The association between serum methylmalonic acid, cobalamin-related biomarkers, and long-term mortality risk in cancer survivors: a prospective cohort study.

BACKGROUND: Elevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown. OBJECTIVES: To explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors. METHODS: We analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas. RESULTS: Among 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types. CONCLUSIONS: Serum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.

Cost-related medication nonadherence in adults with COPD in the United States 2013-2020.

BACKGROUND: Cost-related medication nonadherence (CRN) is associated with poor prognosis among patients with chronic obstructive pulmonary disease (COPD), a population that requires long-term treatment for secondary prevention. In this study, we aimed to estimate the prevalence and sociodemographic characteristics of CRN in individuals with COPD in the US. METHODS: In a nationally representative survey of US adults in the National Health Interview Survey (2013-2020), we identified individuals aged ≥18 years with a self-reported history of COPD. Cross-sectional study. RESULTS: Of the 15,928 surveyed individuals, a weighted 18.56% (2.39 million) reported experiencing CRN, including 12.50% (1.61 million) missing doses, 13.30% (1.72 million) taking lower than prescribed doses, and 15.74% (2.03 million) delaying filling prescriptions to save costs. Factors including age < 65 years, female sex, low family income, lack of health insurance, and multimorbidity were associated with CRN. CONCLUSIONS: In the US, one in six adults with COPD reported CRN. The influencing factors of CRN are multifaceted and necessitating more rigorous research. Targeted interventions based on the identified influencing factors in this study are recommended to enhance medication adherence among COPD patients.

Association between serum anion gap and risk of in-hospital mortality in patients with acute heart failure.

A high serum anion gap (AG) at the time of patient admission can lead to the deterioration or even death; data are lacking for patients who suffer acute heart failure (AHF). The present study aimed at exploring the impact of serum AG (SAG) levels on the in-hospital mortality in AHF patients. The study conducted retrospective analysis on the data from the medical information mart for intensive care (MIMIC-IV) database in severe AHF cases. Serum AG, age, sex, concomitant diseases and laboratory tests were collected from patients at admission. Multivariate Cox proportional hazard regression model together with Kaplan Meier (K-M) survival curve served for analyzing the relationship of serum AG with the hospital all-cause mortality (ACM). In addition, subgroup analysis assisted in assessing the concordance. Data from 2774 AHF patients were collected in the study. The hospital ACM rate was 9.2% (254/2774). After correcting potential confounders, multivariate analysis compared the high serum AG level (≥ 16 mmol/L) and the low serum AG level (< 16 mmol/L) (hazard ratio (HR): 1.89 [95% CI 1.42-2.51]). In a similar way, K-M survival curve indicated that hospital survival was lower in patients with high serum, suggesting that high serum AG level could lead to poor AHF prognosis. In patients with AHF, high serum AG level could increase the hospital ACM.

Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway.

Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both in vitro and in vivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.

Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis.

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice.

BACKGROUND: Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear. METHODS: ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). RESULTS: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation. CONCLUSION: ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.

Pseudo-targeted metabolic profile differences between emergency patients with type 1 and type 2 myocardial infarction diagnosed by optical coherence tomography.

BACKGROUND: It is difficult to distinguish type 2 myocardial infarction (T2MI) from type 1 myocardial infarction (T1MI), although their management varies. OBJECTIVES: Using optical coherence tomography (OCT) and pseudo-targeted metabolomics to identify biomarkers, investigate metabolic differences, and establish a T2MI subclassification. METHODS: Among 1519 patients with MI, 97 T2MI patients are identified who are 1:1 matched with 97 T1MI patients after considering age, gender, ST-segment elevation, time from onset to coronary angiography, and hs-cTnI on admission by propensity score matching. Plasma pseudo-targeted metabolomics at baseline was determined. RESULTS: The clinical characteristics of the two groups were comparable, while the T1MI showed more severe coronary lesions than T2MI according to OCT imaging. 90 differential metabolites were identified between the two groups, among 1027 endogenous metabolites in 20 classes. N-Acetyl-L-Leucine, free fatty acid (15:1), Thymidine-5'-triphosphate, Mevalonic acid 5-pyrophosphate, and five oligopeptides were candidate biomarkers (AUC ≥ 0.85) distinguishing T2MI from T1MI. 12 KEGG pathways showed significant differences, mainly involving amino acid, nucleotide, and their derivatives metabolism, and signaling pathways such as mTOR, cGMP-PKG, and cAMP. Other differences were observed in TCA cycle (P = 0.08) and ROS (P = 0.05). Proteolysis and coronary heart disease risk lipid level were lower in T2MI. T2MI had a decrease of differential abundance score in almost all the KEGG enrichment pathways. Furthermore, T2MI can be subdivided into three subtypes by hierarchical cluster analysis of AUCs with causes/triggers of T2MI. CONCLUSIONS: There are significant metabolic profile differences between T1MI and T2MI. Several candidate metabolic biomarkers can effectively distinguish the two groups. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov NCT03297164.

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study.

BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Trends in Electronic Cigarette Use Among US Adults With a History of Cardiovascular Disease.

This cross-sectional study analyzes the prevalence of electronic cigarette (e-cigarette) use among adults with cardiovascular disease in the US between 2014 and 2020.

Cost-related medication nonadherence in US adults with asthma: The National Health Interview Survey, 2013-2020.

BACKGROUND: Asthma is a chronic disease that needs long-term control for secondary prevention. Health-related expenditures resulting from asthma are rising in the United States, and medication nonadherence is associated with adverse health outcomes in patients with asthma. OBJECTIVE: To estimate the prevalence and risk factors of cost-related medication nonadherence (CRN) in individuals with asthma in the United States. METHODS: We identified patients aged above or equal to 18 years with a history of asthma in nationally representative cross-sectional data, the National Health Interview Survey 2013 to 2020. Participants were considered to have experienced CRN if at any time in the 12 months they reported skipping doses, taking less medication, or delaying filling a prescription to save money. The weighted prevalence of CRN was estimated overall and by subgroups. Logistic regression was used to identify CRN-related characteristics. RESULTS: Of the 26,539 National Health Interview Survey participants with a history of asthma, 4360 (15.77%; representing 3.92 million of the US population) reported CRN, with 10.12% (weighted 2.51 million) of patients skipping doses to save money, 10.82% (weighted 2.69 million) taking less medication to save money, and 13.35% (weighted 3.31 million) delaying filling a prescription to save money. The subgroups young, women, low income, no health insurance, currently smoking, and with comorbidities had a higher prevalence of CRN. The results of this sensitivity analysis did not differ from the overall results. CONCLUSION: In the United States, 1 in 6 adults with a history of asthma is nonadherence with medications due to costs. Removing financial barriers to accessing medication can improve medication adherence in patients with asthma.

The association between sarcopenia and incident chronic lung disease in the general population: A longitudinal study based on CHARLS data.

BACKGROUND: Data regarding the association of sarcopenia with chronic lung disease (CLD) has led to inconclusive results. The main goal of this research was to investigate the association between sarcopenia and CLD in middle-aged and elderly individuals in China. METHODS: The study sample consisted of 11,077 individuals without CLD at baseline chosen from the China Health and Retirement Longitudinal Study (CHARLS) data from 2015, followed up until 2018. Sarcopenia was identified utilizing the criteria set by the Asian Working Group on Sarcopenia (AWGS 2019) in 2019. Individuals were categorized into no-sarcopenia, possible-sarcopenia, and sarcopenia groups. The outcome of the study was considered to be incident CLD, which included chronic bronchitis, emphysema, pulmonary heart disease, and asthma. The association between sarcopenia and the risk of CLD was also examined by employing weighted Cox proportional hazard regression models. RESULTS: A total of 356 (3.20 %) participants developed CLD during the 3.6-year follow-up period. The cumulative incidence of CLD in the no-sarcopenia, possible-sarcopenia, and sarcopenia groups was 2.80 % (230/8222), 4.37 % (55/1260), and 4.45 % (71/1595), respectively. Individuals with possible sarcopenia {hazard ratio [HR] [95 % confidence interval (CI)]: 1.48 [1.04-2.09]} and sarcopenia [HR (95 % CI): 1.68 (1.12-2.51)] demonstrated a considerably high risk of developing CLD compared to individuals in the no-sarcopenia group. Moreover, individuals diagnosed with sarcopenia, as per the criteria established by the European Working Group on Sarcopenia in Older People (EWGSOP) 2018, were at considerably high risk for developing CLD compared to those in the no-sarcopenia group. CONCLUSION: This research involving adult Chinese individuals demonstrated a significant association between, possible sarcopenia and sarcopenia with an elevated risk of incident CLD, thereby emphasizing the importance of monitoring respiratory health in this population. KEY POINTS: Question: Whether muscle mass and sarcopenia are associated with the development of chronic lung disease (CLD) in Asian middle-aged and elderly individuals. FINDINGS: This longitudinal study encompassing 11,077 adults aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS) data with 3.6 years of follow-up revealed a positive association between sarcopenia at baseline and incidence of CLD. Meaning: The findings suggest that possible sarcopenia and sarcopenia are linked to the development of CLD. Consequently, middle-aged and elderly individuals with possible sarcopenia and sarcopenia can be considered vulnerable regarding the primary prevention strategies for CLD.

Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study.

BACKGROUND: Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes. METHODS: This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999-2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015. RESULTS: During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95%CIs) per doubling of MMA for all-cause mortality were 1.19 (1.04-1.37) in females with diagnosed diabetes versus 1.58 (1.36-1.86) in male counterparts. In addition, MMA levels had an insignificant or weak correlation with sex hormone profiles at baseline, regardless of diabetes status and sex. CONCLUSIONS: Sex difference in mortality risk was especially significant in diagnosed type 2 diabetes. Increasing equivalent exposure to mitochondrial metabolite MMA was associated with a greater excess risk of future mortality in males with diabetes than in females.

Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy.

BACKGROUND: Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy. METHODS: Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16-20 h after inducing fatal sepsis. RESULTS: We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague-Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation. CONCLUSIONS: These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

L-shaped association between dietary zinc intake and the risk of developing cardiovascular disease in Chinese adults: A cohort study.

Background: Although the association of zinc (Zn) with cardiovascular disease (CVD) has been studied, no consensus has been reached on this relationship, particularly dietary Zn intake. The purpose of this study was to assess the effect of dietary Zn intake on the risk of CVD and to analyze whether this effect varied according to zinc consumption using representative data from China. Methods: 11,470 adults from the China Health and Nutrition Survey (CHNS) were eventually enrolled. The dietary information was collected by the 3 day 24-h dietary recalls combined with dietary weighting method. CVD was defined as participants with self-reported physician-diagnosed apoplexy and/or myocardial infarction during the follow-up. Cox regression was used to calculate the hazard ratios (HRs) of CVD with 95% confidence intervals. Restricted cubic spline function plus Cox regression was used to visualize the influence trend of dietary Zn intake on new-onset CVD and to test whether this trend is linear. 2-segment Cox regression was established to address the nonlinear trend. Results: 431 participants developed CVD, including 262 strokes and 197 myocardial infarctions. Compared with the lowest quintile (Q1), the adjusted hazard ratios and 95% confidence interval (CI) of CVD in Q2 to Q5 of dietary Zn intake were 0.72 (0.54, 0.97), 0.59 (0.42, 0.81), 0.50 (0.34, 0.72) and 0.44 (0.27, 0.71), respectively. The influence trend of dietary Zn intake on new-onset CVD was nonlinear and L-shaped. When dietary Zn intake <13.66 mg/day, increased dietary Zn intake was significantly associated with decreased risk of developing CVD (HR = 0.87, 95% CI: 0.82-0.92, p-value <0.0001). Conclusion: An L-shaped trend was observed between dietary Zn intake and the risk of developing CVD, indicating that dietary Zn intake should be improved moderately, but not excessively, for the benefit of cardiovascular disease.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.

IRGM/Irgm1 deficiency inhibits neutrophil-platelet interactions and thrombosis in experimental atherosclerosis and arterial injury.

BACKGROUND: Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools. METHODS: The thrombi images, platelet activation makers and NETs makers were detected in the serum of STEMI patients and controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherothrombosis in vivo, ApoE-/-Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK-cPLA2 signals inhibitors were used. RESULTS: Serum IRGM was positively correlated with PF4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production. CONCLUSIONS: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis.

Renin-angiotensin system antagonists and mortality due to pneumonia, influenza, and chronic lower respiratory disease in patients with hypertension.

BACKGROUND: It is controversial whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) have a potentially beneficial role in the respiratory system. This study investigated the association between ACEI/ARB medications and respiratory-related mortality in hypertensive patients in a real-world nationally representative cohort. METHODS: This was a retrospective analysis based on a prospective cohort study. A total of 10,530 patients with hypertension aged ≥ 20 years were included. The data was extracted from the US National Health and Nutrition Examination Survey during 1988-1994 and 1999-2006. The study was approved by the Institutional Review Boards. Moreover, inform concent was taken form all the participants. RESULTS: Overall, 27.7% (n = 2920) patients took ACEI/ARB agents. During a median follow-up of 12.4 years, 278 individuals died of respiratory disease, including chronic lower respiratory disease (n = 155) and influenza or pneumonia (n = 123). Compared with the patients without ACEI/ARB use, those taking ACEI/ARB were not associated with respiratory-specific mortality in a multivariable-adjusted Cox model. After 1: 1 matching, taking ACEI/ARB was also not related to respiratory mortality (Hazard ratio (HR) = 1.07, 95% CI: 0.79-1.43), influenza- or pneumonia-related (HR = 1.00, 95% CI: 0.65-1.54) and chronic pulmonary mortality (HR = 1.13, 95% CI: 0.75-1.69). After separating ACEI and ARB from anti-hypertensive medications, those associations remained unchanged. CONCLUSIONS: We discovered no significant link between ACEI or ARB medication and pulmonary-related mortality in hypertensive patients. In hypertensive patients, standard ACEI/ARB administration may have little effect on the respiratory system.

The Regulation and Characterization of Mitochondrial-Derived Methylmalonic Acid in Mitochondrial Dysfunction and Oxidative Stress: From Basic Research to Clinical Practice.

Methylmalonic acid (MMA) can act as a diagnosis of hereditary methylmalonic acidemia and assess the status of vitamin B12. Moreover, as a new potential biomarker, it has been widely reported to be associated with the progression and prognosis of chronic diseases such as cardiovascular events, renal insufficiency, cognitive impairment, and cancer. MMA accumulation may cause oxidative stress and impair mitochondrial function, disrupt cellular energy metabolism, and trigger cell death. This review primarily focuses on the mechanisms and epidemiology or progression in the clinical study on MMA.

A Concomitant Cancer Diagnosis Is Associated With Poor Cardiovascular Outcomes Among Acute Myocardial Infarction Patients.

BACKGROUND AND AIMS: With the increasing coexistence of cardiovascular disease and cancer in contemporary clinical practice, studies on the outcomes in acute myocardial infarction (AMI) patients with cancer has not been systematically investigated. This study sought to investigated the effect of coexisting cancer on the treatment and clinical outcomes among AMI patients. METHODS: We retrospectively integrated and analyzed cardiovascular data of 6,607 AMI patients between June 2016 and December 2019. Patients with cancer were compared with pair-matched cancer-naive patients. Cox proportional hazards models were constructed to compare the differences in outcomes. RESULTS: Of 6,607 patients, 2.3% (n = 150) had been diagnosed with cancer. Patients with cancer were older (70.3 ± 10.0 vs. 63.9 ± 11.5 years, P < 0.001) and had a higher burden of comorbidities. Moreover, patients with cancer tended to receive clopidogrel (52.0 vs. 40.0%, P = 0.004) rather than ticagrelor (45.6 vs. 58.2%, P = 0.003) than those without cancer. After pairwise matching, patients with cancer were less likely to undergo in-hospital percutaneous coronary intervention (61.3 vs. 70.0%, P = 0.055). And after 3-year follow-up, the cumulative incidence of cardiovascular death (14.0 vs. 8.3%; adjusted HR, 1.93; 95% CI, 1.11-3.39; P = 0.021) among patients with cancer was significantly higher than that among the matched controls, a similar pattern was observed for the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (16.0 vs. 10.3%; adjusted HR, 1.98; 95% CI, 1.21-3.26; P = 0.007). Moreover, patients with a historical cancer diagnosis within 5 years had a higher risk of cardiovascular ischemic events. CONCLUSIONS: AMI patients with a concomitant diagnosis of cancer tended to be treated with conservative therapies and were at substantially higher risk for adverse cardiovascular outcomes.