Daily Cardiology Research Analysis
Three impactful cardiology-related studies stood out today: a mechanistic discovery identifying macrophage WEE1 as a direct upstream kinase of NF-κB p65 that drives atherosclerosis; a randomized controlled trial showing perioperative nitric oxide reduces acute kidney injury after cardiac surgery in patients with chronic kidney disease; and a large real-world target-trial emulation demonstrating that SGLT2 inhibitors and GLP-1 receptor agonists lower cardiovascular events in elderly patients with
Summary
Three impactful cardiology-related studies stood out today: a mechanistic discovery identifying macrophage WEE1 as a direct upstream kinase of NF-κB p65 that drives atherosclerosis; a randomized controlled trial showing perioperative nitric oxide reduces acute kidney injury after cardiac surgery in patients with chronic kidney disease; and a large real-world target-trial emulation demonstrating that SGLT2 inhibitors and GLP-1 receptor agonists lower cardiovascular events in elderly patients with type 2 diabetes compared with DPP-4 inhibitors.
Research Themes
- Inflammation signaling targets in atherosclerosis
- Perioperative organ protection in cardiac surgery
- Comparative effectiveness of glucose-lowering therapies on cardiovascular outcomes in older adults
Selected Articles
1. Macrophage WEE1 Directly Binds to and Phosphorylates NF-κB p65 Subunit to Induce Inflammatory Response and Drive Atherosclerosis.
This mechanistic study identifies WEE1 as a macrophage kinase that directly binds NF-κB p65 and phosphorylates S536, amplifying inflammatory signaling and atherogenesis. Genetic deletion or pharmacologic inhibition of WEE1 attenuated inflammation and atherosclerosis in mice, highlighting WEE1 as a druggable upstream regulator of NF-κB.
Impact: Revealing WEE1 as a direct upstream kinase for NF-κB p65 provides a novel, actionable target in atherosclerosis with immediate translational relevance given existing WEE1 inhibitors.
Clinical Implications: While preclinical, the work supports evaluating WEE1 inhibitors for anti-inflammatory atheroprotection and encourages biomarker development (p65 S536 phosphorylation) to select responders.
Key Findings
- Macrophage WEE1 is phosphorylated (S642) in human and mouse atherosclerotic tissues.
- WEE1 phosphorylation (not expression) mediates oxLDL-induced macrophage inflammation.
- Macrophage-specific WEE1 deletion or pharmacologic inhibition reduces inflammation and atherosclerosis in mice.
- WEE1 directly binds NF-κB p65 and phosphorylates S536, activating NF-κB signaling.
Methodological Strengths
- Multi-system validation including human and mouse tissues, in vivo models, and in vitro macrophage assays
- Convergent genetic (cell-specific deletion) and pharmacologic inhibition evidence with RNA-seq and proteomics
Limitations
- Preclinical models; lack of human interventional validation
- Potential off-target and safety considerations with systemic WEE1 inhibition
Future Directions: Test WEE1 inhibitors in atherosclerosis models with cardiovascular endpoints; develop macrophage-targeted delivery; validate p65 S536 phosphorylation as a pharmacodynamic biomarker in human plaques.
Atherosclerosis has an urgent need for new therapeutic targets. Protein kinases orchestrate multiple cellular events in atherosclerosis and may provide new therapeutic targets for atherosclerosis. Here, a protein kinase, WEE1 G2 checkpoint kinase (WEE1), promoting inflammation in atherosclerosis is identified. Kinase enrichment analysis and experimental evidences reveal macrophage WEE1 phosphorylation at S642 in human and mouse atherosclerotic tissues. RNA-seq analysis, combined with experiment studies using mutant WEE1 plasmids, shows that WEE1 phosphorylation, rather than WEE1 expression, mediated oxLDL-induced inflammation in macrophages. Macrophage-specific deletion of WEE1 or pharmacological inhibition of WEE1 kinase activity attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA-seq and co-immunoprecipitation followed by proteomics analysis are used to explore the mechanism and substrate of WEE1. p-WEE1 promoted inflammatory response through activating NF-κB shown and further revealed that WEE1 can directly bind to the p65 subunit. It is confirmed that p-WEE1 directly interacts with the RHD domain of p65 and phosphorylates p65 at S536, thereby facilitating subsequent NF-κB activation and inflammatory response in macrophages. The findings demonstrate that macrophage WEE1 drives NF-κB activation and atherosclerosis by directly phosphorylating p65 at S536. This study identifies WEE1 as a new upstream kinase of p65 and a potential therapeutic target for atherosclerosis.
2. Perioperative Nitric Oxide Conditioning Reduces Acute Kidney Injury in Cardiac Surgery Patients with Chronic Kidney Disease (the DEFENDER Trial): A Randomized Controlled Trial.
In CKD patients undergoing CPB cardiac surgery, perioperative nitric oxide at 80 ppm intraoperatively and for 6 hours postoperatively reduced 7-day AKI, improved 6-month GFR, and decreased postoperative pneumonia without safety concerns. This randomized, sham-controlled trial supports NO conditioning as a renal-protective strategy.
Impact: Offers a pragmatic, scalable intervention with clinically meaningful renal and respiratory benefits in a high-risk surgical population.
Clinical Implications: Cardiac surgery teams could consider perioperative NO (80 ppm intraop + 6h post) for CKD patients to lower AKI risk, with monitoring for methemoglobinemia and gas byproducts; multicenter validation is warranted.
Key Findings
- 7-day AKI incidence reduced: 23.5% (NO) vs 39.7% (control), RR 0.59 (95% CI 0.35–0.99; P=0.043).
- Higher GFR at 6 months: 50 vs 45 ml·min−1·1.73 m−2 (P=0.038).
- Lower postoperative pneumonia: 14.7% vs 29.4%, RR 0.5 (95% CI 0.25–0.99; P=0.039).
- Safety: methemoglobin/NO2− within acceptable ranges; no increase in oxidative-nitrosyl stress; no differences in transfusion, platelets, blood loss.
Methodological Strengths
- Randomized, sham-controlled design with predefined primary endpoint
- Comprehensive safety monitoring and clinically relevant renal and pulmonary outcomes
Limitations
- Modest sample size and potential single-center context limit generalizability
- No detailed subgroup analyses by CKD stage or surgical complexity reported
Future Directions: Conduct multicenter RCTs to confirm efficacy, optimize NO dosing/duration, and evaluate effects across CKD stages and surgical types.
BACKGROUND: Postoperative acute kidney injury (AKI) is a significant concern for cardiac surgery patients with chronic kidney disease (CKD). Effective pharmacologic interventions to mitigate these risks are urgently needed. This study aimed to evaluate the efficacy and safety of perioperative nitric oxide (NO) administration in preventing AKI and limiting CKD progression in patients undergoing cardiac surgery. METHODS: A total of 136 patients with CKD undergoing elective cardiac surgery with cardiopulmonary bypass were randomized into two equal groups: the NO group (n = 68), receiving 80 parts per million NO during the intraoperative period and for 6 h postsurgery, and the control group (n = 68), receiving a sham treatment. The primary outcome was AKI incidence within 7 days postsurgery. RESULTS: AKI incidence was significantly lower in the NO group (16 of 68 patients, 23.5%) compared to the control group (27 of 68 patients, 39.7%) with a relative risk of 0.59 (95% CI, 0.35 to 0.99; P = 0.043). Six months postsurgery, the glomerular filtration rate was higher in the NO group (50 ml · min -1 · 1.73 m -2 [45; 54]) compared to the control group (45 ml · min -1 · 1.73 m -2 [41; 51]; P = 0.038). Postoperative pneumonia was significantly less frequent in the NO group: 10 of 68 (14.7%) versus 20 of 68 (29.4%) with a relative risk of 0.5 (95% CI, 0.25 to 0.99; P = 0.039). NO administration was safe: methemoglobin and nitrogen dioxide levels remained within acceptable ranges, oxidative-nitrosyl stress did not increase, and there were no significant differences between the groups in blood transfusion requirements, platelet counts, or postoperative blood loss volumes. CONCLUSIONS: Perioperative NO administration in CKD patients undergoing cardiac surgery with cardiopulmonary bypass is safe, reduces the incidence of AKI, and slows the progression of renal dysfunction.
3. Comparative cardiovascular effectiveness of newer glucose-lowering drugs in elderly with type 2 diabetes: a target trial emulation cohort study.
In a nationwide target trial emulation of 35,679 elderly patients, both GLP-1 receptor agonists and SGLT2 inhibitors reduced 3P-MACE and heart failure hospitalization versus DPP-4 inhibitors. SGLT2 inhibitors provided additional reductions in heart failure hospitalization compared with GLP-1 receptor agonists, largely independent of age.
Impact: Provides robust real-world comparative effectiveness in an elderly population often underrepresented in RCTs, supporting guideline-concordant therapy selection.
Clinical Implications: For patients ≥70 years with T2D, prioritize SGLT2 inhibitors or GLP-1 receptor agonists over DPP-4 inhibitors to reduce MACE and heart failure hospitalization; favor SGLT2 inhibitors when heart failure risk predominates.
Key Findings
- GLP-1RA vs DPP-4i: 3P-MACE IRR 0.68 (95% CI 0.65–0.71); HHF IRR 0.81 (95% CI 0.74–0.88).
- SGLT2i vs DPP-4i: 3P-MACE IRR 0.65 (95% CI 0.63–0.68); HHF IRR 0.60 (95% CI 0.55–0.66).
- SGLT2i vs GLP-1RA: lower HHF, IRR 0.75 (95% CI 0.67–0.83); effects largely independent of age.
Methodological Strengths
- Nationwide registries with target trial emulation and weighting to balance baseline factors
- Large sample size with head-to-head effectiveness comparisons and age-stratified analyses
Limitations
- Observational design with potential residual confounding and exposure misclassification
- Medication dosing, adherence dynamics, and lifestyle factors not fully captured
Future Directions: Pragmatic randomized trials in ≥70-year-olds to confirm comparative benefits; evaluate frailty, renal function, and polypharmacy subgroups; integrate cost-effectiveness.
BACKGROUND: Reducing risk of cardiovascular disease is crucial in managing type 2 diabetes (T2D). This study assessed the comparative cardiovascular effectiveness of newer glucose-lowering drugs in real-world elderly individuals with T2D, and examined how age modified these effects. METHODS: We conducted a cohort study using Danish nationwide registries to emulate a three-arm randomized clinical trial. Participants aged ≥70 years were new users of glucagon-like peptide 1 receptor agonists (GLP1-RAs), sodium-glucose cotransporter 2 inhibitors (SGLT-2is), or dipeptidyl peptidase 4 inhibitors (DPP-4is), between 2012 and 2020. We estimated the overall and age-specific incidence rate ratios (IRR) of 3-point major adverse cardiovascular events (3P-MACE) and hospitalization for heart failure (HHF) using Poisson regression models. Summarized weights were used to balance baseline characteristics and treatment adherence. FINDINGS: The study included 35,679 participants (DPP-4is: 21,848 (62%), GLP1-RAs: 5702 (16%), SGLT-2is: 8129 (23%)). In the as-treated analysis, GLP1-RAs and SGLT-2is were associated with significantly reduced rates of 3P-MACE and HHF compared to DPP-4is. The overall IRR for 3P-MACE was 0.68 (95% CI 0.65-0.71) (GLP1-RAs vs. DPP4is) and 0.65 (95% CI 0.63-0.68) (SGLT-2is vs. DPP4is), while for HHF the IRR was 0.81 (95% CI 0.74-0.88) (GLP1-RAs vs. DPP4is) and 0.60 (95% CI 0.55-0.66) (SGLT-2is vs. DPP4is). These effects were predominantly independent of age. No significant difference was observed between SGLT-2is and GLP1-RAs on 3P-MACE, however, SGLT-2is were associated with a significant reduction of HHF, compared to GLP1-RAs, with an overall IRR of 0.75 (95% CI 0.67-0.83), and with age-dependent variations for both outcomes. INTERPRETATION: In the elderly, use of GLP1-RAs and SGLT-2is was associated with reduced rates of 3P-MACE and HHF compared to DPP-4is, independent of age. SGLT-2is were also associated with reduced rates of HHF compared to GLP1-RAs, largely independent of age, in this population of individuals aged 70 years and above. This provides real-world evidence on the comparative cardiovascular effectiveness of the three most recent glucose-lowering medications and may help strengthen implementation of guidelines into clinical practice. FUNDING: None.