Topic: Journal Club Selection

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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification.

Kumari R, Ranjan P, Suleiman ZG, Goswami SK, ... Prasad R, Verma SK
Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or \'m6A writers\'. The family of proteins that recognize this methylation are termed \'m6A readers\' and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or \'m6A erasers\'. At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischaemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure. RNA methylation in cardiovascular diseases: altered m6A RNA (coding and non-coding RNA) methylation is identified during different cardiovascular diseases. Increased cardiac hypertrophy is observed following METTL3 overexpression. In contrast, reduced FTO level was seen in mice following myocardial infarction. Increased cardiac fibroblasts activation or increased atherosclerotic plaques were also co-related with m6A RNA methylation.

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; 118:1680-1692
Kumari R, Ranjan P, Suleiman ZG, Goswami SK, ... Prasad R, Verma SK
Cardiovasc Res: 22 Jun 2022; 118:1680-1692 | PMID: 33956076
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10.

Bouvard C, Tu L, Rossi M, Desroches-Castan A, ... Guignabert C, Bailly S
Aims
BMP9 and BMP10 mutations were recently identified in patients with pulmonary arterial hypertension, but their specific roles in the pathogenesis of the disease are still unclear. We aimed to study the roles of BMP9 and BMP10 in cardiovascular homeostasis and pulmonary hypertension using transgenic mouse models deficient in Bmp9 and/or Bmp10.
Methods and results
Single- and double-knockout mice for Bmp9 (constitutive) and/or Bmp10 (tamoxifen inducible) were generated. Single-knock-out (KO) mice developed no obvious age-dependent phenotype when compared with their wild-type littermates. However, combined deficiency in Bmp9 and Bmp10 led to vascular defects resulting in a decrease in peripheral vascular resistance and blood pressure and the progressive development of high-output heart failure and pulmonary hemosiderosis. RNAseq analysis of the lungs of the double-KO mice revealed differential expression of genes involved in inflammation and vascular homeostasis. We next challenged these mice to chronic hypoxia. After 3 weeks of hypoxic exposure, Bmp10-cKO mice showed an enlarged heart. However, although genetic deletion of Bmp9 in the single- and double-KO mice attenuated the muscularization of pulmonary arterioles induced by chronic hypoxia, we observed no differences in Bmp10-cKO mice. Consistent with these results, endothelin-1 levels were significantly reduced in Bmp9 deficient mice but not Bmp10-cKO mice. Furthermore, the effects of BMP9 on vasoconstriction were inhibited by bosentan, an endothelin receptor antagonist, in a chick chorioallantoic membrane assay.
Conclusions
Our data show redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions (only combined deletion of both Bmp9 and Bmp10 was associated with severe defects) but highlight specific roles under chronic hypoxic conditions. We obtained evidence that BMP9 contributes to chronic hypoxia-induced pulmonary vascular remodelling, whereas BMP10 plays a role in hypoxia-induced cardiac remodelling in mice.

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

Cardiovasc Res: 22 Jun 2022; 118:1805-1820
Bouvard C, Tu L, Rossi M, Desroches-Castan A, ... Guignabert C, Bailly S
Cardiovasc Res: 22 Jun 2022; 118:1805-1820 | PMID: 34086873
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.