Heartburn: the inflammation fibrillation conversation

I wrote previously about how atrial fibrillation (AF) can be avoided or stabilised (1, 2), but I skated over a key part of the story. I will try to rectify that in this post.

It’s important because the numbers of individuals with atrial fibrillation are projected to double or even triple by the year 2050 (3). It’s important because AF is progressive, and worsens over time (4). It’s important because the disease increases the risk of stroke and heart failure, and therefore mortality (5). And it’s important to me, at least, because I have lived with this condition for nearly two decades.

We know why the pandemic is spreading (1, 2). Chronic inflammation is a trigger for developing AF (1, 2, 6), and many of the common causes of inflammatory stress (including diabetes, obesity, chronic kidney disease, surgery and ageing) are increasing (1, 2).

But why is the condition progressive?

The Classic Model

Rapid and irregular heart rate damages the atrial tissue in a process termed remodeling. This involves structural and electrical changes that make the arrythmia worse. Structural remodeling describes physical changes in the extracellular matrix, including the deposition of fibrous tissue – basically the formation of micro-scars – which lead to atrial distortion and enlargement (7). Electrical remodeling involves structural and electrophysiological changes in the myocytes (8) analogous to kindling (9-11), and re-routing of conduction pathways as a result of the localized fibroses (12).

This model doesn’t really explain why micro-scarring occurs, how it can be prevented and why the affected myocytes become conduits for new re-entry currents. For that, we have to return to the insidious process of chronic inflammation.

The Inflammatory Model

All cells have electrical capacity and function, but nerve cells are uniquely and specifically designed to permit the repetitive transfer of electrical impulses. They have more active ion transport pumps, and wrap themselves in protective insulation (myelin) so that their electrical activity is contained, directed and non-destructive. In the absence of neuroinflammatory stress (see below), they remain unharmed by the micro-currents they transmit unless these are excessive, as in status epilepticus (13).

When micro-currents are transmitted through non-neuronal (and non-protected) tissues, those tissues are more likely to be damaged because they are not designed, protected and insulated as neurons are. The repeated passage of micro-currents through skeletal muscle, for example, causes chronic inflammation and eventually rhabdomyolysis, with subsequent fibrosis (14).

There is an analogous situation in the heart.

Myocytes in the cardiac conduction system are adapted to survive and propagate repeated electrical impulses; they have high resistance to ionic overload and relatively few myofibrils, so are not very contractile.

Standard-issue myocardial myocytes are more vulnerable. Exposure to high-frequency micro-currents now causes cellular calcium overload and excessive ROS formation, leading to fibrosis (micro-scarring) and culminating, if unchecked, in myolysis and apoptosis. This, together with excessive mechanical stretch and fibroblast activation, triggers local chronic inflammation; affected atria show infiltrations of inflammatory cells and up-regulated inflammatory cytokines (15, 16).

The process of chronic inflammation affects the electrical properties of surviving cells through which misdirected current is passing, making them more excitable (16). More specifically, the process of chronic inflammation alters membrane chemistry, disrupts ion channels and shifts the resting membrane potential, making it easier for affected cells to initiate an action potential. (Much of this research was done in neurons (17-21), but myocytes show similar programming (22-24) and it is likely to be a general response.)

Chronic inflammation probably also damages the original electrical pathways. The cardiac conduction system is routed and insulated by a fibrous sleeve, consisting of specialized ECM. ECM is eroded by chronic inflammation (25), and a chronic inflammatory milieu could theoretically increase the likelihood of currents leaking out of the conduction system and entering the atrial myocardium at random.

However, this would be only a part of it. In the fibrillating heart multiple micro-currents are firing simultaneously from different sites, often in the pulmonary veins, creating electrical and contractile chaos – and forming a vicious cycle.

Chronic inflammation drives ECM decay, leakage, micro-scarring and abnormal electrical routing. Affected myocytes become more excitable and some die, leading to the wider propagation of abnormal micro-currents, further focal inflammatory stress and further recruitment of myocytes with excessive excitability. This leads to more diffuse inflammation, more extensive fibrosis, more widespread electrical activity, further cell death and atrial distortion (enlargement). The process, if untreated, culminates in permanent atrial fibrillation.

Atrial fibrillation begets atrial fibrillation.

There is further evidence for the pivotal role of chronic inflammation in driving AF (15, 26) and subsequently heart failure (27). For example, AF patients tend to have raised inflammatory adipokines in peri- and epicardial fat (28), and in people with raised inflammatory markers in blood, the risk of developing AF is subsequently raised (29).

These inflammatory components have become targets for new AF drug development (30).

Watch this space … but while you’re waiting, consider a less inflammatory lifestyle. There is pervasive evidence that simple changes will greatly reduce your risk.

The incidence of AF is almost ten times higher in the USA than in Asia (31), and as this is not due to genetic factors (32), diet and lifestyle must make up the difference. Key factors have been identified. Smoking (33), booze (34), Red Bull (35), sleep apnoea (36) and hypertension (37) increase the risk of developing AF in the first place; as does the Western diet (38, 39), which is pro-inflammatory and promotes all of the above.

POP-AF is a prospective, randomized, controlled trial involving patients referred for their first AF ablation. It found that an integrated and broadly anti-inflammatory lifestyle modification program (inc. weight loss, smoking cessation, treating sleep apnea and hypertension), cut repeat ablations and direct current cardioversions by half in the first year after ablation (40).

In addition, change your diet. The Mediterranean diet, for example, appears to reduce the risk of acquiring AF (38, 39). The PREDIMAR study found that the Mediterranean diet also reduced the risk of AF recurrence, after ablation, by roughly one third (41). Ablation aside, once AF has started, the most effective way of reducing the risk of progression is weight loss plus moderate exercise (42), and to this I would add anti-inflammatory pharmaconutrition.

The risk factors are broadly pro-inflammatory, the risk reduction factors broadly anti-inflammatory. This is why I treated my own AF with flecainide, combined with the anti-inflammatory health protocol.

Anti-arrhythmic drugs such as flecainide typically lose their effectiveness over time as the substrate of the heart declines, which it must do if the patient maintains a pro-inflammatory diet and therefore internal environment. Doses can be increased as needed but by 3 years, about a third of AF patients have run out of control (43-44). By ten years, up to 2/3 are lost.

After 17 years of intermittently fibrillating I remain at the entry-level dose of 100 flecainide mg/day. I believe that my anti-inflammatory regimen has made this possible, and that I am accordingly protected against heart failure and, to an extent, stroke (4, 27, 28).

Flecainide (sold as Tambocor) gained a bad reputation when it was first launched. It was expected to save lives by preventing ventricular fibrillation in post-infarct patients, but instead increased the risk of death 4-fold (45). It subsequently emerged that atheromatous disease is a substantial contraindication; in the uncompromised heart, Tambocor is far less likely to precipitate ventricular arrhythmia or heart failure (46).

This forms an even more powerful rationale for anti-inflammatory pharmaco-nutrition. The anti-inflammatory program embedded in the health protocol will not only interrupt the otherwise nearly inevitable progression of atrial fibrillation, but also reduce and perhaps even remove the atheroma risk factor. This, I believe, is good medicine.

References:

• 1. https://drpaulclayton.eu/blog/your-cheating-heart/
  2. https://drpaulclayton.eu/blog/1376/
  3. Kannel WB, Benjamin EJ. Status of the epidemiology of atrial fibrillation. Med Clin North Am. 2008 Jan;92(1):17-40, ix.
  4. Shah AJ, Hocini M, Komatsu Y, Daly M, Zellerhoff S, Jesel L, Amaroui S, Ramoul K, Denis A, Derval N, Sacher F, Jais P, Haissaguerre M. The Progressive Nature of Atrial Fibrillation: A Rationale for Early Restoration and Maintenance of Sinus Rhythm. J Atr Fibrillation. 2013 Aug 31;6(2):849.
  5. Sankaranarayanan R, Kirkwood G, Visweswariah R, Fox DJ. How does Chronic Atrial Fibrillation Influence Mortality in the Modern Treatment Era? Curr Cardiol Rev. 2015;11(3):190-8.
  6. Nso N, Bookani KR, Metzl M, Radparvar F. Role of inflammation in atrial fibrillation: A comprehensive review of current knowledge. J Arrhythm. 2020 Dec 23;37(1):1-10.
  7. Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, Weyman AE. Atrial enlargement as a consequence of atrial fibrillation. A prospective echocardiographic study. Circulation. 1990 Sep;82(3):792-7. 
  8. Veenhuyzen GD, Simpson CS, Abdollah H. Atrial fibrillation. CMAJ. 2004 Sep 28;171(7):755-60.
  9. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation. 1996;94(11):2968–74.
  10. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91(1):265–325.
  11. Shan J, Xie W, Betzenhauser M, Reiken S, Chen B‐X, Wronska A, et al. Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2012;111(6):708–17.
  12. Jalife J, Kaur K. Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc Med. 2015 Aug;25(6):475-84.
  13. Dingledine R, Varvel NH, Dudek FE. When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv Exp Med Biol. 2014;813:109-22.
  14. Song Y, Forsgren S, Yu J, Lorentzon R, Stål PS. Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise. PLoS One. 2012;7(12):e52230.
  15. Wu L, Emmens RW, van Wezenbeek J, Stooker W, Allaart CP, Vonk ABA, van Rossum AC, Niessen HWM, Krijnen PAJ. Atrial inflammation in different atrial fibrillation subtypes and its relation with clinical risk factors. Clin Res Cardiol. 2020 Oct;109(10):1271-1281.
  16. Obeagu EI. Inflammatory cytokines and cardiac arrhythmias: from pathogenesis to potential therapies. Ann Med Surg (Lond). 2025 Jun 16;87(9):5607-5613.
  17. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocrinol. 2012 Jan;33(1):116-25.
  18. https://www.preprints.org/manuscript/202503.2070
  19. Lamotte RH, Zhang J-M, Petersen M. Alterations in the functional properties of dorsal root ganglion cells with unmyelinated axons after a chronic nerve constriction in the rat. Prog Brain Res. 1996;10:105–111.
  20. Cesare P, McNaughton P. Peripheral pain mechanisms. Curr Opin Neurobiol. 1997;7:493–499.
  21. Farr M, Mathews J, Zhu DF, Ambron RT. Inflammation causes a long-term hyperexcitability in the nociceptive sensory neurons of Aplysia. Learn Mem. 1999 May-Jun;6(3):331-40.
  22. Francis Stuart SD, De Jesus NM, Lindsey ML, Ripplinger CM. The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. J Mol Cell Cardiol. 2016 Feb;91:114-22.
  23. Hu YF, Chen YJ, Lin YJ, Chen SA. Inflammation and the pathogenesis of atrial fibrillation. Nat. Rev. Cardiol. (2105) 12 (4), 230–243.
  24. Zhou X, Dudley SC Jr. Evidence for Inflammation as a Driver of Atrial Fibrillation. Front Cardiovasc Med. 2020 Apr 29;7:62. 
  25. Marangio A, Biccari A, D’Angelo E, Sensi F, Spolverato G, Pucciarelli S, Agostini M. The Study of the Extracellular Matrix in Chronic Inflammation: A Way to Prevent Cancer Initiation? Cancers (Basel). 2022 Nov 29;14(23):5903.
  26. Korantzopoulos P, Letsas KP, Tse G, Fragakis N, Goudis CA, Liu T. Inflammation and atrial fibrillation: A comprehensive review. J Arrhythm. 2018 Jun 4;34(4):394-401
  27. Li L, Su S, Wu L, Hu Z, Liu L, Zhou L, Peng X, Xu M, Zhang T, Xiong Y, Zhang Z, Zheng L, Ding L, Yao Y. Inflammation and heart failure risk in atrial fibrillation: Prospective evidence from UK Biobank. Heart Rhythm. 2025 Nov 13:S1547-5271(25)03065-6.
  28. Maan A, Mansour M, Ruskin JN, Heist EK. Role of Epicardial Fat in Atrial Fibrillation Pathophysiology and Clinical Implications. J Innov. Cardiac Rhythm Mngmnt (2013), DOI: 10.19102/icrm.2013.04010
  29. Luo Y, Yang L, Cheng X, Bai Y, Xiao Z. The association between blood count based inflammatory markers and the risk of atrial fibrillation heart failure and cardiovascular mortality. Sci Rep. 2025 Mar 24;15(1):10056. 
  30. Ndakotsu A, Mamoh UN, Dwumah-Agyen M, Alkhatib AM, Kiyani M, Nwaezeapu KI, Mansour MA, Asuka E. Autonomic Nervous System and Atrial Fibrillation: Mechanistic Insights and Therapeutic Targets.
  31. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH Jr, Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014 Feb 25;129(8):837-47. 
  32. Dewland TA, Olgin JE, Vittinghoff E, Marcus GM. Incident atrial fibrillation among Asians, Hispanics, blacks, and whites. Circulation. 2013 Dec 3;128(23):2470-7.
  33. Heeringa J, Kors JA, Hofman A, van Rooij FJA, Witteman JCM. Cigarette smoking and risk of atrial fibrillation: the Rotterdam study. Am Heart J. 2008;156:1163–1169.
  34. Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. Am Coll Cardiol. 2014 Jul 22;64(3):281-9.
  35. Di Rocco JR, During A, Morelli PJ, Heyden M, Biancaniello TA. Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports. J Med Case Rep. 2011;5:18.
  36. Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, Sahadevan J, Redline S; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med. 2006 Apr 15;173(8):910-6. 
  37. Staerk L, Wang B, Preis SR, Larson MG, Lubitz SA, Ellinor PT, McManus DD, Ko D, Weng LC, Lunetta KL, Frost L, Benjamin EJ, Trinquart L. Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study. BMJ. 2018 Apr 26;361:k1453.
  38. Geisler BP. Cardiovascular Benefits of the Mediterranean Diet Are Driven by Stroke Reduction and Possibly by Decreased Atrial Fibrillation Incidence. Am J Med. 2016 Jan;129(1):e11. 
  39. Martínez-González MÁ, Toledo E, Arós F, Fiol M, Corella D, Salas-Salvadó J, Ros E, Covas MI, Fernández-Crehuet J, Lapetra J, Muñoz MA, Fitó M, Serra-Majem L, Pintó X, Lamuela-Raventós RM, Sorlí JV, Babio N, Buil-Cosiales P, Ruiz-Gutierrez V, Estruch R, Alonso A; PREDIMED Investigators. Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED (Prevención con Dieta Mediterránea) trial. Circulation. 2014 Jul 1;130(1):18-26.
  40. Vermeer J, Vinck-de Greef T, van den Broek M, de Louw B, van Steenbergen G, van Veghel D, Dekker L. Improving outcomes of atrial fibrillation ablation by integrated personalized lifestyle interventions: a randomized controlled trial. Eur Heart J. 2026 Feb 11;47(6):669-679.
  41. Barrio-Lopez MT, Martinez-Gonzalez MA, Almendral J, Ardanaz PR, Tercedor L, Ibanez Criado JL, Goni CL, de la O V, Garcia-Bolao I, Macias R, Ibanez-Criado A, Ruiz-Canela M. Mediterranean Diet Enriched With Extra-Virgin Olive Oil Reduced Risk Of Tachyarrhythmia Recurrence After Atrial Fibrillation Ablation: The PREDIMAR Trial. Heart Rhythm 21(7), p1202July 2024
  42. Pathak RK, Middeldorp ME, Meredith M, Mehta AB, Mahajan R, Wong CX, Twomey D, Elliott AD, Kalman JM, Abhayaratna WP, Lau DH, Sanders P. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol. 2015 May 26;65(20):2159-69. 
  43. Siotis A, Johansson S, Graff C, Madsen Hardig B, Platonov PG. Long-term adherence to flecainide as a rhythm control therapy in recurrent atrial fibrillation – a retrospective cohort study. Scand Cardiovasc J. 2025 Dec;59(1):2525110. 
  44. Valembois L, Audureau E, Takeda A, Jarzebowski W, Belmin J, Lafuente-Lafuente C. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev. 2019 Sep 4;9(9):CD005049.
  45. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8. 
  46. Villatore A, Murray B, Tichnell C, Te Riele ASJM, Loh P, Compagnucci P, Casella M, Martini M, Schiavone M, Tondo C, Cappelletto C, Sinagra G, Merlo M, Jankelson L, Delmar M, Targetti M, Pieroni M, Olivotto I, Calò L, Graziosi M, Biagini E, Tandri H, Bauce B, James C, Cerrone M, Calkins H, Gandjbakhch E, Gasperetti A. Long-Term Follow-Up Data on Flecainide Use as an Antiarrhythmic in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multicenter Study. JACC Clin Electrophysiol. 2025 Jun;11(6):1159-1170.