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.

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.

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.

BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways.

BACKGROUND: Mitochondrial fission has been identified as the pathogenesis underlying the development of cardiac microvascular ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac microvascular IR injury and mitochondrial homeostasis remains unclear. METHODS: The cardiac microvascular IR injury was performed in WT mice and BI1 transgenic (BITG) mice. The alterations of microvascular structure and function were detected via electron microscope, immunohistochemistry and immunofluorescence in vivo. Cardiac microvascular endothelial cells were isolated form WT and BITG mice and underwent hypoxia/reoxygenation injury in vitro. Cellular viability and apoptosis were analyzed via MTT assay and caspase-3 activity. Mitochondrial function, morphology and apoptosis were detected. Signaling pathways were analyzed via inhibitor, siRNA and mutant plasmid. RESULTS: Herein, we demonstrated that Bax inhibitor 1 (BI1) was downregulated following cardiac microvascular IR injury, and its expression correlated negatively with microvascular collapse, endothelial cell apoptosis and mitochondrial damage. However, compared to wild-type mice, BI1 transgenic mice were actually protected from the acute microvascular injury and mitochondrial dysfunction. Functional studies illustrated that reintroduced BI1 directly interacted with and inhibited the Syk pathway, leading to the inactivation of Nox2. Subsequently, less Nox2 was associated with ROS downregulation, inhibiting Drp1 phosphorylated activation. Through repression of the Syk-Nox2-Drp1 signaling axis, BI1 strongly disrupted mitochondrial fission, abolishing mitochondrial apoptosis and thus sustaining endothelial cell viability. CONCLUSIONS: In summary, our report illustrates that BI1 functions as a novel microvascular guardian in cardiac IR injury that operates via inhibition of the Syk-Nox2-Drp1-mitochondrial fission signaling axis. Thus, novel therapeutic strategies to regulate the balance between BI1 and mitochondrial fission could provide a survival advantage to microvasculature following IR stress.

NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α.

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury.

The molecular features of necroptosis in cardiac ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.

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.

Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways.

Platelet activation is a major (patho-) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator-activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P-selectin, and final formation of micro-thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1-required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.

Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis.

The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin-treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP-activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, which subsequently induced voltage-dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy-mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p-Drp1S616 downregulation and p-Drp1S37 upregulation, which blunted Drp1-dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1-HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy-mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis via activation of AMPKα.

Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells.

Hypoxia/reoxygenation (H/R) is one of the cellular stresses in pathological conditions, such as myocardial infarction, stroke and organ transplantation. Oxidative stress caused by reactive oxygen species (ROS) is a crucial element of H/R injury in vascular endothelial cells (ECs). Xanthine oxidase (XO) has been recognized to contribute to H/R injury. Of note, xanthine oxidoreductase is synthesized as xanthine dehydrogenase (XDH) and needs to be converted to XO to become a source of superoxide. Hepatocyte growth factor (HGF) has been found to protect ECs against H/R injury. The relation, however, between HGF and XO in ECs under H/R conditions remains to be determined. Primary cultured rat cardiac microvascular endothelial cells (CMECs) were exposed to 4 h of hypoxia and followed by 1 h of reoxygenation. Generation of ROS and cytosolic Ca2+ concentration was measured by flow cytometry qualification of DCFHDA and fluo-3 AM staining cells, respectively. XDH mRNA was qualified by qRT-PCR analysis. XO activity was determined by colorimetric assay and XO protein levels were determined by Western blot. Cell apoptosis was assessed by caspase-3 activity and Annexin V/PI staining. After H/R, cellular ROS production significantly increased. Both XO activity and XO protein increased after H/R. Cellular ROS elevation was inhibited by allopurinol (a potent XO inhibitor), indicting XO accounting for the generation of ROS after H/R. In addition, XDH mRNA increased after H/R, indicating a de novo XDH synthesis, which needs to be converted to XO to become a source of superoxide. Pretreatment of HGF inhibited the elevation of XO activity and XO protein level after H/R; however, HGF has no effect on the increase of XDH mRNA. We also find an increase of the cytosolic Ca2+ in CMECs after H/R. BAPTA-AM, a cell-permeable Ca2+ chelator, prevented the increase of XO activity and XO protein levels, implicating the elevated cytosolic Ca2+ concentration involvement in XO conversion and XO activation. HGF inhibited the elevation of cytosolic Ca2+ concentration in CMECs after H/R. Furthermore, HGF ameliorated H/R-induced CMECs apoptosis. These findings suggest a novel mechanism whereby HGF inhibited XO-generated ROS production after H/R treatment. H/R induces a de novo synthesis of XDH, the XO precursor. In addition, H/R increases cytosolic Ca2+ concentration and promotes a Ca2+ -involved XO conversion and XO activation. HGF has no effect on the increase of XDH mRNA; however, HGF inhibited the elevation of XO protein level and XO activity after H/R in the post-transcriptional level primarily by inhibiting the increase of cytosolic Ca2+ concentration. HGF protects CMECs from H/R-induced apoptosis by inhibiting the elevation of XO protein level and XO activity.

The stem cell adjuvant with Exendin-4 repairs the heart after myocardial infarction via STAT3 activation.

The poor survival of cells in ischaemic myocardium is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on its pleiotropic activity. This study investigated whether Exendin-4 in conjunction with adipose-derived stem cells (ADSCs) could improve the stem cell survival and contribute to myocardial repairs after infarction. Myocardial infarction (MI) was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying double-fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)] were quickly injected into border zone of MI in rats treated with or without Exendin-4. Exendin-4 enhanced the survival of transplanted ADSCs, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSCs adjuvant with Exendin-4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSCs into cardiomyocytes and vascular smooth muscle cells in vivo. Then, ADSCs were exposed to hydrogen peroxide/serum deprivation (H(2)O(2)/SD) to mimic the ischaemic environment in vitro. Results showed that Exendin-4 decreased the apoptosis and enhanced the paracrine effect of ADSCs. In addition, Exendin-4 activated signal transducers and activators of transcription 3 (STAT3) through the phosphorylation of Akt and ERK1/2. Furthermore, Exendin-4 increased the anti-apoptotic protein Bcl-2, but decreased the pro-apoptotic protein Bax of ADSCs. In conclusion, Exendin-4 could improve the survival and therapeutic efficacy of transplanted ADSCs through STAT3 activation via the phosphorylation of Akt and ERK1/2. This study suggests the potential application of Exendin-4 for stem cell-based heart regeneration.

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.

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.

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.

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.

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.