Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Differential DNA methylation landscape of miRNAs genes in mice liver fibrosis.

BACKGROUND: Patients with chronic liver disease were found nearly all to have liver fibrosis, which is characterized by excess accumulation of extracellular matrix (ECM) proteins. While ECM accumulation can prevent liver infection and injury, it can destroy normal liver function and architecture. miRNA's own regulation was involved in DNA methylation change. The purpose of this study is to detect DNA methylation landscape of miRNAs genes in mice liver fibrosis tissues. METHODS: Male mice (10-12 weeks) were injected CCl4 from abdominal cavity to induced liver fibrosis. 850 K BeadChips were used to examine DNA methylation change in whole genome. The methylation change of 16 CpG dinucleotides located in promoter regions of 4 miRNA genes were detected by bisulfite sequencing polymerase chain reaction (BSP) to verify chip data accuracy, and these 4 miRNA genes' expressions were detected by RT-qPCR methods. RESULTS: There are 769 differential methylation sites (DMS) in total between fibrotic liver tissue and normal mice liver tissue, which were related with 148 different miRNA genes. Chips array data were confirmed by bisulfite sequencing polymerase chain reaction (R = 0.953; P < 0.01). GO analysis of the target genes of 2 miRNA revealed that protein binding, cytoplasm and chromatin binding activity were commonly enriched; KEGG pathway enrichment analysis displayed that TGF-beta signaling pathway was commonly enriched. CONCLUSION: The DNA of 148 miRNA genes was found to have methylation change in liver fibrosis tissue. These discoveries in miRNA genes are beneficial to future miRNA function research in liver fibrosis.

Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development.

BACKGROUND: Clinical studies show that the most common single-point mutation in humans, ALDH2 (aldehyde dehydrogenase 2) rs671 mutation, is a risk factor for the development and poor prognosis of atherosclerotic cardiovascular diseases, but the underlying mechanism remains unclear. Apoptotic cells are phagocytosed and eliminated by macrophage efferocytosis during atherosclerosis, and enhancement of arterial macrophage efferocytosis reduces atherosclerosis development. METHODS: Plaque areas, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated in APOE-/- mice with bone marrow transplanted from APOE-/-ALDH2-/- and APOE-/- mice. RNA-seq, proteomics, and immunoprecipitation experiments were used to screen and validate signaling pathways affected by ALDH2. Efferocytosis and protein levels were verified in human macrophages from wild-type and rs671 mutation populations. RESULTS: We found that transplanting bone marrow from APOE-/-ALDH2-/- to APOE-/- mice significantly increased atherosclerosis plaques compared with transplanting bone marrow from APOE-/- to APOE-/- mice. In addition to defective efferocytosis in plaques of APOE-/- mice bone marrow transplanted from APOE-/-ALDH2-/- mice in vivo, macrophages from ALDH2-/- mice also showed significantly impaired efferocytotic activity in vitro. Subsequent RNA-seq, proteomics, and immunoprecipitation experiments showed that wild-type ALDH2 directly interacted with Rac2 and attenuated its degradation due to decreasing the K48-linked polyubiquitination of lysine 123 in Rac2, whereas the rs671 mutant markedly destabilized Rac2. Furthermore, Rac2 played a more crucial role than other Rho GTPases in the internalization process in which Rac2 was up-regulated, activated, and clustered into dots. Overexpression of wild-type ALDH2 in ALDH2-/- macrophages, rather than the rs671 mutant, rescued Rac2 degradation and defective efferocytosis. More importantly, ALDH2 rs671 in human macrophages dampened the apoptotic cells induced upregulation of Rac2 and subsequent efferocytosis. CONCLUSIONS: Our study has uncovered a pivotal role of the ALDH2-Rac2 axis in mediating efferocytosis during atherosclerosis, highlighting a potential therapeutic strategy in cardiovascular diseases, especially for ALDH2 rs671 mutation carriers.

LincRNA-p21 Upregulates Nuclear Orphan Receptor Nr4a2 and Aggravates Myocardial Ischemia/Reperfusion Injury via Targeting MiR-466i-5p.

Myocardial ischemia/reperfusion (I/R) injury can bring about more cardiomyocyte death and aggravate cardiac dysfunction, but its pathogenesis remains unclear. This study aimed to investigate the role of long intergenic noncoding RNA-p21 (LincRNA-p21) in myocardial I/R injury and its underlying mechanism. Mice were subjected to myocardial I/R injury by ligation and release of the left anterior descending artery, and HL-1 cardiomyocytes were treated with hydrogen peroxide. Infarct area, cardiac function, and cardiomyocyte apoptosis were determined. Consequently, LincRNA-p21 was found to significantly be elevated both in the reperfused hearts and H2O2-treated cardiomyocytes. Moreover, genetic inhibition of LincRNA-p21 brought about reduced infarct area and improved cardiac function in mice subjected to myocardial I/R injury. LincRNA-p21 knockdown was also demonstrated to inhibit cardiomyocyte apoptosis both in vivo and in vitro. Notably, LincRNA-p21 silencing increased the expression of microRNA-466i-5p (miR-466i-5p) and suppressed the expression of nuclear receptor subfamily 4 group A member 2 (Nr4a2). Mechanically, LincRNA-p21 downregulated and directly interacted with miR-466i-5p, while application of miR-466i-5p inhibitor promoted cardiomyocyte apoptosis that was improved by LincRNA-p21 inhibition. Furthermore, Nr4a2 upregulation caused by LincRNA-p21 overexpression was partially reversed by miR-466i-5p mimics. Thus, LincRNA-p21 positively regulated the expression of Nr4a2, through sponging miR-466i-5p, promoting cardiomyocyte apoptosis in myocardial I/R injury. The current study revealed a novel LincRNA-p21/miR-466i-5p/Nr4a2 pathway for myocardial I/R injury, indicating that LincRNA-p21 may serve as a potential target for future therapy.

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

AIMS: Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS: Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS: ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

ALDH2 Activation Inhibited Cardiac Fibroblast-to-Myofibroblast Transformation Via the TGF-ß1/Smad Signaling Pathway.

Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-ß1 (TGF-ß1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-ß1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-ß1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-ß1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.

The Role of ALDH2 in Sepsis and the To-Be-Discovered Mechanisms.

Sepsis, defined as life-threatening tissue damage and organ dysfunction caused by a dysregulated host response to infection, is a critical disease which imposes global health burden. Sepsis-induced organ dysfunction, including circulatory and cardiac dysfunction, hepatic dysfunction, renal dysfunction, etc., contributes to high mortality and long-term disability of sepsis patients. Altered inflammatory response, ROS and reactive aldehyde stress, mitochondrial dysfunction, and programmed cell death pathways (necrosis, apoptosis, and autophagy) have been demonstrated to play crucial roles in septic organ dysfunction. Unfortunately, except for infection control and supportive therapies, no specific therapy exists for sepsis. New specific therapeutic targets are highly warranted. Emerging studies suggested a role of potential therapeutic target of ALDH2, a tetrameric enzyme located in mitochondria to detoxify aldehydes, in septic organ dysfunction. In this article, we will review the presentations and pathophysiology of septic organ dysfunction, as well as summarize and discuss the recent insights regarding ALDH2 in sepsis.

ALDH2 mediates the dose-response protection of chronic ethanol against endothelial senescence through SIRT1/p53 pathway.

Aldehyde dehydrogenase 2 (ALDH2) plays essential roles in drinking-associated diseases or effects. As we have previously reported, ALDH2 mediates acute ethanol-induced eNOS activation in vitro. However, whether chronic ethanol treatment has a dose-response endothelial protection, as well as the possible mediating role of ALDH2 involved, is unclear. Here, we show that appropriate dose of ethanol preserved the expression and activity of ALDH2 and eNOS, and alleviated senescence-associated phenotypes in human aortic endothelial cells. Furthermore, ALDH2 deficiency impairs the dose-response protection of ethanol against endothelial senescence by promoting the accumulation of 4-HNE, the formation of 4-HNE-SIRT1 protein adducts and the subsequent decrease in SIRT1-dependent p53 deacetylation. Collectively, our data indicate that ALDH2 mediates the protection of appropriate ethanol by modulating SIRT1/p53-dependent endothelial senescence.

Targeting acetaldehyde dehydrogenase 2 (ALDH2) in heart failure-Recent insights and perspectives.

Heart failure is one of the major causes of the ever-rising mortality globally. ALDH2 rs671 polymorphism is proven to be closely related to the prevalence of CAD, hypertension, diabetes mellitus and alcoholism, which are etiological factors of heart failure. In addition, growing evidence supports a possible role for ALDH2 in different forms of heart failure. In this mini-review, we will review the recent insights regarding the effects of ALDH2 polymorphism on etiological factors of heart failure and underlying mechanisms involved. In addition, we will also discuss the booming epigenetic information in this field which will greatly improve our understanding of the cardiovascular effect of ALDH2. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure edited by Dr. Jun Ren & Yingmei Zhang.

Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1-AMPK signaling and autophagy.

Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Mitochondrial aldehyde dehydrogenase in myocardial ischemia-reperfusion injury: from bench to bedside.

Acute myocardial infarction is one of the major causes of mortality worldwide. Reperfusion in a timely fashion is the most effective way to limit infarct size. However, reperfusion can itself prompt further myocardial injury. This phenomenon is commonly known as myocardial ischemia-reperfusion (IR) injury. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme metabolizing acetaldehyde and toxic aldehydes. Increasing evidence has revealed a cardioprotective role of ALDH2 in myocardial IR injury. Evidence from animal studies has shown that ALDH2 diminishes acute myocardial infarct size, ameliorates cardiac dysfunction and prevents reperfusion arrhythmias. The activity of ALDH2 is severely compromised if it is encoded by the mutant ALDH2*2 gene, with an incidence of approximately 40% in Asian populations. Epidemiological surveys in the Asian population have depicted that ALDH2 polymorphism is closely associated with higher prevalence of acute myocardial infarction and coronary artery disease. Therefore, targeting ALDH2 may represent a promising avenue to protect against IR injury. This review recapitulates the underlying mechanisms involved in the protective effect of ALDH2 in cardiac IR injury. Translational potential of ALDH2 in the management of coronary heart disease is also discussed.

Sex differences in the management of patients with suspected acute coronary syndrome in China.

Few studies have assessed sex differences in the management of suspected acute coronary syndrome (ACS). We aimed to compare the evaluation, treatment, and outcomes between males and females with suspected ACS in the emergency department. Data were obtained from a prospective registry of acute chest pain involving 21 emergency departments in Shandong Province, China. The primary endpoint was 30-day major adverse cardiac events (MACEs). Overlap propensity score weighting was used to address potential confounding. A total of 8046 patients were analysed (42.8% female). Overlap-weighted analysis showed no significant association of female sex with 30-day MACEs (odds ratio, 0.91; 95% CI 0.75 to 1.11; P = 0.363). Secondary analyses found that women were less likely to be identified as high risk at first presentation (odds ratio, 0.86; 95% CI 0.78 to 0.94; P < 0.001). In the emergency department, women were less likely to undergo antiplatelet therapy (odds ratio, 0.87; 95% CI 0.79 to 0.96; P = 0.004) or coronary angiography (odds ratio, 0.78; 95% CI, 0.69 to 0.88; P < 0.001). Women had a longer length of stay in the emergency department and were less likely to be admitted to a ward at disposition. These sex differences existed only in the non-ST-elevation subgroup and were independent of risk stratification. Women with non-ST-elevation chest pain in China received suboptimal treatment in the emergency department. However, their clinical outcomes were not significantly different from those of men. Further studies are needed to determine the causes and impacts of these sex differences.

Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS.

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

Alpha-lipoic acid ameliorates oxidative stress by increasing aldehyde dehydrogenase-2 activity in patients with acute coronary syndrome.

Aldehyde dehydrogenase-2 (ALDH2) is the main enzyme responsible for acetaldehyde oxidation in ethanol metabolism and also provides protection against oxidative stress. Alpha-lipoic acid (α-LA), a natural dithiol compound with antioxidant properties, has been reported to increase ALDH2 activity in cultured cells. We analyzed the therapeutic efficacy of α-LA in 63 patients with confirmed acute coronary syndrome (ACS). These patients (52 men and 11 women, with age range 49-72 years) were randomized into two groups: untreated group (n = 30) and α-LA group (n = 33). Patients in the α-LA group were given an intravenous injection of 600 mg α-LA every day for 5 days while the patients in the untreated group were given saline. An isoprostane, 8-iso-prostaglandin F2α (8-iso-PGF2α), one product of arachidonic acid metabolism, was measured as a marker for oxidative stress. The serum levels of 8-iso-PGF2α and ALDH2 activity were determined at admission to the hospital (time 0), and at 24 hours and 1 week after treatment. At 24 hours and 1 week after treatment, ALDH2 activity was significantly higher in the α-LA group than in the untreated group (P < 0.05), whereas the levels of 8-iso-PGF2α were significantly lower in the α-LA group than in the untreated group (all P < 0.05). Importantly, the decrease of 8-iso-PGF2α levels correlated with the increased ALDH2 activity at both 24 hours (r = 0.6234, P < 0.001) and 1 week after treatment (r = -0.3941, P = 0.0014). α-LA may ameliorate oxidative stress through up-regulating ALDH2 activity in patients with ACS.

Effects of Chest Compression on Ventilation Quality during Cardiopulmonary Resuscitation.

Ventilation is an important part of cardiopulmonary resuscitation (CPR). The advanced airway mode and 30:2 mode are used for intubated and non-intubated patients, respectively. It is debatable that passive produced by 30 compressions can provide adequate tidal volume for 30:2 mode. In addition, the fragmented ventilation caused by continuous compression may result in ineffective ventilation. In the study, one pig was anaesthetized and intubated for 2 CPRs. Continuous chest compressions with ventilation and continuous chest compressions without mechanical ventilation were performed in 2 CPRs, respectively. Three 10-minute data segments including a period of normal ventilation (V segment), a period of only compressions without ventilation (C segment), and a period of compressions with ventilation (C-V segment) were used to analyze peek flow (PF), peek pressure (PP) and tidal volume. All the data was presented as mean ± standard deviation. Chest compression resulted in 14.90% increase in mean PP (2401.40 ± 94.75 Pa vs 2822.06 ± 291.10 Pa, p<0.05), 81.46% increase in average PF (319.58 ± 56.93 ml/s vs 579.92 ± 80.27 ml/s, p<0.05). The mean tidal volumes for C segment, V segment and C-V segment were 189.13 ml, 514.72 ml, and 429.26ml, respectively. Continuous compressions reduced the accumulative tidal volume, but when five compressions were made in one inspiratory phase, there is almost no loss of tidal volume (510.86 ± 47.24 ml vs 514.72 ± 29.25 ml, p<0.05). The study suggested the ventilator without feedback regulation might reduce the peek pressure during CPR and 5 compressions in 2 s inspiratory phase provided higher tidal volume.Clinical Relevance- This study shows that 150 chest compressions per minute provided greater tidal volume than 100 and 120 compressions per minute; continuous chest compressions could also provide a certain amount of oxygen supply.

Electrical-mechanical dynamical coupling between electrocardiographic and photoplethysmographic signals during cardiopulmonary resuscitation.

BACKGROUND AND OBJECTIVE: Cardiac arrest (CA) remains a significant cause of death and disability. High-quality cardiopulmonary resuscitation (CPR) can improve the survival rate of CA. A challenging issue is to find physiological indicators for screening and evaluating the cardiovascular function associated with CPR. This study aimed to investigate the electrical-mechanical dynamic coupling between electrocardiographic (ECG) and photoplethysmographic (PPG) signals for indicating cardiovascular function in the progress of CPR. METHOD: The ECG and PPG signals were simultaneously collected from a porcine CA model (n = 10) induced by ventricular fibrillation, and were further divided into four periods: Baseline, CA, CPR, and recovery of spontaneous circulation (ROSC). Recurrence quantitative analysis (RQA) was applied to examine the nonlinear dynamics of the ECG and PPG signals individually, and cross recurrence quantitative analysis (CRQA) was used to examine the ECG-PPG dynamical coupling. RESULTS: The CA influenced the dynamic patterns of electrical and mechanical activities and the electrical-mechanical coupling, which can be observed from the reduced entropy (ENTR) (p < 0.01), reduced determinism (DET) (p < 0.01) and reduced trapping time (TT) (p < 0.01) at CA compared to Baseline. The recurrence rate (RR), ENTR, DET, and TT at CPR were significantly lower than the parameters at ROSC but higher than those at CA. CONCLUSIONS: The electrical-mechanical dynamical coupling was sensitive to CPR and able to reflect the changes in cardiac function in the process of CPR.

The role of aldehyde dehydrogenase 2 in cardiovascular disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.

Co-registration of OPM-MCG signals with CT using optical scanning.

Magnetocardiography (MCG) can be used to noninvasively measure the electrophysiological activity of myocardial cells. The high spatial resolution of magnetic source localization can precisely determine the location of cardiomyopathy, which is of great significance for the diagnosis and treatment of cardiovascular disease. To perform magnetic source localization, MCG data must be co-registered with anatomical images. We propose a co-registration method that can be applied to OPM-MCG systems. In this method, the sensor array and the trunk of the subject are scanned using structured light-scanning technology, and the scan results are registered with the reconstructed structure using computed tomography (CT). This can increase the number of effective cloud points acquired and reduce the interference from respiratory motion. The scanning bed of the OPM-MCG system was modified to be consistent with the CT device, ensuring that the state of the body remains consistent between the cardiac magnetometry measurements and CT scans.

SUPER Score Contributes to Warning and Management in Early-Stage COVID-19.

Background: Some COVID-19 patients deteriorate to severe cases with relatively higher case-fatality rates, which increases the medical burden. This necessitates identification of patients at risk of severe disease. Early assessment plays a crucial role in identifying patients at risk of severe disease. This study is to assess the effectiveness of SUPER score as a predictor of severe COVID-19 cases. Methods: We consecutively enrolled COVID-19 patients admitted to a comprehensive medical center in Wuhan, China, and recorded clinical characteristics and laboratory indexes. The SUPER score was calculated using parameters including oxygen saturation, urine volume, pulse, emotional state, and respiratory rate. In addition, the area under the receiver operating characteristic curve (AUC), specificity, and sensitivity of the SUPER score for the diagnosis of severe COVID-19 were calculated and compared with the National Early Warning Score 2 (NEWS2). Results: The SUPER score at admission, with a threshold of 4, exhibited good predictive performance for early identification of severe COVID-19 cases, yielding an AUC of 0.985 (95% confidence interval [CI] 0.897-1.000), sensitivity of 1.00 (95% CI 0.715-1.000), and specificity of 0.92 (95% CI 0.775-0.982), similar to NEWS2 (AUC 0.984; 95% CI 0.895-1.000, sensitivity 0.91; 95% CI 0.587-0.998, specificity 0.97; 95% CI 0.858-0.999). Compared with patients with a SUPER score<4, patients in the high-risk group exhibited lower lymphocyte counts, interleukin-2, interleukin-4 and higher fibrinogen, C-reactive protein, aspartate aminotransferase, and lactate dehydrogenase levels. Conclusions: In conclusion, the SUPER score demonstrated equivalent accuracy to the NEWS2 score in predicting severe COVID-19. Its application in prognostic assessment therefore offers an effective early warning system for critical management and facilitating efficient allocation of health resources.

GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD.

AIMS: We aimed to investigate the independent associations between growth differentiation factor 15 (GDF-15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). METHODS AND RESULTS: We measured the plasma concentrations of GDF-15 centrally in patients from the BIomarker-based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post-discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non-coronary artery bypass grafting-related major bleeding and clinically significant bleeding (CSB)] during the 12 month follow-up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter-quartile range (IQR)] 56.0-70.1 years}, the median concentration of plasma GDF-15 at admission was 1091 (IQR 790.5-1635.0) ng/L. Higher concentrations of GDF-15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35-2.88, P < 0.001], A/H HF (HR 2.69, 95% CI 1.92-3.77, P < 0.001), cardiogenic shock (HR 1.46, 95% CI 1.04-2.05, P = 0.029), and CSB (HR 1.48, 95% CI 1.22-1.79, P < 0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF-15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. CONCLUSIONS: In patients with CAD, admission levels of GDF-15 were associated with an increased 1 year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF-15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04044066.