Daily Cardiology Research Analysis
Analyzed 130 papers and selected 3 impactful papers.
Summary
A large Danish population-based study shows that multi-modality cardiovascular screening at age 67 reduces 5-year all-cause mortality in both men and women. A comprehensive meta-analysis of 139 heart failure RCTs finds no sex differences in pharmacologic efficacy, countering concerns that under-enrollment of women masked treatment effects. Mechanistic work implicates C3a–C3a receptor–Rac1 signaling in endothelial glycocalyx degradation during STEMI, highlighting a potential therapeutic target to mitigate vascular injury.
Research Themes
- Population cardiovascular screening and mortality reduction
- Sex differences in heart failure pharmacotherapy
- Complement-mediated endothelial injury mechanisms in STEMI
Selected Articles
1. Multi-modality non-invasive cardiovascular screening and sex-specific outcomes: the Viborg Screening Program.
Inviting all 67-year-olds to a comprehensive cardiovascular screening program lowered 5-year all-cause mortality (HR 0.76) with benefits in both sexes and particularly in those without prior CVD. Major adverse limb events were reduced, while MACE modestly increased, underscoring trade-offs that warrant further study.
Impact: This is a large, real-world, population-based study demonstrating mortality reduction from a feasible, multi-modality screening strategy, including women. It provides a policy-relevant foundation for targeted screening at a fixed age.
Clinical Implications: Health systems could consider implementing multi-modality screening at age 67, prioritizing individuals without prior CVD, with attention to downstream testing and potential increase in MACE. Cost-effectiveness and resource planning are needed before scale-up.
Key Findings
- All-cause mortality reduced over 5.8 years among invitees vs controls (HR 0.76; 95% CI 0.68–0.85).
- Number-needed-to-invite to save one life was 49.
- Benefits observed in both men (HR 0.73) and women (HR 0.82), and strongest in those without prior CVD (HR 0.70).
- Major adverse limb events decreased (HR 0.70), whereas MACE modestly increased (HR 1.10).
Methodological Strengths
- Prospective population-based design with intention-to-invite analysis and long median follow-up (5.8 years).
- Robust confounding control via 1:3 propensity score matching and sex-stratified analyses.
Limitations
- Non-randomized design with potential residual confounding.
- Post hoc sex-stratified analyses and observed increase in MACE require careful interpretation.
Future Directions: Conduct pragmatic cluster-RCTs or stepped-wedge trials to validate mortality benefits, optimize screening bundles, and assess cost-effectiveness and equity impacts.
BACKGROUND AND AIMS: Cardiovascular screening has been shown to reduce mortality in trials involving men. This study evaluated the effect of cardiovascular screening in both sexes, with all-cause mortality as the primary outcome. METHODS: The Viborg Screening Program, a prospective, population-based study in Denmark, in which the intervention consisted of inviting all 67-year olds to screening for carotid plaque, lower extremity artery disease, abdominal aortic aneurysm, hypertension, cardiac arrhythmia/ischaemia, and diabetes mellitus. This cohort included invitees from the first 5 years (2014-2019). Controls were 67-year olds without screening access. Effects were evaluated using propensity score matching (1:3 ratio, nearest-neighbour matching) and analysed using Cox proportional hazards models under the intention-to-invite principle. Sex-stratified analyses of all-cause mortality were conducted post hoc. RESULTS: Among 5505 invitees, three died before inclusion and 4602 participated (83.6%). Ninety individuals lacked registry information. After matching, 5412 invitees and 16 236 controls were included. During a median follow-up of 5.8 years, 372 (6.9%) invitees and 1444 (8.9%) controls died [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.68-0.85; P < .001]. The number needed to invite to save one life was 49. The HR for cardiovascular mortality was 0.76 (95% CI 0.56-1.03), for major adverse cardiovascular events 1.10 (95% CI 1.01-1.19), and for major adverse limb events 0.70 (95% CI 0.50-0.98). All-cause mortality HRs were 0.73 (95% CI 0.63-0.84) for men, 0.82 (95% CI 0.68-0.98) for women, 0.70 (95% CI 0.61-0.80) for those without prior cardiovascular disease (CVD), and 0.97 (95% CI 0.78-1.21) for those with prior CVD. CONCLUSIONS: Multi-modality non-invasive cardiovascular screening reduced 5-year all-cause mortality among 67-year olds, also when stratified by sex. Prioritizing individuals without known CVD may enhance population-level impact.
2. Sex differences in pharmacological treatment of heart failure: a meta-analysis of randomized trials.
Across 139 HF RCTs including 292,027 participants, pooled analyses showed no sex differences in pharmacologic efficacy, and trial-level female enrollment proportion did not influence treatment effect estimates. Results argue against hidden sex-specific efficacy signals due to underrepresentation.
Impact: Provides high-level evidence addressing a critical equity and efficacy question in HF therapeutics, guiding clinicians to apply guideline-directed therapy irrespective of sex while still promoting equitable enrollment.
Clinical Implications: Clinicians should not withhold or modify HF pharmacotherapies based on sex alone; guideline-directed medical therapy should be applied equally while advocating for better female representation in future trials.
Key Findings
- No sex differences in primary efficacy across 78 RCTs with sex-stratified effects (delta ln[REM] 0.00; 95% CI -0.04 to 0.03; P=0.85; I2=4.1%).
- The proportion of women enrolled did not modify sex differences in treatment effect or overall efficacy estimates in meta-regression.
- Pooled evidence across 139 RCTs (292,027 patients; 28.1% women) supports equivalent pharmacologic efficacy in women and men with HF.
Methodological Strengths
- Large-scale meta-analysis of 139 RCTs with random-effects models and low heterogeneity for sex-difference estimate (I2=4.1%).
- Meta-regression assessing influence of female enrollment proportion on treatment effects.
Limitations
- Sex-stratified effects were available in 78/139 RCTs; reliance on reported aggregate measures may bias estimates.
- Trial-level meta-regression may be underpowered to detect nuanced interactions; individual patient data meta-analysis could refine estimates.
Future Directions: Pursue individual patient data meta-analyses to evaluate sex-by-treatment interactions across subgroups and outcomes; ensure sex balance and sex-specific endpoints in future HF RCTs.
BACKGROUND AND AIMS: Women remain underrepresented in heart failure (HF) trials, raising concerns about potential undetected sex-specific differences in treatment efficacy. This study assesses sex differences in the primary efficacy endpoint of HF treatments and examines whether the proportion of women enrolled in a trial influences (variations in) treatment effect estimates. METHODS: A systematic search was conducted up to 21 March 2025, including randomized controlled trials (RCTs) (≥100 patients) evaluating pharmacological HF treatments vs. placebo or usual care, with clinical events as the primary outcome. Sex differences in the primary outcome were assessed using a random-effects meta-analysis of the reported relative effect measures (REM) and pooled estimates. For key clinical outcomes, meta-regression analyses were performed to examine the association between the proportion of women enrolled and sex differences in REMs, as well as the overall REMs without separating sex. RESULTS: Of 5749 screened publications, 139 RCTs met inclusion criteria, with 292 027 patients (28.1% women). Based on 78 RCTs that reported sex-stratified treatment effects, pooled analysis showed no difference in treatment efficacy between women and men (delta ln[REM] 0.00; 95% confidence interval (CI) -0.04 to 0.03; P = .85; I2 = 4.1%). Meta-regression found no association between the proportion of women and sex differences in REM (78 RCTs, P = .25), overall efficacy (139 RCTs, P = .24), or other clinical outcomes. CONCLUSIONS: These findings suggest that pharmacological efficacy in HF does not differ by sex and that historical female underrepresentation in trials is unlikely to have masked important sex differences. Nonetheless, improving sex balance in HF trials remains essential for societal and ethical reasons.
3. Activation of the C3a-C3aReceptor-axis is associated with endothelial dysfunction and glycocalyx damage in ST-elevation myocardial infarction.
High C3a levels in STEMI are linked to endothelial glycocalyx loss, cortical stiffening, reduced NO, and increased leukocyte adhesion. Recombinant C3a reproduces these effects via Rac1 activation and C3aR signaling, which are reversed by C3aR or Rac1 inhibition, nominating C3a–C3aR–Rac1 as a therapeutic axis.
Impact: This study provides mechanistic and target-validation evidence linking an upstream complement fragment (C3a) to endothelial glycocalyx injury in STEMI, expanding therapeutic opportunities beyond C5a and identifying druggable nodes (C3aR, Rac1).
Clinical Implications: Pharmacologic C3aR antagonists or Rac1 modulators could be explored to protect the endothelial glycocalyx and microvascular function after STEMI. Translational studies are warranted to assess timing, safety, and synergy with current reperfusion strategies.
Key Findings
- STEMI patients with high C3a had reduced endothelial glycocalyx height (−44%), increased cortical stiffness (+35%), elevated shedding markers (Syndecan-1 +203%; heparan sulfate +181%), and decreased NO (−34%).
- C3a levels inversely correlated with eGC height (r = −0.736) and positively with Syndecan-1 (r = 0.856).
- Recombinant C3a induced Rac1 activation, actin polymerization, eGC loss, reduced NO, and increased monocyte adhesion—reversed by C3aR antagonists and Rac1 inhibition.
Methodological Strengths
- Case–control human data with matched controls combined with multi-modal endothelial phenotyping (ELISA, AFM nanoindentation, adhesion assays) and NO bioassay.
- Pharmacologic pathway validation using C3aR antagonists and Rac1 inhibition demonstrating reversibility and specificity.
Limitations
- Observational human data limit causal inference; sample sizes are modest.
- Acute STEMI context may not generalize to other atherothrombotic settings; in vitro concentrations may not fully mimic in vivo pharmacokinetics.
Future Directions: Early-phase clinical trials of C3aR antagonism or Rac1 modulation post-PCI to test endothelial protection and microvascular outcomes; development of biomarkers to select high-C3a phenotypes.
Complement activation is an early event in ischemia-reperfusion injury during ST-elevation myocardial infarction (STEMI) and drives endothelial dysfunction via glycocalyx (eGC) degradation. While downstream fragments such as C5a contribute to vascular injury, the role of the early anaphylatoxin C3a remains unclear. This study delineates the effects of the C3a:C3a-Receptor-axis on endothelial function, cytoskeletal dynamics, and eGC integrity. Sixty-four first-time STEMI patients and sixty-four age- and sex-matched healthy controls were enrolled. Patients were stratified into quartiles based on serum C3a concentrations, and comparisons were performed between the lowest vs. highest quartiles as well as between all STEMI patients vs. controls. Inflammatory and glycocalyx parameters were assessed via ELISA, AFM nanoindentation, and monocyte adhesion assays. NO bioavailability was measured chemiluminescence-based. C3a-receptor-antagonists (SB290157 and JR14a), C5a-Receptor1-antagonism (PMX53), as well as Rac1-Inhibition (NSC23766) were used to verify pathway specificity and downstream signaling involvement. High C3a levels were associated with marked endothelial injury: eGC height was reduced (- 44%; p < 0.001), cortical stiffness increased (+ 35%; p < 0.001), and shedding of Syndecan-1 and heparan sulfate was elevated (+ 203%, p < 0.001; + 181%, p < 0.01). NO bioavailability decreased by 34% (p < 0.05). C3a correlated inversely with eGC height (r = - 0.736) and positively with Syndecan-1 (r = 0.856). Treatment with recombinant C3a (250 ng/mL) induced cortical stiffening (+ 10.8%; p < 0.001), eGC loss (- 24.7%; p < 0.001), actin polymerization (+ 27.9%; p < 0.001), Rac1 activation (p < 0.05), reduced NO (- 38%; p < 0.05), and increased monocyte adhesion (+ 37%), all reversed by both C3a-Receptor-inhibitiors and by Rac1-inhibition. C3a:C3a-Receptor signaling drives Rac1-mediated cytoskeletal stiffening, eGC degradation, NO reduction, and leukocyte adhesion, promoting endothelial dysfunction in STEMI in both macrovascular and microvascular endothelial cells. This pathway represents a potential therapeutic target to mitigate complement-mediated vascular injury in acute myocardial infarction.