Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 3, pp 231–233 | Cite as

Targeting atrial fibrillation promoting atrial structural remodeling: is this a viable strategy in patients with heart failure?


Atrial fibrillation (AF) is the most common cardiac arrhythmia in adulthood, affecting millions of people worldwide (Andrade et al. 2014). Heart failure (HF) is also an epidemic cardiovascular disease that similarly exhibits an increase in prevalence. Most important, both AF and HF are disproportionately common in the elderly population. A growing body of epidemiological, clinical, and experimental data has demonstrated an interrelationship between AF and HF (Woods and Olgin 2014; Batul and Gopinathannair 2017). For example, AF is often an adverse prognostic outcome in HF patients, especially in the patients with mild-to-moderate left ventricular dysfunction. Conversely, HF per se increases the risk of AF (Lubitz et al. 2010). The prevalence of AF increases in HF with reduced ejection fraction (HFrEF) patients, from 10% in New York Heart Association (NYHA) class I to 50% in NYHA class IV patients (Batul and Gopinathannair 2017). AF and HF also share common risk factors such as hypertension, obesity, diabetes mellitus, and ischemic heart disease (Lubitz et al. 2010; Batul and Gopinathannair 2017). In addition, several pathological features coexist in both AF and HF, such as structural remodeling, neuro-hormonal imbalance, and increased level of inflammatory cytokines. However, besides being induced by AF itself, atrial fibrosis, a prominent feature of atrial structural remodeling (ASR) underlying AF development (Burstein and Nattel 2008), could be secondary to the enhanced wall stress, increased formation of inflammatory cytokines, and circulating neuro-hormonal factors seen in HF patient (Patel et al. 2017). Enhanced renin-angiotensin-aldosterone system axis in HF patients can promote atrial fibrosis (Batul and Gopinathannair 2017; Khan et al. 2017), which could act synergistically with oxidative stress and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGFβ1) to promote ASR. Overall, the evolution of such very complex changes in atrial structure has made the treatment of AF in HF patients extremely challenging, with many patients being resistant to current AF treatment (Heijman et al. 2013). Although “upstream therapy” aiming to reverse the AF-maintaining substrate including ASR has been pursued for many years (Woods and Olgin 2014), the efficacy of such approaches for secondary prevention is rather low and it remains largely unknown, whether correcting or preventing the ASR-promoting factors is sufficient to prevent AF onset or reduce AF recurrence in HF patients (Nattel and Dobrev 2017).

In the current issue of Naunyn-Schmiedeberg’s Archives of Pharmacology, Qiu and colleagues (Qiu et al. 2017) determined whether a novel compound, DL-3-n-butylphthalide (NBP), can prevent the development of AF in an established rat model of ischemic cardiomyopathy resembling the atrial phenotype of HF patients. The authors evaluated the impact of NBP on ASR in a left-anterior-descending-coronary-artery ligation induced myocardium infarction (MI) rat model. The results revealed that NBP treatment for 4 weeks reduced both the inducibility and the duration of inducible AF episodes in MI-induced HF versus control rats, which was associated with an improvement of ventricular function along with a reduction in both ventricular and atrial dilatation. The alleviated structural remodeling was accompanied with less interstitial fibrosis and normalized localization and expression of the gap junction protein connexin-43, which might further contribute to an improved electrical conduction and could help maintain sinus rhythm.

Since the molecular mechanisms underlying AF pathophysiology are multifactorial (Heijman et al. 2014; Nattel and Dobrev 2016), a potential anti-AF reagent that targets the ASR-promoting mechanisms by a multimodal action is expected to be more effective against AF in patients with structural heart disease (Heijman et al. 2016). Previous work has demonstrated that NBP can prevent stroke and can protect the heart against ischemic-reperfusion injury, by promoting anti-oxidant and anti-inflammatory effects (Wang et al. 2013, 2014, 2016). Consistently, the anti-AF actions of NBP in the present study were associated with profound effects on oxidative stress and inflammatory signaling (Qiu et al. 2017). There is ample evidence for involvement of oxidative stress in the pathophysiology of AF (Jalife 2016). Thus, it is not surprising that reducing oxidative stress via elevating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling and increasing the level of anti-oxidants such as catalase and superoxide dismutase with NBP should exert beneficial cardiac effects (Qiu et al. 2017). NBP could prevent atrial fibrosis or prevent oxidation-mediated posttranslational modifications of ion-channel and calcium-handling proteins. While inflammation and particularly inflammatory cytokines such as TNF-α and TGFβ1 clearly facilitate ASR by promoting atrial fibrosis (Jalife 2016), emerging evidence point also to a critical involvement of inflammatory signaling in the evolution of electrical remodeling which accompanies atrial arrhythmogenesis during AF. Specifically, recent work from our group revealed that the activation of a canonical inflammatory signaling pathway called inflammasome is sufficient to promote both atrial electrical and atrial structural remodeling (Yao et al. 2016). NBP’s ability to directly or indirectly reduce the levels of the inflammatory signaling mediators such as TNF-α, TGFβ1, and nuclear factor-kappa B (Qiu et al. 2017) suggests that anti-inflammatory efficacy could be a key feature for the development of future anti-AF approaches that properly target the AF-maintaining atrial structural substrate.

The work of Qiu et al. (2017) raises many questions. It remains unclear whether the amelioration on AF inducibility by NBP is a primary action in atria or a secondary effect following an improved left ventricular function, which deems further investigation. In addition, the different types of HF, for instance, pressure overload-induced HF versus ischemic HF or HFrEF versus heart failure with preserved ejection fraction (HFpEF) (Patel et al. 2017), are likely to produce different cellular and molecular signatures in atria. Therefore, whether the different types of HF respond similarly to NBP treatment remains to be determined in subsequent studies. Regardless of these limitations, it is very encouraging to establish that a compound can reverse structural remodeling in both atria and ventricles of a HF animal model and ultimately prevent AF development. Thus, such drugs might provide a lead structure for the development of novel anti-AF approaches, which target inflammatory and oxidative signaling pathways that critically contribute to the AF-promoting substrate, particularly in the context of HF.


Funding information

This work was supported by the National Institutes of Health (R01-HL136389 to N.L. and D.D., R01-HL131517 to D.D.), the American Heart Association (14SDG20080008 to N.L.), the German Research Foundation DFG (Do 769/4-1 to D.D.), and DZHK (German Center for Cardiovascular Research, 81X2800108, 81X2800161, and 81X2800136 to D.D.).


  1. Andrade J, Khairy P, Dobrev D, Nattel S (2014) The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 114(9):1453–1468. CrossRefPubMedGoogle Scholar
  2. Batul SA, Gopinathannair R (2017) Atrial fibrillation in heart failure: a therapeutic challenge of our times. Korean Circ J 47(5):644–662. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Burstein B, Nattel S (2008) Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 51(8):802–809. CrossRefPubMedGoogle Scholar
  4. Heijman J, Algalarrondo V, Voigt N, Melka J, Wehrens XH, Dobrev D, Nattel S (2016) The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc Res 109(4):467–479. CrossRefPubMedGoogle Scholar
  5. Heijman J, Voigt N, Abu-Taha IH, Dobrev D (2013) Rhythm control of atrial fibrillation in heart failure. Heart Fail Clin 9(4):407–415, vii–viii. CrossRefPubMedGoogle Scholar
  6. Heijman J, Voigt N, Nattel S, Dobrev D (2014) Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 114(9):1483–1499. CrossRefPubMedGoogle Scholar
  7. Jalife J (2016) Novel upstream approaches to prevent atrial fibrillation perpetuation. Heart Fail Clin 12(2):309–322. CrossRefPubMedGoogle Scholar
  8. Khan MS, Fonarow GC, Khan H, Greene SJ, Anker SD, Gheorghiade M, Butler J (2017) Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis. ESC Heart Fail 4(4):402–408. CrossRefPubMedGoogle Scholar
  9. Lubitz SA, Benjamin EJ, Ellinor PT (2010) Atrial fibrillation in congestive heart failure. Heart Fail Clin 6(2):187–200. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Nattel S, Dobrev D (2016) Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation. Nat Rev Cardiol 13(10):575–590. CrossRefPubMedGoogle Scholar
  11. Nattel S, Dobrev D (2017) Controversies about atrial fibrillation mechanisms: aiming for order in chaos and whether it matters. Circ Res 120(9):1396–1398. CrossRefPubMedGoogle Scholar
  12. Patel RB, Vaduganathan M, Shah SJ, Butler J (2017) Atrial fibrillation in heart failure with preserved ejection fraction: insights into mechanisms and therapeutics. Pharmacol Ther 176:32–39. CrossRefPubMedGoogle Scholar
  13. Qiu H, Wu H, Ma J, Cao H, Huang L, Qiu W, Peng Y, Ding C (2017) DL-3-nbutylphthalide reduces atrial fibrillation susceptibility by inhibiting atrial structural remodeling in rats with heart failure. Naunyn Schmiedeberg's Arch Pharmacol.
  14. Wang F, Ma J, Han F, Guo X, Meng L, Sun Y, Jin C, Duan H, Li H, Peng Y (2016) DL-3-n-butylphthalide delays the onset and progression of diabetic cataract by inhibiting oxidative stress in rat diabetic model. Sci Rep 6(1):19396. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Wang HM, Zhang T, Huang JK, Sun XJ (2013) 3-N-Butylphthalide (NBP) attenuates the amyloid-beta-induced inflammatory responses in cultured astrocytes via the nuclear factor-kappa B signaling pathway. Cell Physiol Biochem 32(1):235–242. CrossRefPubMedGoogle Scholar
  16. Wang YG, Li Y, Wang CY, Ai JW, Dong XY, Huang HY, Feng ZY, Pan YM, Lin Y, Wang BX, Yao LL (2014) L-3-n-Butylphthalide protects rats’ cardiomyocytes from ischaemia/reperfusion-induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol (Oxf) 210(3):524–533. CrossRefGoogle Scholar
  17. Woods CE, Olgin J (2014) Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res 114(9):1532–1546. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Yao C, Scott L, Wehrens X, Dobrev D, Li N (2016) Activation of NLRP3 inflammasome promotes atrial fibrillation. Circulation 134:A14531Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cardiovascular Research InstituteBaylor College of MedicineHoustonUSA
  2. 2.Department of Medicine (Section of Cardiovascular Research)Baylor College of MedicineHoustonUSA
  3. 3.Department of Molecular Physiology & BiophysicsBaylor College of MedicineHoustonUSA
  4. 4.Baylor College of MedicineHoustonUSA
  5. 5.Institute of Pharmacology, West German Heart and Vascular CenterUniversity Duisburg-EssenEssenGermany
  6. 6.Faculty of MedicineUniversity Duisburg-EssenEssenGermany

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