Journal: Eur Heart J

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Abstract

A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity.

Lu D, Chatterjee S, Xiao K, Riedel I, ... Bär C, Thum T
Aims
Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF.
Methods and results
The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity.
Conclusion
Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 27 Jun 2022; epub ahead of print
Lu D, Chatterjee S, Xiao K, Riedel I, ... Bär C, Thum T
Eur Heart J: 27 Jun 2022; epub ahead of print | PMID: 35758064
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Abstract

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci.

Ghouse J, Tragante V, Muhammad A, Ahlberg G, ... Bundgaard H, Olesen MS
Aims
To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs).
Methods and results
A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits.
Conclusion
This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Jun 2022; epub ahead of print
Ghouse J, Tragante V, Muhammad A, Ahlberg G, ... Bundgaard H, Olesen MS
Eur Heart J: 25 Jun 2022; epub ahead of print | PMID: 35751511
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Abstract

Rivaroxaban and aspirin vs. aspirin alone in Asian compared with non-Asian patients with chronic coronary artery disease or peripheral arterial disease: the COMPASS trial.

Hori M, Zhu J, Liang Y, Bhatt DL, ... Yusuf S, Eikelboom JW
Aims
It is unknown whether Asian and non-Asian patients with atherosclerotic vascular disease derive similar benefits from long-term antithrombotic therapy.
Methods and results
In patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, the effects of rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. were compared with those of aspirin 100 mg o.d. in Asian vs. non-Asian patients (race was self-identified). Asians (n = 4269) vs. non-Asians (n = 23 126) had similar rates of major adverse cardiovascular events (MACEs) (4.85% vs. 4.83%, P = 0.30) and modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (2.72% vs. 2.58%, P = 0.22), but higher rates of intracranial haemorrhage (ICH) (0.63% vs. 0.29%, P = 0.01) and minor bleeding (13.61% vs. 6.49%, P < 0.001). In Asians vs. non-Asians, the combination of rivaroxaban and aspirin compared with aspirin alone produced consistent reductions in MACE [Asians: hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.45-0.90; non-Asians: HR: 0.78, 95% CI: 0.67-0.90; P(heterogeneity) = 0.29], increases in modified ISTH major bleeding (Asians: HR 2.24, 95% CI: 1.40-3.58; non-Asians: HR: 1.60, 95% CI: 1.30-1.97; P = 0.20), and net clinical outcome (Asians: HR: 0.77, 95% CI: 0.56-1.05; non-Asians: HR: 0.81, 95% CI: 0.70-0.93, P = 0.78), but borderline higher rates of ICH (Asians: HR: 3.50, 95% CI: 0.98-12.56; non-Asians: HR: 0.81, 95% CI: 0.43, 1.53; P = 0.04).
Conclusion
Asian compared with non-Asian patients with chronic CAD and/or PAD have higher rates of ICH and minor bleeding. The combination of rivaroxaban and aspirin vs. aspirin alone produces similar effects for MACE, modified ISTH major bleeding, and net clinical outcome but may be associated with higher rates of ICH in Asian patients.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Jun 2022; epub ahead of print
Hori M, Zhu J, Liang Y, Bhatt DL, ... Yusuf S, Eikelboom JW
Eur Heart J: 25 Jun 2022; epub ahead of print | PMID: 35751528
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This program is still in alpha version.