Circulation最新文献

Background: Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell (EC) dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, regulates cardiovascular homeostasis. In the present study, we aimed to test whether endothelial TFEB protects against EC damage and alleviates cardiac dysfunction induced by DOX treatment.

Methods: EC-specific TFEB transgenic mice, EC-specific TFEB knockout mice, and their corresponding littermate controls were administered DOX intravenously. Survival curves were generated, and cardiac functions were measured in mice. The effects of TFEB on mitochondrial reactive oxygen species production, autophagic flux, and apoptosis were evaluated in human and mouse cardiac microvascular ECs treated with DOX. RNA sequencing, single-cell RNA sequencing, and chromatin immunoprecipitation with quantitative polymerase chain reaction was performed to dissect molecular mechanisms in DOX-treated ECs in vitro and in vivo. Mice with endothelium-specific deficiency of DAB adaptor protein 2 (Dab2) were subjected to measurement of cardiac function and fibrosarcoma growth under DOX treatment.

Results: EC-specific TFEB transgenic mice showed significantly reduced mortality and improved cardiac function, together with attenuation of perivascular fibrosis after DOX treatment. By contrast, EC-specific TFEB knockout exacerbated DOX-induced cardiac dysfunction in mice. Furthermore, we observed that TFEB enhanced autophagy and reduced oxidative stress in cardiac microvascular ECs treated with DOX. In addition, TFEB preserved EC barrier integrity, alleviated proinflammatory cytokine release from cardiac microvascular ECs, and maintained the EC-cardiomyocyte communication, contributing to the protective effects of EC TFEB on cardiomyocyte function. Mechanistically, DAB2, a clathrin- and cargo-binding endocytic adaptor protein, was identified as a TFEB target gene in ECs. Accordingly, DAB2 knockdown attenuated the inhibitory effects of TFEB on apoptosis and the secretion of proinflammatory cytokines from cardiac microvascular ECs. In vivo, EC-specific Dab2 deficiency abolished the protective effect of EC TFEB on DOX-induced cardiac dysfunction.

Conclusions: Taken together, endothelial TFEB protects against EC damage and cardiac dysfunction, constituting a potential target for treating cardiotoxicity induced by DOX. Our study provides new mechanistic insights into cardiotoxicity associated with chemotherapy.

Background: Atrial fibrillation and other cardiac arrhythmias pose a major public health burden, but prevention remains difficult. We investigated a genetic variant that we found to act like a natural lifelong cardiac sodium channel blockade.

Methods: We studied the impact of the Finnish-enriched SCN5A missense variant (rs45620037 [T220I]) on cardiac arrhythmias, associated mortality, and ECG phenotypes in a multicohort observational study with >1 million individuals across 3 cohorts (FinnGen, UK Biobank, and Health 2000).

Results: We identified protective effects of T220I on multiple common cardiac arrhythmias, most notably atrial fibrillation (cause-specific hazard ratio [HR], 0.56 [95% CI, 0.50-0.63]; P<0.0001), but also ventricular premature depolarization or ventricular tachycardia, as well as increasing susceptibility to conduction-slowing conditions, such as sick sinus syndrome (mostly in older age groups). Overall, T220I conveyed protection from death resulting from cardiac arrhythmia (HR, 0.65 [95% CI, 0.46-0.92]; P=0.015) without a significant effect on overall mortality risk (HR, 0.92; P=0.27). T220I heterozygosity had similar electrophysiological effects as some pharmacological sodium channel blockers, such as significantly shortening QT intervals (-7.49 ms [95% CI, -10.07 to -4.91] ms; P=0.0037; n=3188) in the Health 2000 cohort, which we replicated in the UK Biobank (n=66 616). In addition, T220I protected from (left) heart failure and dilated cardiomyopathy. After myocardial infarction, we found that T220I increased mortality risk, consistent with known sodium channel blocker effects, which, however, normalized to baseline 10 to 15 years after myocardial infarction. We found that T220I could lower a high genetic burden (ie, a high polygenic score) for atrial fibrillation to population average.

Conclusions: The SCN5A T220I variant, consistent with a previously described weak loss-of-function effect, acted like a genetic proxy for cardiac sodium channel blockade. This enabled us to gain new potentially clinically relevant insights for pharmacological sodium channel blockade, such as after myocardial infarction, which would be too risky to investigate with clinical trials. Our findings may also inspire redesign of cardiac sodium channel blockers.