verified tsRNAs are widely involved in PAH pathways by Kyoto Encyclopedia of Genes and Genomes. Conclusion: This study investigated tsRNA profiles in idiopathic PAH and found that the dysregulated tsRNAs may become a novel type of biomarkers and possible targets for PAH.
Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD). Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1 month. Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7 μmol/L vs. 278.3 ± 84.6 μmol/L; 347.7 ± 105.7 μmol/L vs. 255.7 ± 44.5 μmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8 μmol/L vs. 311.2 ± 82.8 μmol/L; 451.6 ± 117.6 μmol/L vs. 311.2 ± 82.8 μmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = -0.293, -0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8 μmol/L (p = 0.001) after PAH-specific drug treatment for at least 6 months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2. Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.
Although epicardial adipose tissue (EAT) is linked to effects on survival in left-sided heart failure, the association between EAT and right-sided heart failure caused by pulmonary arterial hypertension (PAH) remains unknown.
Exercise training has been reported to ameliorate heart dysfunction in both humans and animals after myocardial infarction (MI). Exercise-induced cardioprotective factors have been implicated in mediating cardiac repair under pathological conditions. These protective factors secreted by or enriched in the heart could exert cardioprotective functions in an autocrine or paracrine manner. Extracellular vesicles, especially exosomes, contain key molecules and play an essential role in cell-to-cell communication via delivery of various factors, which may be a novel target to study the mechanism of exercise-induced benefits, besides traditional signaling pathways. This review is designed to demonstrate the function and underlying protective mechanism of exercise-induced cardioprotective factors in MI, with an aim to offer more potential therapeutic targets for MI.
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