High-fat-diet-induced obesity promotes simultaneous progression of lung cancer and atherosclerosis in apolipoprotein E-knockout mice.

Background: Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co-exist in the same individual. The present study aimed to investigate the role of high-fat-diet (HFD)-induced obesity in the coexistence of the two diseases and the underlying mechanism in apolipoprotein E-knockout (ApoE-/-) mice. Methods: Male ApoE-/- mice were fed with a HFD or a normal diet (ND) for 15 weeks. On the first day of Week 13, the mice were inoculated subcutaneously in the right axilla with Lewis lung cancer cells. At Weeks 12 and 15, serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor levels were measured by enzyme-linked immunosorbent assay, and blood monocytes and macrophages were measured by fluorescence-activated cell sorting. At Week 15, the volume and weight of the local subcutaneous lung cancer and metastatic lung cancer and the amount of aortic atherosclerosis were measured. Results: At Week 15, compared with mice in the ND group, those in the HFD group had a larger volume of local subcutaneous cancer (p = 0.0004), heavier tumors (p = 0.0235), more metastatic cancer in the lungs (p < 0.0001), a larger area of lung involved in metastatic cancer (p = 0.0031), and larger areas of atherosclerosis in the aorta (p < 0.0001). At Week 12, serum LOX-1, serum vascular endothelial growth factor, and proportions of blood monocytes and macrophages were significantly higher in the HFD group than those in the ND group (p = 0.0002, p = 0.0029, p = 0.0480, and p = 0.0106, respectively); this trend persisted until Week 15 (p = 0.0014, p = 0.0012, p = 0.0001, and p = 0.0204). Conclusions: In this study, HFD-induced obesity could simultaneously promote progression of lung cancer and atherosclerosis in the same mouse. HFD-induced upregulation of LOX-1 may play an important role in the simultaneous progression of these two conditions via the inflammatory response and VEGF.

A smartwatch sphygmomanometer-based model for predicting short-term new-onset hypertension in individuals with high-normal blood pressure: a cohort study.

OBJECTIVES: The objective was to utilize a smartwatch sphygmomanometer to predict new-onset hypertension within a short-term follow-up among individuals with high-normal blood pressure (HNBP). METHODS: This study consisted of 3180 participants in the training set and 1000 participants in the validation set. Participants underwent both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) using a smartwatch sphygmomanometer. Multivariable Cox regressions were used to analyze cumulative events. A nomogram was constructed to predict new-onset hypertension. Discrimination and calibration were assessed using the C-index and calibration curve, respectively. RESULTS: Among the 3180 individuals with HNBP in the training set, 693 (21.8%) developed new-onset hypertension within a 6-month period. The nomogram for predicting new-onset hypertension had a C-index of 0.854 (95% CI, 0.843-0.867). The calibration curve demonstrated good agreement between the nomogram's predicted probabilities and actual observations for short-term new-onset hypertension. In the validate dataset, during the 6-month follow-up, the nomogram had a good C-index of 0.917 (95% CI, 0.904-0.930) and a good calibration curve. As the score increased, the risk of new-onset hypertension significantly increased, with an HR of 8.415 (95% CI: 5.153-13.744, p = .000) for the middle-score vs. low-score groups and 86.824 (95% CI: 55.071-136.885, p = .000) for the high-score vs. low-score group. CONCLUSIONS: This study provides evidence for the use of smartwatch sphygmomanometer to monitor blood pressure in individuals at high risk of developing new-onset hypertension in the near future. TRIAL REGISTRATION: ChiCTR2200057354.

Effect of inflammation on association between cancer and coronary artery disease.

BACKGROUND: Cancer and coronary artery disease (CAD) is reported to often co-exist in same individuals, however, whether cancer is directly associated with anatomical severity of CAD is rarely studied. The present study aimed to observe the relationship between newly diagnosed cancer and anatomical severity of CAD, moreover, to investigate effect of inflammation on the relationship of cancer with CAD. METHODS: 374 patients with newly diagnosed cancer who underwent coronary angiography (CAG) were enrolled. Through 1:3 propensity score matching (PSM) to cancer patients based on the age and gender among 51,106 non-cancer patients who underwent CAG, 1122 non-cancer patients were selected as control patients. Anatomical severity of CAD was assessed using SYNTAX score (SXscore) based on coronary angiographic image. SXscore ≤ 22 (highest quartile) was defined as SX-low, and SXscore > 22 as SX-high. The ratio of neutrophil to lymphocyte count (NLR) was used to describe inflammation level. Association between cancer and the anatomical severity of CAD was investigated using logistic regression. RESULTS: Univariate logistic regression analysis showed a correlation between cancer and anatomical severity of CAD (OR: 1.419, 95% CI: 1.083-1.859; P = 0.011). Cancer was associated with increased risk of SX-high after adjusted for common risk factors of CAD (OR: 1.598, 95% CI: 1.172-2.179, P = 0.003). Significant association between cancer and SX-high was revealed among patients with high inflammation (OR: 1.656, 95% CI: 1.099-2.497, P = 0.016), but not among patients with low inflammation (OR: 1.530, 95% CI: 0.973-2.498, P = 0.089). CONCLUSIONS: Cancer was associated with severity of CAD, however, the association between the two diseases was significant among patients with high inflammation rather than among patients with low inflammation.

Can the new adipokine asprosin be a metabolic troublemaker for cardiovascular diseases? A state-of-the-art review.

Adipokines play a significant role in cardiometabolic diseases. Asprosin, a newly discovered adipokine, was first identified as a glucose-raising protein hormone. Asprosin also stimulates appetite and regulates glucose and lipid metabolism. Its identified receptors so far include Olfr734 and Ptprd. Clinical studies have found that asprosin may be associated with cardiometabolic diseases. Asprosin may have diagnostic and therapeutic potential in obesity, diabetes, metabolic syndrome and atherosclerotic cardiovascular diseases. Herein, the structure, receptors, and functions of asprosin and its relationship with cardiometabolic diseases are summarized based on recent findings.

Validating the accuracy of a multifunctional smartwatch sphygmomanometer to monitor blood pressure.

BACKGROUND: Hypertension is the most modifiable factor associated with cardiovascular events and complications. The conventional blood pressure (BP) meter method is simple but is limited in terms of real-time monitoring abnormal BP. Therefore, the development of a multifunction smartwatch (HUAWEI WATCH D) sphygmomanometer could significantly improve integrated BP monitoring. METHODS: We enrolled 361 subjects from Chinese PLA General Hospital, Beijing, China to validate the accuracy of the smartwatch versatile sphygmomanometer using ISO 81060-2:2018. Resting and ambulatory BP accuracy of the smartwatch were compared with gold standard clinical sphygmomanometers using ISO 81060-2:2018 guidelines, the accuracy of 24 h systolic blood pressure (SBP) circadian rhythm monitoring, and diurnal high SBP alert for this smartwatch were assessed using a confusion matrix approach. Additionally, we analyzed online users of different ages for compliance. RESULTS: Eighty-five subjects underwent resting BP measurements; the mean resting BP differences between two devices were -0.683 ± 6.203 mmHg (SBP) (P = 0.723) and 1.628 ± 5.028 mmHg (diastolic blood pressure, DBP) (P = 0.183). In 35 subjects' ambulatory BP measurements, the mean differences of ambulatory BP were -1.943 ± 5.475 mmHg (SBP) (P = 0.923) and 3.195 ± 5.862 mmHg (DBP) (P = 0.065). All data complied with ISO 81060-2:2018 guidelines (mean ≤ ±5 mmHg and standard deviation ≤ ±8 mmHg) with no significant differences. Positive predictive values (PPV) of resting SBP and DBP were 0.635 and 0.671, respectively. The PPV of ambulatory SBP and DBP were 0.686. Also, 24 h SBP circadian rhythm monitoring was performed in 107 subjects: accuracy = 0.850, specificity = 0.864, precision/PPV = 0.833, sensitivity = 0.833, and F1-measure (F1) = 0.833. The accuracy, specificity, precision, sensitivity, and F1 values in 85 subjects undergoing diurnal high SBP alerting were 0.858, 0.876, 0.706, 0.809, and 0.754, respectively. CONCLUSIONS: When compared with the gold standard clinical sphygmomanometer, smartwatch results were consistent and accurate. Online user feedback showed that elderly individuals cared more about BP monitoring accuracy, with better compliance.

Inflammation-based different association between anatomical severity of coronary artery disease and lung cancer.

BACKGROUND: Coronary artery disease (CAD) is associated with cancer. The role of inflammation in the association of CAD with cancer remains unclear. The study investigated whether inflammation could impact the relationship between CAD and lung cancer. METHODS: The study involved 96 newly diagnosed lung cancer patients without receiving anti-cancer therapy and 288 matched non-cancer patients. All the patients underwent coronary angiography and were free from previous percutaneous coronary intervention or coronary artery bypass grafting. SYNTAX score (SXscore) were used to assess severity of CAD. High SXscore (SXhigh) grade was defined as SXscore > 16 (highest quartile). Neutrophil-to-lymphocyte ratio (NLR) served as an inflammatory biomarker. NLR-high grade referred to NLR > 2.221 (median). RESULTS: Among 384 study patients, 380 patients (98.96%) had NLR value (median: 2.221, interquartile range: 1.637-3.040). Compared to non-cancer patients, lung cancer patients had higher rate of SXhigh among total study patients (P = 0.014) and among patients with NLR-high (P = 0.006), but had not significantly higher rate of SXhigh among patients with NLR-low (P = 0.839). Multivariate logistic regression analysis showed that SXhigh was associated with lung cancer [odds ratio (OR) = 1.834, 95% CI: 1.063-3.162, P = 0.029]. Subgroup analysis showed that SXhigh was associated with lung cancer among patients with NLR-high (OR = 2.801, 95% CI: 1.355-5.794, P = 0.005), however, the association between SXhigh and lung cancer was not significant among patients with NLR-low (OR = 0.897, 95% CI: 0.346-2.232, P = 0.823). CONCLUSIONS: Inflammation could lead different association between anatomical severity of CAD and lung cancer. Severity of CAD was significantly associated with increased risk of lung cancer among patients with high inflammation rather than among patients with low inflammation.

Association between the Severity of Coronary Artery Disease and Lung Cancer: A Pilot Cross-Sectional Study. / Associação entre a Gravidade da Doença Arterial Coronariana e Câncer de Pulmão: Um Estudo Piloto Transversal.

BACKGROUND: The direct relationship between coronary artery disease (CAD) and lung cancer is not well known. OBJECTIVE: To investigate the association between the anatomical severity of CAD and lung cancer. METHODS: Three-hundred study patients, including 75 recently diagnosed lung cancer patients and 225 matched non-cancer patients, underwent coronary angiography during hospitalization without previous percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The SYNTAX score (SXscore) was used to assess the severity of CAD. A high SXscore (SXhigh) grade was defined as SXscore > 15 (the highest quartile of the SXscore). The Cochran-Armitage test for trend was used to assess the distribution of patients' SXscores. Logistic regression analysis was used to assess the association between the severity of CAD and lung cancer. P-values were set when significance level was 5%. RESULTS: The distribution trend of patients' SXscore by quartiles was different between lung cancer patients and control patients (from the lowest to the highest quartile: 20.0%, 20.0%, 24.0%, 36.0% vs. 26.7%, 26.2%, 25.8%, 21.3%, p=0.022). The SX high rate was higher in lung cancer patients than in control patients (36.0% vs. 21.3%, p=0.011).The highest quartile of the SXscore showed higher risk of lung cancer in comparison to the lowest quartile (OR: 2,250, 95%CI: 1,077 to 4,699 ; P-trend= 0.016). After adjustment, patients in the highest quartile of the SXscore had higher risk of lung cancer (OR: 2,149, 95%CI: 1,008 to 4,584; P-trend= 0.028). Patients with high SXscore (> 15) had 1,985 times more chances of having lung cancer (95%CI: 1,105-3,563, P= 0.022). CONCLUSIONS: The anatomical severity of CAD is associated with the risk of lung cancer, which indicates that a thorough lung cancer screening may be significant among severe CAD patients.

FUNDAMENTO: A relação direta entre a doença arterial coronariana (DAC) e o câncer de pulmão não é bem conhecida. OBJETIVO: Investigar a associação entre a gravidade anatômica da DAC e do câncer de pulmão. MÉTODOS: Trezentos pacientes, incluindo 75 recém-diagnosticados com câncer de pulmão e 225 pacientes correspondentes sem câncer, foram submetidos à angiografia coronária durante a internação, sem intervenção coronária percutânea (ICP) prévia nem enxerto de bypass da artéria coronária (CABG). O escore SYNTAX foi utilizado para avaliar a gravidade da DAC. Uma pontuação alta no escore foi definida como > 15 (o maior quartil do escore SYNTAX). O teste de tendência de Cochran-Armitage foi utilizado para verificar a distribuição dos escores dos pacientes. Uma análise de regressão logística foi utilizada para avaliar a associação entre a gravidade da DAC e o câncer de pulmão. Os valores de p foram estabelecidos quando o nível de significância era 5%. RESULTADOS: A tendência de distribuição dos escores SYNTAX dos pacientes por quartis foi diferente entre aqueles com câncer de pulmão e controles (do quartil mais baixo ao mais alto: 20,0%; 20,0%; 24,0%; 36,0% vs. 26,7%; 26,2%; 25,8%; 21,3%; p=0,022). A pontuação no escore SYNTAX foi mais alta em pacientes com câncer do que nos pacientes controle (36,0% vs. 21,3%, p=0,011).O maior quartil do escore demonstrou mais riscos de desenvolver câncer de pulmão em comparação ao quartil mais baixo (OR: 2.250, IC95%: 1.077 a 4.699 ; P -trend= 0,016). Após ajustes, os pacientes no maior quartil do escore SYNTAX tinham mais risco de desenvolver câncer de pulmão (OR: 2.1o49, IC95%: 1.008 a 4.584; P -trend= 0,028). Pacientes com escores SYNTAX alto (> 15) tinham 1.985 mais chances de ter câncer de pulmão (IC95%: 1.105­3.563, P= 0,022). CONCLUSÃO: A gravidade anatômica da DAC está associada ao risco de câncer de pulmão, o que indica que um rastreamento completo deste tipo de câncer possa ser mais significativo entre pacientes com DAC.

Associação entre a Gravidade da Doença Arterial Coronariana e Câncer de Pulmão: Um Estudo Piloto Transversal / Association between the Severity of Coronary Artery Disease and Lung Cancer: A Pilot Cross-Sectional Study

Resumo Fundamento A relação direta entre a doença arterial coronariana (DAC) e o câncer de pulmão não é bem conhecida. Objetivo Investigar a associação entre a gravidade anatômica da DAC e do câncer de pulmão. Métodos Trezentos pacientes, incluindo 75 recém-diagnosticados com câncer de pulmão e 225 pacientes correspondentes sem câncer, foram submetidos à angiografia coronária durante a internação, sem intervenção coronária percutânea (ICP) prévia nem enxerto de bypass da artéria coronária (CABG). O escore SYNTAX foi utilizado para avaliar a gravidade da DAC. Uma pontuação alta no escore foi definida como > 15 (o maior quartil do escore SYNTAX). O teste de tendência de Cochran-Armitage foi utilizado para verificar a distribuição dos escores dos pacientes. Uma análise de regressão logística foi utilizada para avaliar a associação entre a gravidade da DAC e o câncer de pulmão. Os valores de p foram estabelecidos quando o nível de significância era 5%. Resultados A tendência de distribuição dos escores SYNTAX dos pacientes por quartis foi diferente entre aqueles com câncer de pulmão e controles (do quartil mais baixo ao mais alto: 20,0%; 20,0%; 24,0%; 36,0% vs. 26,7%; 26,2%; 25,8%; 21,3%; p=0,022). A pontuação no escore SYNTAX foi mais alta em pacientes com câncer do que nos pacientes controle (36,0% vs. 21,3%, p=0,011).O maior quartil do escore demonstrou mais riscos de desenvolver câncer de pulmão em comparação ao quartil mais baixo (OR: 2.250, IC95%: 1.077 a 4.699 ; P -trend= 0,016). Após ajustes, os pacientes no maior quartil do escore SYNTAX tinham mais risco de desenvolver câncer de pulmão (OR: 2.1o49, IC95%: 1.008 a 4.584; P -trend= 0,028). Pacientes com escores SYNTAX alto (> 15) tinham 1.985 mais chances de ter câncer de pulmão (IC95%: 1.105-3.563, P= 0,022). Conclusão A gravidade anatômica da DAC está associada ao risco de câncer de pulmão, o que indica que um rastreamento completo deste tipo de câncer possa ser mais significativo entre pacientes com DAC.

Abstract Background The direct relationship between coronary artery disease (CAD) and lung cancer is not well known. Objective To investigate the association between the anatomical severity of CAD and lung cancer. Methods Three-hundred study patients, including 75 recently diagnosed lung cancer patients and 225 matched non-cancer patients, underwent coronary angiography during hospitalization without previous percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The SYNTAX score (SXscore) was used to assess the severity of CAD. A high SXscore (SXhigh) grade was defined as SXscore > 15 (the highest quartile of the SXscore). The Cochran-Armitage test for trend was used to assess the distribution of patients' SXscores. Logistic regression analysis was used to assess the association between the severity of CAD and lung cancer. P-values were set when significance level was 5%. Results The distribution trend of patients' SXscore by quartiles was different between lung cancer patients and control patients (from the lowest to the highest quartile: 20.0%, 20.0%, 24.0%, 36.0% vs. 26.7%, 26.2%, 25.8%, 21.3%, p=0.022). The SX high rate was higher in lung cancer patients than in control patients (36.0% vs. 21.3%, p=0.011).The highest quartile of the SXscore showed higher risk of lung cancer in comparison to the lowest quartile (OR: 2,250, 95%CI: 1,077 to 4,699 ; P-trend= 0.016). After adjustment, patients in the highest quartile of the SXscore had higher risk of lung cancer (OR: 2,149, 95%CI: 1,008 to 4,584; P-trend= 0.028). Patients with high SXscore (> 15) had 1,985 times more chances of having lung cancer (95%CI: 1,105-3,563, P= 0.022). Conclusions The anatomical severity of CAD is associated with the risk of lung cancer, which indicates that a thorough lung cancer screening may be significant among severe CAD patients.

Doença Arterial Coronariana Anatômica Associada à Quimioterapia em Pacientes com Câncer de Pulmão Avaliada pelo Escore Angiográfico SYNTAX / Chemotherapy-Related Anatomical Coronary-Artery Disease in Lung Cancer Patients Evaluated by Coronary-Angiography SYNTAX Score

Resumo Fundamento A doença arterial coronariana (DAC) associada à quimioterapia está se tornando um tema emergente na prática clínica. Contudo, o mecanismo subjacente da quimioterapia associada à DAC permanence incerto. Objetivos O estudo investigou a associação entre a quimioterapia e as anomalias anatômicas ateroscleróticas das artérias coronárias dentre pacientes com cancer de pulmão. Métodos Foram incluídos pacientes submetidos à angiografia coronária (AGC), entre 2010 e 2017, com câncer de pulmão prévio. Os fatores de risco associados à DAC e os dados sobre o câncer de pulmão foram avaliados. Avaliamos as anomalias das artérias coronárias de acordo com o escore SYNTAX (SXescore) calculado à AGC. Na análise de regressão logística, o escore SYNTAX foi classificado como alto (SXescoreALTO) se ≥22. Os dados foram analisados através de estatística descritiva e análise de regressão. Resultados Ao todo, 94 pacientes foram incluídos no estudo. O SXescore foi mais alto no grupo com quimioterapia quando comparado com o grupo sem quimioterapia (25,25, IIQ [4,50-30,00] versus 16,50, IIQ [5,00-22,00]; p = 0,0195). A taxa do SXescoreALTO foi maior no grupo com quimioterapia do que no no grupo sem quimioterapia (58,33% versus 25,86; p = 0,0016). Tanto a análise de regressão logística univariada (OR: 4,013; 95% IC:1,655-9,731) quanto a multivariada (OR: 5,868; 95% IC:1,778-19,367) revelaram que a quimioterapia aumentou o risco de uma maior taxa do SXescoreALTO. A análise multivariada de regressão logística Stepwise mostrou que o risco para DAC anatômica mais grave aumenta com a quimioterapia como um todo em 5.323 vezes (95% IC: 2,002-14,152), e com o regime à base de platina em 5,850 vezes (95% IC: 2,027-16,879). Conclusões A quimioterapia está associada com a complexidade e gravidade anatômica da DAC, o que pode explicar, em parte, o maior risco de DAC associada à quimioterapia dentre pacientes com câncer de pulmão. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Abstract Background Chemotherapy-related coronary artery disease (CAD) is becoming an emerging issue in clinic. However, the underlying mechanism of chemotherapy-related CAD remains unclear. Objective The study investigated the association between chemotherapy and atherosclerotic anatomical abnormalities of coronary arteries among lung cancer patients. Methods Patients undergoing coronary angiography (CAG) between 2010 and 2017, who previously had lung cancer, were examined. Risk factors associated with CAD and information about lung cancer were evaluated. We assessed coronary-artery abnormalities by SYNTAX score (SXscore) based on CAG. In logistic-regression analysis, we defined high SXscore (SXhigh) grade as positive if ≥22. Data were analyzed through descriptive statistics and regression analysis. Results A total of 94 patients were included in the study. The SXscore was higher in the chemotherapy group than in the non-chemotherapy group (25.25, IQR [4.50-30.00] vs. 16.50, IQR [ 5.00-22.00], p = 0.0195). The SXhigh rate was greater in the chemotherapy group than in the non-chemotherapy group (58.33% vs. 25.86; p = 0.0016). Both univariate (OR:4.013; 95% CI:1.655-9.731) and multivariate (OR:5.868; 95% CI:1.778-19.367) logistic-regression analysis revealed that chemotherapy increased the risk of greater SXhigh rates. Multivariate stepwise logistic-regression analysis showed the risk of more severe anatomical CAD is increased by chemotherapy as a whole by 5.323 times (95% CI: 2.002-14.152), and by platinum-based regimens by 5.850 times (95% CI: 2.027-16.879). Conclusions Chemotherapy is associated with anatomical complexity and severity of CAD, which might partly account for the higher risk of chemotherapy-related CAD among lung cancer patients. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Chemotherapy-Related Anatomical Coronary-Artery Disease in Lung Cancer Patients Evaluated by Coronary-Angiography SYNTAX Score. / Doença Arterial Coronariana Anatômica Associada à Quimioterapia em Pacientes com Câncer de Pulmão Avaliada pelo Escore Angiográfico SYNTAX.

Background Chemotherapy-related coronary artery disease (CAD) is becoming an emerging issue in clinic. However, the underlying mechanism of chemotherapy-related CAD remains unclear. Objective The study investigated the association between chemotherapy and atherosclerotic anatomical abnormalities of coronary arteries among lung cancer patients. Methods Patients undergoing coronary angiography (CAG) between 2010 and 2017, who previously had lung cancer, were examined. Risk factors associated with CAD and information about lung cancer were evaluated. We assessed coronary-artery abnormalities by SYNTAX score (SXscore) based on CAG. In logistic-regression analysis, we defined high SXscore (SXhigh) grade as positive if ≥22. Data were analyzed through descriptive statistics and regression analysis. Results A total of 94 patients were included in the study. The SXscore was higher in the chemotherapy group than in the non-chemotherapy group (25.25, IQR [4.50-30.00] vs. 16.50, IQR [ 5.00-22.00], p = 0.0195). The SXhigh rate was greater in the chemotherapy group than in the non-chemotherapy group (58.33% vs. 25.86; p = 0.0016). Both univariate (OR:4.013; 95% CI:1.655-9.731) and multivariate (OR:5.868; 95% CI:1.778-19.367) logistic-regression analysis revealed that chemotherapy increased the risk of greater SXhigh rates. Multivariate stepwise logistic-regression analysis showed the risk of more severe anatomical CAD is increased by chemotherapy as a whole by 5.323 times (95% CI: 2.002-14.152), and by platinum-based regimens by 5.850 times (95% CI: 2.027-16.879). Conclusions Chemotherapy is associated with anatomical complexity and severity of CAD, which might partly account for the higher risk of chemotherapy-related CAD among lung cancer patients. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0).

Mesenchymal Stem Cells Promote the Resolution of Cardiac Inflammation After Ischemia Reperfusion Via Enhancing Efferocytosis of Neutrophils.

Background Neutrophils play a major role in inflammation after myocardial ischemia-reperfusion (I/R) injury. The effects of mesenchymal stem cells (MSCs) on neutrophils in I/R are complex and not fully understood. This study was designed to investigate the effects and mechanism of MSCs on alleviating myocardial I/R injury in rats. Methods and Results MSCs induced M2 macrophages polarization in vitro and enhanced macrophage efferocytosis of apoptotic neutrophils, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. Rats myocardial I/R were induced by transient ligation of left anterior descending coronary. Adipose-derived MSCs or vehicle were infused at initiation (immediate after reperfusion) or peak of inflammation (24 hours after I/R). Hematoxylin and eosin, 2,3,5-triphenyltetrazolium chloride/Evans Blue staining and immunofluorescence staining were applied within 72 hours after cell infusion. Cardiac function was assessed by echocardiography and left cardiac catheterization analysis at 28 days post-operation. MSCs infused immediately and 24 hours later both markedly ameliorated myocardial I/R injury, and immediate infusion had more significant outcome. These improvements were associated with neutrophils infiltration, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. When infused immediately, MSCs did not significantly change neutrophil number at 24 hours but CD11b expression was significantly higher. When infused at 24 hours, MSCs markedly decreased neutrophil number by enhanced M2 macrophage infiltration and macrophage efferocytosis of neutrophils within 72 hours. Conclusions Efferocytosis is pivotal to relieve neutrophil-mediated I/R injury and initial the immune response for healing. MSCs infusion improves cardiac function in rats after myocardial I/R via the possible mechanism of enhancing M2 macrophages-induced efferocytosis of apoptotic neutrophils.

Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway.

Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.

BI1 alleviates cardiac microvascular ischemia-reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F-actin pathways.

Pathogenesis of cardiac microvascular ischemia-reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F-actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F-actin-mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac microvascular IR injury. Deregulated BI1 via the XO/ROS/F-actin pathways plays a causative role in the development of cardiac microvascular reperfusion injury.

Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways.

Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia-reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1-related mitochondrial fusion/mitophagy. At the molecular level, OPA1-related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase-9-involved mitochondrial apoptosis. However, genetic approaches with a cardiac-specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1-related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK-OPA1-mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.

Association between Radiotherapy and Anatomic Severity of Coronary Artery Disease: A Propensity Score Matching Comparison Among Adult-Onset Thoracic Cancer Survivors.

OBJECTIVE: To investigate the association between radiotherapy and anatomic severity of coronary artery disease (CAD) using the SYNTAX scores (SXscores) of coronary angiograms in adult-onset thoracic cancer survivors. METHODS: A total of 152 patients who previously had thoracic cancer and underwent coronary angiography between 2010 and 2016 were examined. Propensity score matching (PSM) was used to identify 27 well-matched pairs of patients. Characteristics and coronary angiograms were collected from each patient. Coronary artery abnormalities were assessed using SXscores of coronary angiograms. RESULTS: Among the 152 patients, the SXscores and percentage of high SXscores were higher in the radiotherapy group than in the non-radiotherapy group; however, the latter was not significantly different (p = 0.0266 and p = 0.064, respectively). After PSM, the SXscores and percentage of high SXscores were significantly higher in the radiotherapy group than in the non-radiotherapy group (22 [interquartile range (IQR) 10.00-30.00] vs. 15.00 [IQR 4.00-26.00], p = 0.0459), (70.07 vs. 44.44%, p = 0.027), respectively. After adjusting for related risk factors and chemotherapy, the OR of radiotherapy for a high SXscore was 3.674 (95% CI 1.094-12.343) by logistic regression analysis. CONCLUSION: Thoracic cancer survivors who underwent radiotherapy have higher SXscores and are at a higher risk of developing anatomically severe CAD, independent of chemotherapy.