Daily Cardiology Research Analysis
Three cardiology studies stand out today: a mechanistic discovery showing SIRT6 regulates angiogenesis by demyristoylating VEGFA; a large two-cohort analysis demonstrating continuous preoperative eGFR (with age interaction) is among the strongest predictors of perioperative cardiac events; and a meta-analysis of finerenone across major RCTs showing fewer heart failure hospitalizations and lower all-cause mortality but higher hyperkalemia risk.
Summary
Three cardiology studies stand out today: a mechanistic discovery showing SIRT6 regulates angiogenesis by demyristoylating VEGFA; a large two-cohort analysis demonstrating continuous preoperative eGFR (with age interaction) is among the strongest predictors of perioperative cardiac events; and a meta-analysis of finerenone across major RCTs showing fewer heart failure hospitalizations and lower all-cause mortality but higher hyperkalemia risk.
Research Themes
- Epigenetic enzyme control of angiogenesis via protein demyristoylation
- Perioperative cardiac risk prediction using kidney function (eGFR) as a continuous predictor
- Mineralocorticoid receptor antagonism (finerenone) in HF/CKD: benefits and risks
Selected Articles
1. SIRT6 promotes angiogenesis by enhancing VEGFA secretion via demyristoylation in endothelial cell.
Endothelial SIRT6 promotes angiogenesis by demyristoylating VEGFA, thereby enhancing its secretion under hypoxia and improving endothelial migration and tube formation. Loss of SIRT6 reduces angiogenic responses, and SIRT6 overexpression rescues ALK14-induced defects, highlighting demyristoylation (not deacetylation) as the key activity.
Impact: This study uncovers a previously unrecognized post-translational mechanism—SIRT6-mediated demyristoylation of VEGFA—linking epigenetic enzyme activity to angiogenesis, suggesting a new therapeutic axis for ischemic cardiovascular disease.
Clinical Implications: Targeting SIRT6 demyristoylase activity could modulate therapeutic angiogenesis in ischemic heart disease and peripheral ischemia. It also raises caution that broad SIRT6 modulation may affect VEGFA biology.
Key Findings
- Endothelial SIRT6 knockout attenuated angiogenesis in mice; SIRT6 promoted endothelial migration and tube formation in vitro.
- SIRT6 regulates intracellular VEGFA levels and global protein myristoylation under hypoxia; knockdown or ALK14 reduced VEGFA secretion.
- CLICK-IT assays identified VEGFA as a myristoylated substrate of SIRT6; SIRT6 enhances VEGFA secretion via demyristoylation, not deacetylation.
- SIRT6 overexpression rescued endothelial angiogenic defects induced by ALK14 treatment.
Methodological Strengths
- In vivo endothelial-specific knockout with phenotypic angiogenesis assessment
- Mechanistic validation using CLICK-IT labeling and functional rescue with SIRT6 mutants
Limitations
- Preclinical study without human validation
- Extent of in vivo models and long-term safety of targeting SIRT6 not addressed
Future Directions: Translate findings to human tissues and ischemic models; develop selective SIRT6 demyristoylase modulators; evaluate therapeutic angiogenesis and safety in large-animal models.
Angiogenesis plays a pivotal role in ischemic cardiovascular disease, accompanied by epigenetic regulation during this process. Sirtuin 6 (SIRT6) has been implicated in the regulation of DNA repair, transcription and aging, with its deacetylase activity fully studied. However, the role of SIRT6 demyristoylase activity remains less clear, with even less attention given to its myristoylated substrates. In this study, we report that endothelial specific SIRT6 knockout attenuated angiogenesis in mice, while SIRT6 was observed to promote migration and tube formation in endothelial cell. Notably, we further determined that SIRT6 affects the intracellular VEGFA and global myristoylation level under hypoxia. Moreover, ALK14 (myristic acids analogue) treatment and SIRT6 knockdown results in a significant decrease in VEGFA secretion under hypoxia, implying the involvement of SIRT6 demyristoylase activity in angiogenesis. Mechanistically, CLICK IT assay verified that VEGFA is a myristoylated substrate of SIRT6. Further, overexpression of SIRT6 mutants (R65A, G60A and H133Y) results in profound differences in VEGFA secretion, indicating that SIRT6 promotes VEGFA secretion through demyristoylation but not deacetylation. Finally, overexpression of SIRT6 rescued the diminishment of endothelial migration, tube formation and sprouting caused by ALK14 treatment. Overall, our study demonstrates that SIRT6 regulates angiogenesis by demyristoylating VEGFA and increasing VEGFA secretion. Therefore, modulation of SIRT6 demyristoylase activity may represent a therapeutic strategy for ischemic cardiovascular disease.
2. Preoperative estimated glomerular filtration rate to predict cardiac events in major noncardiac surgery: a secondary analysis of two large international studies.
Across VISION (n=35,815) and POISE-2 (n=9,219), lower continuous preoperative eGFR strongly predicted 30-day perioperative cardiac events, with attenuation at older ages. Adding eGFR (and its age interaction) improved model discrimination and net benefit over common clinical predictors.
Impact: Provides robust, generalizable evidence that continuous eGFR is one of the strongest predictors for perioperative cardiac risk and should be incorporated into risk calculators.
Clinical Implications: Incorporate continuous eGFR and its age interaction into perioperative cardiac risk assessment to better stratify patients and guide monitoring, optimization, and resource allocation.
Key Findings
- In both VISION and POISE-2, lower preoperative eGFR showed a strong, graded association with 30-day cardiac events.
- The predictive association was attenuated in older patients, indicating an age interaction.
- Adding continuous eGFR improved multivariable model C-statistics and net benefit beyond common predictors.
Methodological Strengths
- Very large combined sample size across two international studies
- Evaluation of continuous nonlinear predictor with age interaction and decision-analytic net benefit
Limitations
- Secondary analysis with potential residual confounding despite multivariable adjustment
- Abstract truncation limits detailed reporting of effect sizes and calibration
Future Directions: Implement and prospectively validate eGFR-integrated risk calculators; assess clinical utility in diverse surgical populations and evaluate intervention thresholds.
BACKGROUND: Optimised use of kidney function information might improve cardiac risk prediction in noncardiac surgery. METHODS: In 35,815 patients from the VISION cohort study and 9219 patients from the POISE-2 trial who were ≥45 yr old and underwent nonurgent inpatient noncardiac surgery, we examined (by age and sex) the association between continuous nonlinear preoperative estimated glomerular filtration rate (eGFR) and the composite of myocardial injury after noncardiac surgery, nonfatal cardiac arrest, or death owing to a cardiac cause within 30 days after surgery. We estimated contributions of predictive information, C-statistic, and net benefit from eGFR and other common patient and surgical characteristics to large multivariable models. RESULTS: The primary composite occurred in 4725 (13.2%) patients in VISION and 1903 (20.6%) in POISE-2; in both studies cardiac events had a strong, graded association with lower preoperative eGFR that was attenuated by older age (P CONCLUSIONS: Continuous preoperative eGFR is among the best cardiac risk predictors in noncardiac surgery of the large set examined. Along with its interaction with age, preoperative eGFR would improve risk calculators. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00512109 (VISION) and NCT01082874 (POISE-2).
3. Effect of Finerenone in Cardiovascular and Renal Outcomes: A Systematic Review and Meta-analysis.
Across three RCTs (n=19,027), finerenone reduced heart failure hospitalizations (HR 0.80) and all-cause mortality (RR 0.86), without significant reduction in cardiovascular death, and increased hyperkalemia risk (RR 2.31). Renal failure rates were similar to placebo.
Impact: Synthesizes high-level evidence that finerenone confers important clinical benefits in HF/CKD populations, informing guideline updates while quantifying safety trade-offs.
Clinical Implications: Consider finerenone to reduce HF hospitalizations and all-cause mortality in appropriate HF/CKD patients, with proactive monitoring and management of hyperkalemia.
Key Findings
- Finerenone reduced heart failure hospitalization risk by 20% (HR 0.80, 95% CI 0.72–0.90).
- All-cause mortality was reduced by 14% (RR 0.86, 95% CI 0.77–0.97).
- No significant reduction in cardiovascular death (HR 0.91, p=0.06); renal failure rates were similar to placebo.
- Hyperkalemia risk was significantly increased (RR 2.31, 95% CI 1.98–2.69).
Methodological Strengths
- Meta-analysis restricted to randomized controlled trials with large total sample size
- Prespecified cardiovascular and renal endpoints with standard effect measures (HR, RR, CI)
Limitations
- Heterogeneity across trials in populations (CKD severity, HF phenotype) and follow-up
- Increased hyperkalemia requires careful monitoring; effects on cardiovascular death remained borderline
Future Directions: Clarify cardiovascular mortality effects in dedicated HF phenotypes; define potassium management protocols and patient selection to optimize benefit-risk.
PURPOSE: Heart failure (HF) management is well-defined for reduced ejection fraction (HFrEF) but less so for mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). This meta-analysis evaluates the impact of Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, on cardiovascular and renal outcomes in these patient populations. METHODS: A systematic search in PubMed and Embase identified randomized controlled trials (RCTs) on Finerenone's cardiovascular and renal effects. Three RCTs were included-FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF-encompassing 19,027 participants. Primary outcomes included cardiovascular death, HF hospitalization, and renal failure. Secondary outcomes focused on safety and adverse events like acute kidney injury and hyperkalemia. Meta-analyses were performed using hazard ratios (HR), confidence intervals (CI), and Relative Risk (RR). RESULTS: Finerenone was associated with a 20% reduction in HF hospitalization risk (HR 0.80, 95% CI: 0.72-0.90) and a 14% reduction in all-cause mortality (RR 0.86, 95% CI: 0.77-0.97). Finerenone did not significantly reduce cardiovascular death (HR 0.91, 95% CI: 0.82-1.01, p = 0.06). Renal failure rates were similar between Finerenone and placebo (RR 1.05, 95% CI: 0.65-1.68). Hyperkalemia incidence was significantly higher with Finerenone, with a RR of 2.31 (95% CI: 1.98-2.69). CONCLUSION: This meta-analysis shows that Finerenone significantly reduces HF hospitalizations and all-cause mortality in patients with chronic kidney disease and heart failure. Further studies are needed to clarify its effects on cardiovascular death and renal failure.