Topic: Journal Club Selection

Abstract

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.

Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Aims
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.
Methods and results
Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.
Conclusion
Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 22 Jun 2022; 118:1728-1741
Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Cardiovasc Res: 22 Jun 2022; 118:1728-1741 | PMID: 34028533
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Abstract

Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure.

Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Aims
Hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by post-translational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling. Here, the aim of this study was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF.
Methods and results
We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy.
Conclusion
We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 22 Jun 2022; 118:1771-1784
Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Cardiovasc Res: 22 Jun 2022; 118:1771-1784 | PMID: 34132787
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Abstract

Chronically elevated branched chain amino acid levels are pro-arrhythmic.

Portero V, Nicol T, Podliesna S, Marchal GA, ... Potter PK, Remme CA
Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs-leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1742-1757
Portero V, Nicol T, Podliesna S, Marchal GA, ... Potter PK, Remme CA
Cardiovasc Res: 22 Jun 2022; 118:1742-1757 | PMID: 34142125
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Abstract

Efficacy and limitations of senolysis in atherosclerosis.

Garrido AM, Kaistha A, Uryga AK, Oc S, ... Jørgensen H, Bennett M
Aims
Traditional markers of cell senescence including p16, Lamin B1, and senescence-associated beta galactosidase (SAβG) suggest very high frequencies of senescent cells in atherosclerosis, while their removal via \'senolysis\' has been reported to reduce atherogenesis. However, selective killing of a variety of different cell types can exacerbate atherosclerosis. We therefore examined the specificity of senescence markers in vascular smooth muscle cells (VSMCs) and the effects of genetic or pharmacological senolysis in atherosclerosis.
Methods and results
We examined traditional senescence markers in human and mouse VSMCs in vitro, and in mouse atherosclerosis. p16 and SAβG increased and Lamin B1 decreased in replicative senescence and stress-induced premature senescence (SIPS) of cultured human VSMCs. In contrast, mouse VSMCs undergoing SIPS showed only modest p16 up-regulation, and proliferating mouse monocyte/macrophages also expressed p16 and SAβG. Single cell RNA-sequencing (scRNA-seq) of lineage-traced mice showed increased p16 expression in VSMC-derived cells in plaques vs. normal arteries, but p16 localized to Stem cell antigen-1 (Sca1)+ or macrophage-like populations. Activation of a p16-driven suicide gene to remove p16+ vessel wall- and/or bone marrow-derived cells increased apoptotic cells, but also induced inflammation and did not change plaque size or composition. In contrast, the senolytic ABT-263 selectively reduced senescent VSMCs in culture, and markedly reduced atherogenesis. However, ABT-263 did not reduce senescence markers in vivo, and significantly reduced monocyte and platelet counts and interleukin 6 as a marker of systemic inflammation.
Conclusions
We show that genetic and pharmacological senolysis have variable effects on atherosclerosis, and may promote inflammation and non-specific effects respectively. In addition, traditional markers of cell senescence such as p16 have significant limitations to identify and remove senescent cells in atherosclerosis, suggesting that senescence studies in atherosclerosis and new senolytic drugs require more specific and lineage-restricted markers before ascribing their effects entirely to senolysis.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1713-1727
Garrido AM, Kaistha A, Uryga AK, Oc S, ... Jørgensen H, Bennett M
Cardiovasc Res: 22 Jun 2022; 118:1713-1727 | PMID: 34142149
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Abstract

Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity.

Lai Y, Zhou X, Guo F, Jin X, ... Yu L, Jiang H
Aims
The clinical use of antitumour agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity.
Methods and results
Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS, and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After 6-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde and Interleukin-1β, and decreased superoxide dismutase were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were down-regulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly down-regulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group.
Conclusion
These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodelling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 22 Jun 2022; 118:1821-1834
Lai Y, Zhou X, Guo F, Jin X, ... Yu L, Jiang H
Cardiovasc Res: 22 Jun 2022; 118:1821-1834 | PMID: 34145895
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Abstract

The Impact of Persistent Smoking After Surgery on Long-term Outcomes After Stage I Non-small Cell Lung Cancer Resection.

Heiden BT, Eaton DB, Chang SH, Yan Y, ... Kozower BD, Puri V
Background
Smoking at the time of surgical treatment for lung cancer increases the risk for perioperative morbidity and mortality. The prevalence of persistent smoking in the postoperative period and its association with long-term oncologic outcomes are poorly described.
Research question
What is the relationship between persistent smoking and long-term outcomes in early-stage lung cancer after surgical treatment?
Study design and methods
We performed a retrospective cohort study using a uniquely compiled Veterans Health Administration dataset of patients with clinical stage I non-small cell lung cancer (NSCLC) undergoing surgical treatment between 2006 and 2016. We defined persistent smoking as individuals who continued smoking 1 year after surgery and characterized the relationship between persistent smoking and disease-free survival and overall survival.
Results
This study included 7,489 patients undergoing surgical treatment for clinical stage I NSCLC. Of 4,562 patients (60.9%) who were smoking at the time of surgery, 2,648 patients (58.0%) continued to smoke at 1 year after surgery. Among 2,927 patients (39.1%) who were not smoking at the time of surgical treatment, 573 (19.6%) relapsed and were smoking at 1 year after surgery. Persistent smoking at 1 year after surgery was associated with significantly shorter overall survival (adjusted hazard ration [aHR], 1.291; 95% CI, 1.197-1.392; P < .001). However, persistent smoking was not associated with inferior disease-free survival (aHR, 0.989; 95% CI, 0.884-1.106; P = .84).
Interpretation
Persistent smoking after surgery for stage I NSCLC is common and is associated with inferior overall survival. Providers should continue to assess smoking habits in the postoperative period given its disproportionate impact on long-term outcomes after potentially curative treatment for early-stage lung cancer.

Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chest: 01 Jun 2022; 161:1687-1696
Heiden BT, Eaton DB, Chang SH, Yan Y, ... Kozower BD, Puri V
Chest: 01 Jun 2022; 161:1687-1696 | PMID: 34919892
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Abstract

Epidemiological and clinical boundaries of heart failure with preserved ejection fraction.

Gentile F, Ghionzoli N, Borrelli C, Vergaro G, ... Passino C, Giannoni A
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is associated with relevant morbidity and mortality. However, an evidence-based treatment is still absent. The heterogeneous definitions, differences in aetiology/pathophysiology, and diagnostic challenges of HFpEF made it difficult to define its epidemiological landmarks so far. Several large registries and observational studies have recently disclosed an increasing incidence/prevalence, as well as its prognostic significance. An accurate definition of HFpEF epidemiological boundaries and phenotypes is mandatory to develop novel effective and rational therapeutic approaches.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur J Prev Cardiol: 27 May 2022; 29:1233-1243
Gentile F, Ghionzoli N, Borrelli C, Vergaro G, ... Passino C, Giannoni A
Eur J Prev Cardiol: 27 May 2022; 29:1233-1243 | PMID: 33963839
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This program is still in alpha version.