Arrhythmias & electrophysiologyCohort study
Leveraging a Genetic Proxy to Investigate the Effects of Lifelong Cardiac Sodium Channel Blockade
- Multicohort observational genetic association study
- 3 cohorts (FinnGen, UK Biobank, Health 2000)
Authors' conclusion
The SCN5A T220I variant, consistent with a previously described weak loss-of-function effect, acted like a genetic proxy for cardiac sodium channel blockade.
Study context
- Population
- Individuals in FinnGen, UK Biobank and Health 2000
- Participants
- >1 million individuals · 3 cohorts
- Exposure
- SCN5A T220I carriers vs non-carriers
Main finding
AF
Cause-specific hazard ratio
0.56
95% CI 0.50–0.63
P < 0.0001
T220I vs Non-carriers
cause-specific HR 0.56 (95% CI 0.50–0.63); P < 0.0001
As reported in the abstract
Observational data: associations, not effects.
Further findings
| Outcome | HR (95% CI) | P value | |
|---|---|---|---|
| Death from cardiac arrhythmia | 0.65 (0.46–0.92) | P = 0.015 | |
| 0.512Hazard ratio (log scale) |
| Outcome | difference (ms) (95% CI) | P value | |
|---|---|---|---|
| QT interval (Health 2000, n=3188) · replicated in UK Biobank (n=66 616) | −7.49 (−10.07 to −4.91) | P = 0.0037 | |
| −15−10−505Difference, ms (linear scale) |
| Outcome | HR | P value |
|---|---|---|
| Overall mortality | 0.92 | P = 0.27 |
Other arrhythmias, HF, dilated cardiomyopathy, AF polygenic score
- Protective against ventricular premature depolarization or VT
- Protected from (left) HF and dilated cardiomyopathy
- Could lower a high polygenic score for AF to population average
Safety
Conduction-slowing conditions and post-MI mortality
- Increased susceptibility to conduction-slowing conditions, such as sick sinus syndrome (mostly in older age groups)
- Increased mortality risk after MI, normalized to baseline 10 to 15 years after MI
Original publication
Leveraging a Genetic Proxy to Investigate the Effects of Lifelong Cardiac Sodium Channel Blockade. Circulation. Published 24 November 2025. doi:10.1161/circulationaha.125.075057
Summarised from the published abstract; every number is checked against it