Emerging evidence suggests that cancer survivors who have undergone anthracycline therapy frequently experience late-onset atherosclerosis. However, the mechanisms underlying this phenomenon and potential preventive strategies remain largely unexplored. In this study, we developed a mouse model to replicate doxorubicin (Dox)-induced atherosclerotic lesions. Given the established role of the RNA methyltransferase METTL3 in both atherogenesis and tumorigenesis, we conducted a comprehensive investigation to assess whether targeting METTL3 could mitigate Dox-induced atherosclerosis and enhance the efficacy of Dox in inhibiting tumor progression. Our findings reveal that Dox administration promotes vascular endothelial premature senescence and atherosclerosis, to a large extent by upregulating the expression of METTL3 and its substrate genes, particularly those encoding senescence-associated secreted proteins. To translate METTL3 as a therapeutic target, we developed and characterized an endothelium-targeted (achieved by coating with CD31 antibodies) nanoparticle loaded with the METTL3 inhibitor STM2457 (endothelium-targeted METTL3 nano-inhibitor, ETMN). As anticipated, ETMN effectively protects murine blood vessels against Dox-aggravated endothelial senescence and inflammation, as well as atheroma formation. Furthermore, ETMN, with enhanced enrichment in tumor allografts, significantly potentiates Dox's tumoricidal activity by attenuating METTL3 oncogenic signaling. In summary, our work offers a practical solution for addressing Dox therapy-related atherosclerosis, providing dual benefits and advancing the treatment and management of cancer patients undergoing anthracycline therapy.

Adult murine cardiomyocytes serve as a pivotal model for cardiovascular research. High-quality isolation is essential for studying disease mechanisms and drug screening. Current methods, however, are limited by reliance on specialized equipment and inconsistent efficiency, necessitating a more convenient and reliable protocol. We developed an optimized, Langendorff-free method for isolating cardiomyocytes and cardiac fibroblasts from adult mice. Following anesthesia, an enzymatic digestion solution was infused directly via the aortic root, utilizing the coronary circulation to achieve efficient tissue dissociation. This approach yielded adult mouse cardiomyocytes with high viability, intact morphology, and suitability for long-term culture, comparable to the standard Langendorff technique. Functionally, the isolated cardiomyocytes retained robust responsiveness to pathological stimuli, including hypoxia and adrenergic agonists (isoprenaline, norepinephrine, phenylephrine), demonstrated by characteristic alterations in contractile function, relaxation kinetics, and calcium handling. Furthermore, cardiac fibroblasts co-isolated using this protocol could be successfully activated by TGF-β, showing significant upregulation of myofibroblast markers (e.g., α-smooth muscle actin) and pro-fibrotic signaling pathways. This study establishes a novel, efficient, and accessible method for the simultaneous isolation of functional cardiomyocytes and cardiac fibroblasts from adult mice. The protocol overcomes key limitations of existing techniques and provides a reliable platform for in vitro mechanistic studies and drug discovery in cardiovascular disease.

Atherosclerosis is the underlying cause of cardiovascular disease. Recent studies have shown that N6-methyladenosine (m6A) modification in macrophages is associated with atherosclerosis progression. However, there is a lack of systemic research on the role of m6A modification in macrophage differentiation and activation during atherosclerosis. Here we conducted multiomics analysis (MeRIP-seq and RNA-seq) of macrophages during their differentiation and activation to elucidate the regulatory network of the m6A spectrum at different stages. Western blot, quantitative PCR (qPCR), RNA-seq and RNA immunoprecipitation (RIP)–qPCR results demonstrated that m6A modification modulates KDM6B expression during macrophage activation. Through co-immunoprecipitation, RIP‒qPCR and genetic perturbation experiments, we revealed that Mettl3/Rbm15 regulates the stability of Kdm6b mRNA and that Kdm6b is required for interacting with and demethylating Jak1 to induce its phosphorylation-mediated macrophage activation. Next, through the analysis of single-cell RNA-seq data and coculture experiments, we revealed that Kdm6b-mediated macrophage activation promoted cytotoxic T lymphocyte cytotoxicity following atherosclerosis progression. Moreover, the systemic use of STM2457, a METTL3 inhibitor, revealed the importance of m6A modification in immune cell infiltration and plaque activation. Finally, we utilized macrophage-specific Kdm6b-knockout mice to determine whether Kdm6b facilitates macrophage and cytotoxic T lymphocyte activation and atherosclerosis. Our findings revealed that m6A modification plays a pivotal role in the upregulation of Kdm6b in response to IFN-γ stimulation, which is essential for the phosphorylation of Stat1-induced macrophage activation-mediated atherosclerosis development. In this study, we conduct meRIP-seq analysis on macrophages during their differentiation and activation to elucidate the landscape of the m6A spectrum across different stages. Combined analysis of RNA-seq and meRIP-seq revealed that Kdm6b interacts with and demethylates Jak1, promoting its phosphorylation-mediated activation of macrophages. Activated macrophages interact with T cells to promote atherosclerosis progression. Atherosclerosis, a major cause of heart disease and stroke, involves inflammation and immune responses. Researchers have found that a protein called KDM6B plays a role in this process. The study explored how KDM6B affects immune cells called macrophages during atherosclerosis. Researchers used mice to study macrophages, which are immune cells that can become activated and contribute to inflammation. They focused on a chemical modification called m6A on RNA, which affects how genes are expressed. They used techniques such as meRIP-seq to analyze these modifications. They found that m6A modifications are important for macrophage activation and that KDM6B helps regulate this process. When KDM6B was inhibited, it reduced inflammation and slowed down atherosclerosis progression in mice. The study concludes that targeting KDM6B could be a potential strategy to treat atherosclerosis by reducing inflammation. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

RNA m6A modification plays a vital role in regulating cardiac function; however, its comprehensive mechanisms require further exploration. We observed that the expression of METTL3, a m6A methyltransferase, is significantly increased in hypertrophic hearts as well as during phenylephrine (PE)-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes and transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice. Concordantly, METTL3 knockdown could significantly inhibit PE-induced cardiomyocyte hypertrophy. RNA m6A-RIP-Seq analysis revealed that METTL3 may regulate lipid metabolism in cardiomyocytes by methylating the mRNA of fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), thereby enhancing their stability. We developed a platelet liposome fusion membrane carrier that is loaded with siMETTL3. This carrier significantly reduces the expression of FASN and SCD1, enhances fatty acid oxidation, and promotes ATP production in cardiomyocytes. Overexpression of FASN and SCD1 can partially alleviate the impact on the aforementioned fatty acid oxidation-related effects caused by siMETTL3 platelet liposome fusion membrane carrier. Consequently, our siMETTL3 carrier alleviates TAC-induced pathological hypertrophy and improves cardiac function in vivo. These findings advance our understanding of METTL3-mediated RNA m6A modification in cardiac hypertrophy, holding promise for future treatments through our gene delivery carrier related to pathological cardiac hypertrophy.

The existing risk sores for ST-elevation myocardial infarction (STEMI) patients cannot balance timeliness, feasibility, and accuracy. This study aimed to develop and validate a two-stage scoring system capable of dynamic evaluation for 30-day mortality among STEMI patients. We recruited 3939 patients and randomly assigned (7:3) to derivation (N = 2757) and internal validation (N = 1182) datasets, an independent cohort of 1315 STEMI patients was used for external validation. The two-stage scoring system was developed based on factors associated with 30-day mortality identified by multivariate analysis and their availability in course of management. The first medical contact (FMC) stage risk score comprised six predictors (age, gender, systolic blood pressure, heart rate, Killip class, and anterior myocardial infarction), the in-hospital risk score included serum creatinine and left ventricular ejection fraction on this basis. The area under the curve (AUC) were 0.816, 0.854, 0.843, and 0.876 in derivation and internal validation for FMC and in-hospital stage risk score with satisfactory calibration ability. FMC stage risk score displayed equivalent predictive ability with TIMI risk score and GRACE score, in-hospital stage risk score obtained promotion in AUC, integrated discrimination improvement, and net reclassification improvement (all P < 0.001) compared with the classic risk scores. The reproducibility and effectiveness of the risk scores were statistically confirmed in the external validation cohort. The two-stage scoring system had good ability for predicting 30-day mortality and useful to dynamically identify high-risk STEMI patients. Trial registration: [NCT02641262] [29 December 2015].

N6-adenosine methylation (m6A) of RNA is involved in the regulation of various diseases. However, its role in chemotherapy-related vascular endothelial injury has not yet been elucidated. We found that methyltransferase-like 3 (METTL3) expression was significantly reduced during doxorubicin (DOX)-induced apoptosis of vascular endothelial cells both in vivo and in vitro, and that silencing of METTL3 further intensified this process. Combined transcriptome and proteome sequencing analyses revealed that the expression levels of interferon-stimulated gene 15 (ISG15) mRNA and protein significantly increased after METTL3 silencing. Methylated RNA immunoprecipitation (meRIP)-quantitative polymerase chain reaction (qPCR) and mRNA stability assays confirmed that METTL3 regulates the expression of ISG15 by methylating the 1,014,147 site on ISG15 RNA, thereby decreasing ISG15 mRNA levels. Silencing ISG15 significantly suppressed DOX-induced endothelial cell apoptosis and dysfunction caused by METTL3 silencing. In summary, our study revealed that METTL3-mediated methylation of ISG15 mRNA is involved in DOX-induced endothelial cell apoptosis and explored potential therapeutic targets for alleviating chemotherapy-associated vascular injury.

Rationale: Internal modifications of mammalian RNA have been suggested to be essential for the maintenance of cardiac homeostasis. However, the role of RNA cytosine methylation (m5C) in the heart remains largely unknown. Methods: Bulk and single cell RNA sequencing data and tissues from the human hearts were exploited for analyzing the expression of RNA m5C modifying proteins. Neonatal rat and adult mouse cardiomyocytes were isolated to assess the impact of Nsun2 on cellular hypertrophic response. Cre/LoxP-mediated gene knockout and recombinant adeno-associated virus serotype 9 (rAAV9) were employed respectively to achieve cardiac-specific interference of the expression of related genes in mice that were subjected to heart stresses from aging, aortic constriction, and angiotensin II stimulation. RNA m5C immunoprecipitation sequencing (m5C-RIP-seq), RNA pull-down, polysome profiling, reporter gene analysis, and IonOptix measurement were conducted to elucidate the involved regulatory mechanisms. Results: Nsun2 expression was significantly elevated in human, rat, and mouse hypertrophic myocardial cells. Knockout of Nsun2 (αMHC-CreERT2, Nsun2 flox+/+) abolished the hypertrophic response of mice to diverse stresses, while accelerating the progression of heart failure. Mechanistically, Nsun2 specifically methylates PKA catalytic subunit alpha (PRKACA) mRNA, which substantially promotes PRKACA translation in a YBX1-dependent manner. Nsun2 ablation markedly attenuated the activation of PKA signaling, as evidenced by the reduced PKA activity and protein phosphorylation levels of PKA substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Overexpressing Nsun2 and PRKACA-3'UTR transcripts in the myocardia sensitized and desensitized heart hypertrophic responses, respectively, whereas co-administration of the PKA inhibitor H-89 or overexpressing PRKACA-3'UTR transcript lacking Nsun2 methylating regions failed to produce corresponding responses, reiterating the significance of Nsun2-PRKACA regulation in the cardiac hypertrophic program. Conclusion: These observations reveal the importance of Nsun2-PRKACA regulation in cardiac homeostasis, which provides novel insights into heart function modulation and sheds light on future treatments for hypertrophic remodeling associated heart diseases.

BackgroundThe stress hyperglycemia ratio (SHR) has emerged as a valuable prognostic indicator in patients with ST-elevation myocardial infarction (STEMI). Nevertheless, the impact of SHR on the incidence of in-hospital cardiogenic shock (IHCS) remains insufficiently explored in patients with STEMI. This study aimed to investigate the association between SHR and IHCS incidence while assessing its additional predictive value beyond established risk scores.MethodsData were derived from a prospective, multicenter registry and included 1776 patients with STEMI. Patients were grouped by the optimal cutoff value of SHR. The primary endpoint was the incidence of IHCS. Generalized linear mixed models, restricted cubic splines (RCS), ROC curves, and decision curve analysis (DCA) were utilized, with feature importance assessing its importance.ResultsThe IHCS incidence was notably higher in patients with elevated SHR. RCS analysis indicated a significant dose-response relationship between increasing SHR and IHCS risk (P-Nonlinear > 0.05). SHR was independently associated with IHCS in the overall population (OR: 2.19, 95% CI: 1.20-4.00) and in patients without diabetes (OR: 2.20, 95% CI: 1.11-4.35). Incorporating SHR into established risk scores significantly improved predictive accuracy and net clinical benefit. SHR was comparably important in predicting IHCS compared to established risk factors.ConclusionsElevated SHR is a valuable predictor and manifests additional predictive value beyond established risk scores in predicting IHCS in patients with STEMI, especially among patients without diabetes.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02641262.

Background: It is known that the Class Ic antiarrhythmic drugs exhibit strong use-dependent blockade of fast sodium current (I Na ) due to their slow dissociation kinetics from the sodium channel. Clinically, Class Ic I Na blockers are linked to increased mortality in patients with coronary artery disease or ventricular systolic dysfunction. However, the mechanisms by which Class Ic I Na blockers influence ventricular conduction and mechanical function, thereby contributing to increased mortality, have not been well studied. We hypothesized that Class Ic I Na blockers may transition conduction of normal ventricular myocytes from an "all-or-none" pattern to Wenckebach or decremental conduction, features typically associated with slow response action potentials (APs). This change could markedly alter ventricular electrophysiology and mechanical function. Methods: APs, with ECG and contractility, were recorded concurrently from ventricular epicardium (Epi) and endocardium (Endo) in the isolated arterially perfused rabbit ventricular wedge in control and in presence of flecainide, a class Ic I Na blocker, at 10 microM. The preparations were paced from Endo at basic cycle lengths (BCL) ranging from 300 to 1000 ms. Results: Pacing from a BCL of 1000 ms down to BCLs of 300 to 600 ms resulted in decremental conduction between the ventricular Endo and Epi during pacing rate acceleration or Wenckebach conduction at a constant rapid pacing rate in the presence of flecainide. This unique conduction (Figure 1) was observed in 8 of 8 preparations under flecainide perfusion versus 0 of 8 in the control perfusion (p<0.01). Decremental and Wenckebach conduction was always associated with reduced and dyssynchronous contraction. Additionally, flecainide blunted or even reversed physiologically positive staircase response of contractility (Figure 2). Notably, 2 to 1 conduction and paroxysmal conduction block between the Endo and Epi occurred in 4 of 8 (Figure 3). On the other hand, conduction delay between the ventricular Endo and Epi also promoted echo beats and non-sustained ventricular tachycardia via a reentrant mechanism. Conclusions: Flecainide due to its strong use-dependent blockage of I Na has a capability to transition ventricular fast response APs to slow response APs, leading to Wenckebach or decremental conduction. This conduction not only reduces ventricular contraction but also induces dyssynchrony. Intraventricular conduction block also promotes reentrant arrhythmias.

Cardiovascular disease is one of the leading causes of death worldwide. Early and accurate detection of abnormal cardiac activity can be an effective way to prevent serious cardiovascular events. Electrocardiogram (ECG) and phonocardiogram (PCG) signals provide an objective evaluation of the heart's electrical and acoustic functions, enabling medical professionals to make an accurate diagnosis. Therefore, the cardiologists often use them to make a preliminary diagnosis of abnormal cardiac activity in clinical practice. For this reason, many diagnostic models have been proposed. However, these models fail to utilize the interaction information within and between the signals to aid the diagnosis of disease. To address this issue, we designed a residual dual-attention network (ResAN) for the detection of abnormal cardiac activity using synchronized ECG and PCG signals. First, ResAN uses a feature learning module with two parallel residual networks, for example, ECG-ResNet and PCG-ResNet to automatically learn the deep modal-specific features from the ECG and PCG sequences, respectively. Second, to fully utilize the available information of different modal signals, ResAN uses a dual-attention fusion module to capture the salient features of the integrated ECG and PCG features learned by the feature learning module, as well as the alternating features between them based on the attention mechanisms. Finally, these fused features are merged and fed to the classification module to detect abnormal cardiac activity. Our model achieves an accuracy of 96.1%, surpassing the performances of comparison models by 1.0% to 9.9% when using synchronized ECG and PCG signals. Furthermore, the ablation study confirmed the efficacy of the components in ResAN and also showed that ResAN performs better with synchronized ECG and PCG signals compared to using single-modal signals. Overall, ResAN provides a valid solution for the early detection of abnormal cardiac activity using ECG and PCG signals.

BackgroundThe incidence of mortality is considerable after ST-elevation myocardial infarction (STEMI) hospitalization; risk assessment is needed to guide postdischarge management. Age shock index (SI) and age modified shock index (MSI) were described as useful prognosis instruments; nevertheless, their predictive effect on short and long-term postdischarge mortality has not yet been sufficiently confirmed.MethodsThis analysis included 3389 prospective patients enrolled from 2016 to 2018. Endpoints were postdischarge mortality within 30 days and from 30 days to 1 year. Hazard ratios (HRs) were evaluated by Cox proportional-hazards regression. Predictive performances were assessed by area under the curve (AUC), integrated discrimination improvement (IDI), net reclassification improvement (NRI) and decision curve analysis (DCA) and compared with TIMI risk score and GRACE score.ResultsThe AUCs were 0.753, 0.746 for age SI and 0.755, 0.755 for age MSI for short- and long-term postdischarge mortality. No significant AUC differences and NRI were observed compared with the classic scores; decreased IDI was observed especially for long-term postdischarge mortality. Multivariate analysis revealed significantly higher short- and long-term postdischarge mortality for patients with high age SI (HR: 5.44 (2.73-10.85), 5.34(3.18-8.96)), high age MSI (HR: 4.17(1.78-9.79), 5.75(3.20-10.31)) compared to counterparts with low indices. DCA observed comparable clinical usefulness for predicting short-term postdischarge mortality. Furthermore, age SI and age MSI were not significantly associated with postdischarge prognosis for patients who received fibrinolysis.ConclusionsAge SI and age MSI were valuable instruments to identify high postdischarge mortality with comparable predictive ability compared with the classic scores, especially for events within 30 days after hospitalization.

Background: The higher prevalence of anemia in females and elderly may be attributed to its association with worsened outcomes in ST-elevation myocardial infarction (STEMI) patients. We aimed to evaluate the precise effects of age and gender on the association between anemia and 30-day outcomes. Method: We identified 4350 STEMI patients and divided into anemia and non-anemia. Effects were analyzed as categories using Cox proportional-hazards regression and as continuous using restricted cubic splines. Propensity score matching (PSM) and mediation analysis were applied to identify intermediate effects. Results: Anemic patients were older, more likely to be female, and experienced doubled all-cause death (7.3 % versus 15.0 %), main adverse cardiovascular and cerebrovascular events (MACCE, 11.1 % versus 20.2 %), heart failure (HF, 5.1 % versus 8.6 %), and bleeding events (2.7 % versus 5.4 %). After adjustment, the association between anemia and all-cause death (Hazard ratio (HR) 1.15, 95 % confidence interval (95 %CI) 0.93-1.14), MACCE (HR 1.14, 95 %CI 0.95-1.36) and HF (HR 1.19, 95 %CI 0.92-1.55) were insignificant, the effects persisted nullified across age classes (P-interaction > 0.05) and PSM (P > 0.05). Ulteriorly, age mediated 77.6 %, 66.2 %, 48.0 %, gender mediated 38.1 %, 15.0 %, 3.2 %, age and gender together mediated 99.8 % 72.9 %, 48.1 % of the relationship. Anemia was independently associated with bleeding events (HR 2.02, 95 %CI 1.42-2.88), the effects consisted significant regardless of PSM (P < 0.05), age, and gender classes (P-interaction > 0.05), and no mediating role of age and gender were observed. Conclusions: In STEMI patients, age and gender largely mediated the relationship between anemia and all-cause death, MACCE, and HF, anemia was independently associated with bleeding complications.

Abstract There is currently few research on clinical characteristics and outcomes of coronary heart disease (CHD) with resistant hypertension in central region of China. This study aimed to assess the risk factors and outcomes of CHD and resistant hypertension in population of central region of China. A total of 1467 CHD patients with hypertension were included and considered to three groups according to blood pressure control: controlled group (blood pressure < 140/90 mmHg on three or less antihypertensive drugs); uncontrolled group (blood pressure ≥ 140/90 mmHg on two or less antihypertensive drugs); or resistant group (blood pressure ≥ 140/90 mmHg on three antihypertensive drugs or < 140/90 mmHg on at least four antihypertensive drugs including diuretic). The authors evaluated the clinical outcomes of three groups at 1‐year follow‐up. The prevalence of resistant hypertension was 21.8%. Significant adjusted associated factors of resistant hypertension included per unit changes body mass index (BMI, OR 1.12), and four categorical variable diagnosis by yes or no: heart failure (HF, OR 2.62), left ventricular hypertrophy (LVH, OR 2.83), diabetes (OR 1.55), and chronic kidney disease (CKD, OR 1.63). In multiple adjusted Cox regression analysis, patients in resistant group had a higher risk of the primary outcome (HR, 2.14 [95% CI, 1.47–3.11]; p < .001). Moreover, the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with resistant hypertension is also significantly increased (HR, 2.11 [95% CI, 1.39–3.20]; p < .001). In conclusion, resistant hypertension was a quite common and high proportion finding in patients with CHD and hypertension in central region of China, and these patients have a worse clinical prognosis.

BACKGROUND:Limited data are available on the changes in the quality of care for ST elevation myocardial infarction (STEMI) during China's health system reform from 2009 to 2020. This study aimed to assess the changes in care processes and outcome for STEMI patients in Henan province of central China between 2011 and 2018.METHODS:We compared the data from the Henan STEMI survey conducted in 2011-2012 ( n = 1548, a cross-sectional study) and the Henan STEMI registry in 2016-2018 ( n = 4748, a multicenter, prospective observational study). Changes in care processes and in-hospital mortality were determined. Process of care measures included reperfusion therapies, aspirin, P2Y12 antagonists, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. Therapy use was analyzed among patients who were considered ideal candidates for treatment.RESULTS:STEMI patients in 2016-2018 were younger (median age: 63.1 vs . 63.8 years) with a lower proportion of women (24.4% [1156/4748] vs . 28.2% [437/1548]) than in 2011-2012. The composite use rate for guideline-recommended treatments increased significantly from 2011 to 2018 (60.9% [5424/8901] vs . 82.7% [22,439/27,129], P <0.001). The proportion of patients treated by reperfusion within 12 h increased from 44.1% (546/1237) to 78.4% (2698/3440) ( P <0.001) with a prolonged median onset-to-first medical contact time (from 144 min to 210 min, P <0.001). The use of antiplatelet agents, statins, and β-blockers increased significantly. The risk of in-hospital mortality significantly decreased over time (6.1% [95/1548] vs . 4.2% [198/4748], odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.50-0.88, P = 0.005) after adjustment.CONCLUSIONS:Gradual implementation of the guideline-recommended treatments in STEMI patients from 2011 to 2018 has been associated with decreased in-hospital mortality. However, gaps persist between clinical practice and guideline recommendation. Public awareness, reperfusion strategies, and construction of chest pain centers need to be further underscored in central China.

Background: Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH). Methods: The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (INa-L) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique. Results: Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (P<0.05, versus 0/15 in controls) and were induced by an INa-L enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. INa-L density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by INa-L blocker ranolazine or mexiletine. Conclusions: LVH enhances INa-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. INa-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.

Abstract Background The triglyceride–glucose (TyG) index has been proposed as a potential predictor of adverse prognosis of cardiovascular diseases (CVDs). However, its prognostic value in patients with coronary heart disease (CHD) and hypertension remains unclear. Methods A total of 1467 hospitalized patients with CHD and hypertension from January 2021 to December 2021 were included in this prospective and observational clinical study. The TyG index was calculated as Ln [fasting triglyceride level (mg/dL) × fasting plasma glucose level (mg/dL)/2]. Patients were divided into tertiles according to TyG index values. The primary endpoint was a compound endpoint, defined as the first occurrence of all-cause mortality or total nonfatal CVDs events within one-year follow up. The secondary endpoint was atherosclerotic CVD (ASCVD) events, including non-fatal stroke/transient ischemic attack (TIA) and recurrent CHD events. We used restricted cubic spline analysis and multivariate adjusted Cox proportional hazard models to investigate the associations of the TyG index with primary endpoint events. Results During the one-year follow-up period, 154 (10.5%) primary endpoint events were recorded, including 129 (8.8%) ASCVD events. After adjusting for confounding variables, for per standard deviation (SD) increase in the TyG index, the risk of incident primary endpoint events increased by 28% [hazard ratio (HR) = 1.28, 95% confidence interval (CI) 1.04–1.59]. Compared with subjects in the lowest tertile (T1), the fully adjusted HR for primary endpoint events was 1.43 (95% CI 0.90–2.26) in the middle (T2) and 1.73 (95% CI 1.06–2.82) in highest tertile (T3) (P for trend = 0.018). Similar results were observed in ASCVD events. Restricted cubic spline analysis also showed that the cumulative risk of primary endpoint events increased as TyG index increased. Conclusions The elevated TyG index was a potential marker of adverse prognosis in patients with CHD and hypertension.

近年来,我国心血管病的发病率和病死率不断上升,给社会和居民家庭带来沉重负担.除了控制血脂、血糖、戒烟等危险因素以外,需要在基础领域对心脏与血管组织细胞、发育与功能及发病机制进一步探索.单细胞测序技术(single-cell RNA sequencing,scRNA-seq)和空间转录组(spatial transcriptomic,ST)不仅可以发现全新的细胞类型,而且可以揭示每个细胞独特的变化,极大地推动了基因组学研究.通过研究不同细胞群体之间细胞动态通讯状态及调控通路,探讨研究疾病过程中的分子机制.

BACKGROUND:This study aims to compare whether 2 different routes of renal denervation (RDN) from the intima and adventitia of the renal artery can reduce renal fibrosis in a pig model of hypertension induced by a high-fat diet and to explore possible molecular mechanisms. METHODS:Twenty-four Bama miniature pigs were randomly divided into a control group (normal diet, n = 6) or a hypertension model group (high-fat diet, n = 18). The model group was randomly divided into the intima-RDN group (n = 6), the adventitia-RDN group (n = 6), or the renal arteriography-only group (sham group, n = 6). All animals were fed separately. The model group was fed a high-fat diet after the operation, and the control group was fed conventionally for 6 months. After 6 months, renal artery angiography was performed again to observe the condition of the renal arteries, after which all animals were euthanized. The blood pressure and blood biochemical results of each group were evaluated 6 months after the operation; kidney tissue morphology and collagen fiber content were examined by hematoxylin-eosin staining and Masson staining; superoxide dismutase activity and the malondialdehyde content of kidney tissue were assessed by a biochemical enzyme method; the protein expression level of transforming growth factor-β 1 (TGF-β1), α-smooth muscle actin (α-SMA), and Smad3 was assessed by Western blot, and electron microscopy was used to examine changes in the kidney microstructure. RESULTS:After 6 months of a high-fat diet, the blood lipid levels of the model group were significantly higher compared to baseline and to that of the control group during the same period (all showed p < 0.05); the blood lipid levels of the control group did not change significantly from baseline (p > 0.05). The degree of glomerular damage caused by hyperlipidemia in the intima-RDN group and the adventitia-RDN group was significantly lower than that of the sham and control groups, and the renal fibrosis area percentage was also significantly lower (p < 0.05). Electron microscopy showed that both the intima-RDN group and the adventitia-RDN group had a more even distribution of chromosomes and less mitochondrial swelling compared with the sham group. CONCLUSION:RDN from the adventitia of the renal artery and RDN from the intima of the renal artery have the similar advantages of delaying high-fat-induced renal fibrosis. The antifibrotic effect of RDN may be related to inhibition of the TGF-β1/Smad3 pathway.