The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.

Heart failure with preserved ejection fraction (HFpEF) accounts for almost half of all heart failure (HF) cases worldwide. Unfortunately, its incidence is expected to continue to rise, and effective therapy to improve clinical outcomes is lacking. Numerous efforts currently directed towards the pathophysiology of human HFpEF are uncovering signal transduction pathways and novel therapeutic targets. The nitric oxide-cyclic guanosine phosphate-protein kinase G (NO-cGMP-PKG) axis has been described as an important regulator of cardiac function. Suppression of the NO-cGMP-PKG signalling pathway is involved in the progression of HFpEF. Therefore, the NO-cGMP-PKG signalling pathway is a potential therapeutic target for HFpEF. In this review, we aim to explore the mechanism of NO-cGMP-PKG in the progression of HFpEF and to summarize potential therapeutic drugs that target this signalling pathway.

Peri-operative Takotsubo syndrome after non-cardiac surgery: a retrospective nested case-control study.

AIMS: Takotsubo syndrome (TTS) is an acute reversible cardiac dysfunction that may occur during the peri-operative period and among patients with serious illness. We aimed to evaluate the clinical characteristics, peri-operative management, and prognosis of peri-operative TTS (pTTS) and explore the factors associated with pTTS. METHODS: We conducted a retrospective nested case-control study using the database of patients who underwent in-hospital non-cardiac surgeries between January 2017 and December 2020 in Peking University Third hospital. Cases were adult patients diagnosed TTS at discharge who were matched with four controls based on operative types. Multivariable conditional logistic regression was used to identified the factors associated with pTTS. The area under the curve (AUC) was used to evaluate the diagnostic efficacy. RESULTS: Among the 128 536 patients underwent non-cardiac surgery, 20 patients with pTTS and 80 patients without were enrolled in this study. The incidence of pTTS was about 0.016% in our centre. The median age of patients with pTTS was 52.5 (38.25, 76.25) years, although 90% of them were female. Fifty per cent (9 cases) of female patients were pre-menopausal. Caesarean section has the highest proportion of pTTS (30% of the pTTS cases) with the incidence of caesarean section-related pTTS of 0.06% in our centre. A high prevalence of non-apical ballooning pattern of regional wall motion abnormality (seven cases, 35%) and a high mortality (two cases, 10%) were observed. Left ventricular ejection fraction (LVEF) of patients with pTTS was significantly decreased (41.7 ± 8.8%). In the acute phase, supportive treatments aiming to reduce life-threatening complications were main treatment strategies. After receiving systematic treatment, significant improvements were observed in LVEF (63.1 ± 13.5%), with median recovery time of LVEF of 7.48 days. Leucocyte count [odds ratio (OR): 4.59; 95% confidence interval (CI): 1.10-19.15], haemoglobin (HGB) (OR: 10.52; 95% CI: 1.04-106.36), and the revised cardiac risk index (RCRI) score (OR: 6.30; 95% CI: 1.05-37.88) were the factors significantly associated with pTTS. The RCRI score performed poorly in the prediction of pTTS (AUC: 0.630; 95% CI: 0.525-0.735). After adding leucocyte count and HGB into the RCRI score, the AUC was significantly improved (AUC: 0.768; 95% CI: 0.671-0.865; P = 0.001). CONCLUSIONS: Patients with pTTS have some differences compared with common TTS, including higher proportion of pre-menopausal female, higher prevalence during caesarean section, higher prevalence of non-apical ballooning pattern of regional wall motion abnormality, and higher mortality. The RCRI score performed poorly in the evaluation of pTTS. Adding HGB and leucocyte count into the RCRI score could significantly improve its predictive performance.

Development and Validation of Predictive Model-HASBLAD Score-For Major Adverse Cardiovascular Events During Perioperative Period of Non-cardiac Surgery: A Single Center Experience in China.

Background: Major adverse cardiovascular events (MACEs) represent a significant reason of morbidity and mortality in non-cardiac surgery during perioperative period. The prevention of perioperative MACEs has always been one of the hotspots in the research field. Current existing models have not been validated in Chinese population, and have become increasingly unable to adapt to current clinical needs. Objectives: To establish and validate several simple bedside tools for predicting MACEs during perioperative period of non-cardiac surgery in Chinese hospitalized patients. Design: We used a nested case-control study to establish our prediction models. A nomogram along with a risk score were developed using logistic regression analysis. An internal cohort was used to evaluate the performance of discrimination and calibration of these predictive models including the revised cardiac risk index (RCRI) score recommended by current guidelines. Setting: Peking University Third Hospital between January 2010 and December 2020. Patients: Two hundred and fifty three patients with MACEs and 1,012 patients without were included in the training set from January 2010 to December 2019 while 38,897 patients were included in the validation set from January 2020 and December 2020, of whom 112 patients had MACEs. Main Outcome Measures: The MACEs included the composite outcomes of cardiac death, non-fatal myocardial infarction, non-fatal congestive cardiac failure or hemodynamically significant ventricular arrhythmia, and Takotsubo cardiomyopathy. Results: Seven predictors, including Hemoglobin, CARDIAC diseases, Aspartate aminotransferase (AST), high Blood pressure, Leukocyte count, general Anesthesia, and Diabetes mellitus (HASBLAD), were selected in the final model. The nomogram and HASBLAD score all achieved satisfactory prediction performance in the training set (C statistic, 0.781 vs. 0.768) and the validation set (C statistic, 0.865 vs. 0.843). Good calibration was observed for the probability of MACEs in the training set and the validation set. The two predictive models both had excellent discrimination that performed better than RCRI in the validation set (C statistic, 0.660, P < 0.05 vs. nomogram and HASBLAD score). Conclusion: The nomogram and HASBLAD score could be useful bedside tools for predicting perioperative MACEs of non-cardiac surgery in Chinese hospitalized patients.

Short-term exposure to traffic-related air pollution and STEMI events: Insights into STEMI onset and related cardiac impairment.

AIMS: Evidence on the impacts of traffic-related air pollution (TRAP) on ST-segment elevation myocardial infarction (STEMI) events is limited. We aimed to assess the acute effects of TRAP exposure on the clinical onset of STEMI and related cardiac impairments. METHODS AND RESULTS: We recruited patients who were admitted for STEMI and underwent primary percutaneous coronary intervention at Peking University Third Hospital between 2014 and 2020. Indicators relevant to cardiac impairments were measured. Concomitantly, hourly concentrations of traffic pollutants were monitored throughout the study period, including fine particulate matter, black carbon (BC), particles in size ranges of 5-560 nm, oxides of nitrogen (NOX), nitrogen dioxide, and carbon monoxide. The mean (SD) age of participants was 62.4 (12.5) years. Daily average (range) concentrations of ambient BC and NOX were 3.9 (0.1-25.0) µg/m3 and 90.8 (16.6-371.7) µg/m3. Significant increases in STEMI risks of 5.9% (95% CI: 0.1, 12.0) to 21.9% (95% CI: 6.0, 40.2) were associated with interquartile range increases in exposure to TRAP within a few hours. These changes were accompanied by significant elevations in cardiac troponin T levels of 6.9% (95% CI: 0.2, 14.1) to 41.7% (95% CI: 21.2, 65.6), as well as reductions in left ventricular ejection fraction of 1.5% (95% CI: 0.1, 2.9) to 3.7% (95% CI: 0.8, 6.4). Furthermore, the associations were attenuated in participants living in areas with higher residential greenness levels. CONCLUSIONS: Our findings extend current understanding that short-term exposure to higher levels of traffic pollution was associated with increased STEMI risks and exacerbated cardiac impairments, and provide evidence on traffic pollution control priority for protecting vulnerable populations who are at greater risks of cardiovascular events.

Clinical efficacy of "ICE-FIRE" ablation for non-paroxysmal atrial fibrillation.

PURPOSE: Catheter ablation is less successful for non-paroxysmal atrial fibrillation (NPAF) according to numerous follow-up studies. The choice of ablation strategy for patients with NPAF remains controversial. The objective of the study was to explore the clinical efficacy of the "ICE-FIRE" ablation. METHODS: Ninety NPAF patients were enrolled. Patients were randomly divided into RF (treated with circumferential pulmonary vein isolation (CPVI) and additional substrate modification by radiofrequency ablation) group and I-F (treated with CPVI by cryoablation and additional substrate modification by radiofrequency ablation) group. After CPVI and cardioversion to sinus rhythm, high-density mapping was performed. Eight-one of 90 participants restored to sinus rhythm. Seventy-four of 81 NPAF patients showed low-voltage zone. Substrates with low-voltage zone were targeted for further modification. Participants were followed at baseline, 3, 6, 9, and 12 months after the initial ablation. RESULTS: The I-F group shared more X-ray exposure (I-F, 264.4 ± 97.4 mGy; RF, 224.9 ± 62.0 mGy; P = 0.039) and less duration of the procedure (I-F, 150.3 ± 27.5 min; RF, 174.2 ± 38.5 min; P = 0.003) compared to RF group. The freedom from atrial arrhythmia recurrence at 12 months post-ablation was similar between the RF and I-F groups (RF, 57.1%; I-F, 71.8%; P = 0.197). However, I-F group experienced lower rehospitalization rate of AF recurrence (RF, 42.9%; I-F, 20.5%; P = 0.038). CONCLUSIONS: In NPAF patients requiring substrate mapping and modification, the "ICE-FIRE" ablation demonstrated non-inferior clinical efficacy and lower rehospitalization rate of AF recurrence when compared with pure radiofrequency ablation strategy.

Screening and functional analysis of differentially expressed lncRNAs in rapid atrial pacing dog atrial tissue.

PURPOSE: Atrial fibrillation (AF) is one of the most commonly sustained arrhythmias in clinical practice. Long non-coding RNAs (lncRNAs) are gene regulatory elements involved in the development of several diseases. We aimed to explore the expression characteristics of lncRNAs associated with AF. METHODS: We randomly assigned 12 adult healthy mongrel dogs into a control group and an atrial pacing group. Atrial pacing stimulation was performed at a high frequency of 500 beats per min for 14 consecutive days in the atrial pacing group. HE and Masson staining were used to detect rapid atrial pacing induced atrial fibrosis. Total RNA extraction was performed on dog atrial tissues and was used for high-throughput sequencing of lncRNAs. RESULTS: A total of 10,310 lncRNAs were detected, and 33 differentially expressed lncRNAs were screened. Among them, 19 lncRNAs were upregulated in the atrial pacing group, and 14 lncRNAs were downregulated. Gene Ontology (GO) classification, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and interaction networks showed that AF-related lncRNAs participate in the regulation of AF in diverse biological processes, cellular components, molecular functions, signaling pathways, and complex interactions with miRNAs and mRNAs. Five differentially expressed lncRNAs were selected for RT-PCR validation, and the verification results were consistent with the results of lncRNA sequencing. CONCLUSIONS: In summary, our study enhances our understanding of the biological functions of AF-related lncRNAs by screening and analyzing differentially expressed lncRNAs, and the results help to enrich the theoretical basis for the treatment of atrial fibrillation.

Overexpression of MicroRNA-16 Alleviates Atherosclerosis by Inhibition of Inflammatory Pathways.

BACKGROUND: Our previous study demonstrated that the expression of miR-16 was downregulated in the cell and animal models of atherosclerosis (AS), a main contributor to coronary artery disease (CAD). Overexpression of miR-16 inhibited the formation of foam cells by exerting anti-inflammatory roles. These findings indicated miR-16 may be an anti-atherogenic and CAD miRNA. The goal of this study was to further validate the expression of miR-16 in CAD patients and explore its therapeutic roles in an AS animal model. METHODS: A total of 40 CAD patients and 40 non-CAD people were prospectively registered in our study. The AS model was established in ApoE-/- mice fed a high-fat diet. The model mice were randomly treated with miR-16 agomiR (n = 10) or miR-negative control (n = 10). Hematoxylin-eosin staining was conducted for histopathological examination in thoracic aorta samples. ELISA and immunohistochemistry were performed to determine the expression levels of inflammatory factors (IL-6, TNF-α, MCP-1, IL-1ß, IL-10, and TGF-ß). qRT-PCR and western blotting were carried out to detect the mRNA and protein expression levels of PDCD4, miR-16, and mitogen-activated protein kinase pathway-related genes. RESULTS: Compared with the normal control, miR-16 was downregulated in the plasma and peripheral blood mononuclear cell of CAD patients, and its expression level was negatively associated with IL-6 and the severity of CAD evaluated by the Gensini score, but positively related with IL-10. Injection of miR-16 agomiR in ApoE-/- mice reduced the formation of atherosclerotic plaque and suppressed the accumulation of proinflammatory factors (IL-6, TNF-α, MCP-1, and IL-1ß) in the plasma and tissues but promoted the secretion of anti-inflammatory factors (IL-10 and TGF-ß). Mechanism analysis showed overexpression of miR-16 might downregulate target mRNA PDCD4 and then activate p38 and ERK1/2, but inactivate the JNK pathway. CONCLUSIONS: Our findings suggest miR-16 may be a potential diagnostic biomarker and therapeutic target for atherosclerotic CAD.

The correlation between trimethylamine N-oxide, lipoprotein ratios, and conventional lipid parameters in patients with unstable angina pectoris.

PURPOSE: Trimethylamine N-oxide (TMAO) is recently the main risk factor for coronary heart disease (CHD). Plasma lipid levels are conventionally used to predict coronary risk, but the correlation between TMAO and plasma lipid levels in unstable angina pectoris (UAP) was unclear. Our objective was to compare the plasma level of TMAO to lipoprotein ratios and conventional lipid parameters in UAP patients. METHODS: A total of 114 control participants and 184 UAP patients were enrolled. Demographic characteristics were collected. Plasma levels of TMAO and lipid in all patients were measured and analyzed. The receiver operating characteristic analysis (ROC), univariate, and multivariate logistic regression analyses were carried out to examine the relationship between TMAO, lipoprotein ratios, conventional lipid parameters, and UAP. RESULTS: The plasma levels of TMAO were remarkably increased in UAP patients (3.28 ± 1.97 µM) compared with control participants (1.52 ± 0.59 µM, P < 0.01). TMAO was significantly correlated with lipid levels in UAP patients. The ROC, univariate and multivariate logistic regression analysis both showed that the TMAO significantly increased the risk for occurrence of UAP. CONCLUSIONS: Our data indicate that the TMAO is superior to lipoprotein ratios and conventional lipid parameters in predicting occurrence of UAP.