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.
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.
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.