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Correction: Beyond wind speed: Integrating oceanic indices and time-lagged features for superior wind energy prediction
Correction: Assessment of temporomandibular disorders and their relationship with life quality and salivary biomarkers in patients with dentofacial deformities: A clinical observational study
Correction: A scoping review protocol on childhood immunization reminder strategies available to parents in Canada and the United States of America
Retraction: DiabetesXpertNet: An innovative attention-based CNN for accurate type 2 diabetes prediction
Retraction: Role of globalziation defining the incidence of entrepreneurship
Correction: Evaluation of short-term hair follicle storage conditions for maintenance of RNA integrity
Correction: Assessing factors that influence perceived burnout in postdoctoral fellows and identifying recommendations to support their well-being
Correction: What the public wants to know about the recycling of contaminated soil
Editorial Note: Gender expectations, socioeconomic inequalities and definitions of career success: A qualitative study with university students
Correction: Pepper Mild Mottle Virus, a Plant Virus Associated with Specific Immune Responses, Fever, Abdominal Pains, and Pruritus in Humans
Editorial Note: Tilianin attenuates inflammasome activation in endothelial progenitor cells to mitigate myocardial ischemia-reperfusion injury
DAPK2 Regulates PKM2 Phosphorylation at Threonine 45 to Facilitate Disturbed Flow-Induced Atherosclerosis
BACKGROUND: Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis. METHODS: Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess the role of Dapk2 in vivo, EC-specific Dapk2 -deficient mice on an Apoe -/- (apolipoprotein E -/- ) background were utilized in carotid artery ligation and Western diet–induced atherosclerosis models. Mice with EC-specific overexpression of Pkm2 harboring either a phospho-refractory mutation (Pkm2 T45A ) or a phospho-mimicking mutation (Pkm2 T45E ) were subjected to carotid artery ligation to further elucidate the functional implications of Pkm2 phosphorylation. RESULTS: DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries. Mechanistically, Krüppel-like factor 2 (KLF2) suppressed DAPK2 transcription, whereas OSS-induced KLF2 downregulation led to DAPK2 upregulation. EC-specific Dapk2 deficiency or pharmacological inhibition suppressed EC activation and atherogenesis in Apoe -/- mice, effects reversed by overexpression of wild-type Dapk2 but not by a dominant-negative mutant. Mass spectrometry identified that DAPK2 interacted with the key glycolytic enzyme PKM2 and directly phosphorylated it at threonine 45, leading to PKM2 dimerization and nuclear translocation. Nuclear PKM2 activated the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 by directly interacting with and activating signal transducer and activator of transcription 1. Elevated PKM2 T45 and signal transducer and activator of transcription 1 Y701 phosphorylation were observed in atheroprone endothelium. Finally, EC-specific overexpression of Pkm2 T45A mitigated disturbed flow-induced atherogenesis, whereas Pkm2 T45E overexpression abrogated the protective effects of Dapk2 deficiency in Apoe -/- mice. CONCLUSIONS: DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis.
Letter by Zhuang et al Regarding Article, “Experiences of Stalking and Obtaining a Restraining Order Are Associated With Onset of Cardiovascular Events in Women: A Prospective Analysis in the Nurses’ Health Study II”
Risk of Heart Failure Hospitalization for GLP-1 Receptor Agonists Versus DPP-4 Inhibitors or SGLT-2 Inhibitors in Patients With Type 2 Diabetes: A Target Trial Emulation
BACKGROUND: Novel treatments are needed for the primary and secondary prevention of heart failure in patients with type 2 diabetes, including individuals with and those without a history of heart failure. Conflicting trial evidence exists on whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of hospitalization for heart failure (HHF) in this broad population and whether this is a class effect or varies by specific agent. Furthermore, their comparative effectiveness against sodium-glucose cotransporter-2 inhibitors (SGLT-2is) is unknown. METHODS: We emulated 2 target trials using population-based health care data from Stockholm, Sweden (2010–2021). Target trial 1 included adult patients with type 2 diabetes who newly initiated GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4is), and target trial 2 compared GLP-1RA with SGLT-2i. The primary outcome was HHF. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders. Major adverse cardiovascular events were used as the positive control outcome. Analyses were conducted for the GLP-1RA class overall and for individual agents, including liraglutide and semaglutide. RESULTS: Target trial 1 included 32 979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female; and target trial 2 included 30 104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Starting a GLP-1RA was associated with a lower 3-year absolute risk of HHF than starting a DPP-4i (3.4% versus 4.3%), corresponding to a weighted hazard ratio of 0.77 (95% CI, 0.66–0.91). Absolute 3-year risks for GLP-1RA compared with SGLT-2i on HHF were 3.6% and 3.3% with a weighted hazard ratio of 1.02 (95% CI, 0.85–1.18). The absolute risk difference was largest for patients with higher predicted risk of heart failure at baseline. Results were consistent for single agents, in per-protocol analyses, and in the majority of subgroups. In positive control outcome analyses, GLP-1RA use was associated with a lower rate of major adverse cardiovascular events than DPP-4i use (weighted hazard ratio, 0.85 [95% CI, 0.74–0.99]), consistent with trial findings. CONCLUSIONS: GLP-1RA use is associated with a lower risk of HHF compared with DPP-4i and similar risks compared with SGLT-2i in routine clinical care for patients with type 2 diabetes.
Differences in Disease Trajectory, Comorbidities, and Mortality in Sarcomeric and Nonsarcomeric Hypertrophic Cardiomyopathy
BACKGROUND: Sarcomere gene variants are a key cause of hypertrophic cardiomyopathy (HCM), and have been associated with worse prognosis. However, it is unclear how comorbidities influence clinical trajectories, the timing of events, and causes of death in sarcomeric and nonsarcomeric HCM. METHODS: We conducted a multicenter longitudinal cohort study of genotyped patients with HCM in the Sarcomeric Human Cardiomyopathy registry (SHaRe). Patients were classified as sarcomeric HCM (pathogenic/likely pathogenic sarcomere variant) or nonsarcomeric HCM (genetically elusive). The influence of genetic classification and comorbidities on the sequence of cardiovascular events were assessed in time-varying Cox proportional hazards models. RESULTS: Among 6120 patients (40% women; 87% probands; 50% sarcomeric HCM), followed for a median of 5.3 years, sarcomeric HCM (n=3082) was associated with a younger age at diagnosis (median 38.1 versus 54.3 years; P <0.001), a higher proportion of women and less obesity, hypertension, and left ventricular (LV) obstruction. After age standardization, sarcomeric HCM was associated with a higher burden of atrial fibrillation (age-standardized incidence [ASI] ratio, 1.28 [CI, 1.16–1.40]), LV systolic dysfunction (ASI ratio, 1.31 [CI, 1.15–1.48]), and ventricular arrhythmias (ASI ratio, 1.37 [CI, 1.17–1.52]) than nonsarcomeric HCM. All-cause mortality was similar (10.4% versus 9.4%; P =0.20); however, patients with sarcomeric HCM died younger (mean 7.8 years; P <0.001), with model-based survival-analysis estimating 3.5 life-years lost between ages 44 and 85. Sarcomeric HCM was also associated with higher HCM-related mortality (hazard ratio [HR], 1.61 [CI, 1.18–2.20]). Temporal analysis identified atrial fibrillation as the strongest disease-modifier, increasing the risk of LV systolic dysfunction (HR, 2.54 [CI 2.07–3.11]), ventricular arrhythmias (HR, 3.13 [CI, 2.36–4.20]), and mortality (HR, 1.94 [CI, 1.64–2.31]) in both groups. Genotype-interaction analyses demonstrated a larger impact of atrial fibrillation and LV systolic dysfunction on adverse outcomes in sarcomeric versus nonsarcomeric HCM, with effect ratios up to 1.98 for severe heart failure and 2.01 for mortality (both P <0.01). CONCLUSIONS: Genotype can refine risk stratification and inform clinical management in HCM. Sarcomeric HCM is associated with worse prognosis and may benefit from more vigilant surveillance for arrhythmias and systolic dysfunction, with a lower threshold for advanced therapies. Comorbidities, including hypertension and obesity, may be modifiable risk factors for patients with nonsarcomeric HCM.
Response by Murchland et al to Letter Regarding Article, “Experiences of Stalking and Obtaining a Restraining Order Are Associated With Onset of Cardiovascular Events in Women: A Prospective Analysis in the Nurses’ Health Study II”
Dysregulated Aldosterone Production in Obesity Is Associated With Adverse Cardiac Structure, Function, and Adiposity
Insulin Resistance Compromises the Pentose Phosphate Pathway and Impairs Left Ventricular Assist Device–Mediated Myocardial Recovery in Obese Patients With Heart Failure
BACKGROUND: End-stage heart failure (HF) remains a major global health challenge, and left ventricular assist devices (LVADs) represent an important therapeutic option. LVAD-mediated mechanical unloading improves cardiac function and promotes myocardial recovery in many patients with HF; however, this recovery response is suboptimal in obese patients. The mechanisms by which LVAD-mediated unloading induces myocardial recovery, and how obesity alters these processes to blunt myocardial recovery, remain poorly understood. METHODS: Patients with HF receiving LVAD support were recruited to investigate the correlation between patients' body mass index and the myocardial recovery response following LVAD implantation. In parallel, a mouse model of heterotopic cervical heart transplantation was used to simulate LVAD-mediated cardiac unloading. Single-nucleus RNA sequencing and stable-isotope tracing metabolomics were performed to explore the changes of signaling pathways and metabolic processes in unloaded hearts. In vitro cyclic stretch assays were used to evaluate how reduced mechanical load regulates cardiomyocyte metabolic pathways. Unloaded hearts from HF mice were used to determine whether the identified metabolic processes contribute to unloading-induced myocardial recovery. Furthermore, the unloaded hearts from obese HF mice were used to evaluate whether these metabolic adaptations are attenuated by obesity. RESULTS: HF patients with a higher body mass index (≥28.0) and greater insulin resistance tended to have poorer LVAD-mediated myocardial recovery. Single-nucleus RNA sequencing showed that mechanical unloading activated myocardial insulin signaling and increased glucose uptake. Stable-isotope tracing metabolomics further revealed that glucose taken up by unloaded hearts was preferentially shunted into the pentose phosphate pathway. Mechanistically, reduced mechanical stress attenuated Hippo pathway activation in cardiomyocytes, facilitating insulin signaling and enhancing pentose phosphate pathway flux. In unloaded hearts from HF mice, increased pentose phosphate pathway flux could reduce oxidative stress and exert cardioprotective effects. However, these benefits were blunted by insulin resistance in obese mice, whereas treatment with insulin sensitizers alleviated insulin resistance and restored unloading-mediated cardioprotection. CONCLUSIONS: In failing hearts, mechanical unloading leads to activation of insulin signaling, resulting in increased glucose uptake and enhanced pentose phosphate pathway flux to protect cardiomyocytes against oxidative stress. However, this cardioprotective effect is attenuated by obesity-induced insulin resistance. Administration of insulin sensitizers has the potential to improve LVAD-mediated myocardial recovery in obese patients with HF.