The Unbroken Heart

Hi, my name is Paul and I’ve had a drug habit for 15 years.

It started with personal trauma, which triggered Graves’ Disease, which led to persistent atrial fibrillation (AF). I was in fib, on anticoagulants and walking around with snakes writhing in my chest for 5 months prior to being scanned, electro-converted and put onto flecainide. Thanks, NHS.

50 mg flecainide b.i.d. has kept my heart beating more or less regularly since 2007 (1). It’s been good for me. I never experienced adverse effects, nor would I expect to at such a low dose.

I admit that I didn’t take it sufficiently seriously at first. I missed doses, which meant marching off to warfarin and weekly blood tests. In the first year I had to be cardioverted twice – I don’t remember the details as I was under general anesthesia.

After that I generally took the tablets but I was travelling widely for work and couldn’t always get my drug of choice. Other anti-arrhythmic drugs didn’t work for me. I ran out of flecainide twice and lost my stash once, probably at an airport.

A missed dose meant breakthrough fib within 12 hours or so, which I could chemo-convert at 350 mg. If there were no pills in my pocket, after about a week my unruly heart would throw a clot. Once into the lungs, which made me cough until I vomited. Once into my left ankle, which left bruising halfway up my calf and made walking so very difficult. Poor oxygenation feels like extreme muscle fatigue. I forced myself to limp for miles to encourage new collaterals, and made a full recovery.

If one of those clots had entered a coronary or cerebral artery I might not be here, but during that period in my life I didn’t much care whether I lived or died.

Time passed and the world changed. I knew, however, that the characteristic inflammatory changes in the myocardium which inevitably make atrial fibrillation worse and eventually lead to drug failure, and late-stage complications such as heart failure and stroke (2), had not happened.

I was still on the dose of flecainide I started with because, I surmised, the anti-inflammatory regime I was experimenting with had prevented progressive atrial myocardial fibrosis and the related development of re-entry circuits. The original myocardial sin, however, was surely still there. Whatever future still existed would be dispensed in 50 mg b.i.d., at best.

A few weeks ago, with work piling up in snow drifts on my desk, I forgot the evening dose. Next morning’s too. By the time I remembered what I had forgotten, my meds were 200 miles away. I expected to start fibrillating at any moment but remained in sinus rhythm until after midnight, when I got back to the office. I took the 50 mg emergency half-tab from the Ray-Ban case in the top desk drawer and fell asleep.

The next morning I woke late, but still in time. I began to wonder if the heart could heal itself.

It is well known that a form of short-term healing is possible. Flecainide loses much of its ability to cardiovert when atrial fibrillation has been present for more than 24 hours, probably due to atrial electrical remodeling involving changes in the spatial distribution and function of ion channels.

This kind of remodeling can be thought of as kindling, or ‘learning’, and it can be ‘forgotten’. It is generally reversible after restoration of at least 4 days of sustained sinus rhythm (3). After 4 days of restored electrical normality the ion channels have presumably reverted to their previous configuration and flecainide is once again effective.

This phase of recovery, however, is temporary. Flecainide and other anti-arrhythmics eventually lose their effectiveness, over a period of months or a few years at most, in a secondary and irreversible phase (4-7). The longer-term remodeling that leads to eventual drug failure in the vast majority of fib patients is no longer just electrical, but also structural (4-7).

Micro-structural disorganization develops over time, involving chronic inflammatory and other destructive components (1, 8, 9), to the point where the routes through which aberrant electrical impulses are now traveling are too well-established, and perhaps too many to respond to safe doses of the antiarrhythmics.

Now you must progress to anti-coagulants / anti-platelet drugs, and/or ablation. For the well-heeled and adventurous there is 5-box mini-maze surgery. This complex procedure has lower recurrence rates than ablation but it may cause phrenic nerve damage and pericarditis, which can lead to secondary, life-changing problems.

Wouldn’t it be better if the heart could be helped to repair itself?

I have maintained an anti-inflammatory milieu since I first developed Graves’. Within the first year, my immune system forgot its target, and I have remained euthyroid to this day. During that time my myocardium has also presumably been prevented from developing inflammation-mediated structural degenerative changes, and for almost all of that time, flecainide has chained my heart in sinus rhythm.

What does that mean for the structural elements involved in AF? They are locally altered regions of the extra-cellular matrix (ECM), consisting primarily of misaligned and increasingly fibrotic bundles which participate in the electrical mis-direction and loss of myocardial coordination (10-13).

The ECM is a dynamic tissue that is highly responsive to changes in tension and load, and to various hormones including thyroxine (14). Graves’ disease is a common trigger for AF (15), and there is good evidence that initial changes in ECM (driven inter alia by thyroxine) predispose to the electrical and subsequently the electro-mechanical substrate of AF (16)

Once misaligned bundles of micro-fibers have formed and electrical mis-routing and fibrillation have become established, kindling and chronic inflammatory and other stresses (ie 1, 16-18) drive the system towards progression.

But perhaps this does not have to be a one-way process.

The proteins which make up the bundles do turn over, albeit very slowly; and if the internal milieu is no longer conducive to chronic inflammation, carbonylation, carbamylation, glycation and ECM damage in general, drug-enforced sinus rhythm and subsequently re-normalised patterns of atrial micro-currents and contraction will tend to remodel atrial ECM into a more functional and less chaotic configuration.

Such a milieu will also reduce arterial stiffness (19, 20), so it’s worth following a dietary and/or supplemental regime that supports it.

Having now been drug- and symptom-free for a few weeks, I am beginning to hope that the structural changes that occurred before I settled in with my drug habit have finally been overwritten, and that the micro-architecture of my heart has reverted to something like its original configuration.

A process like this occurs early in life, when the heart is forming as an organ. Electrical and structural changes occur in a synchronized manner, culminating in the form and function of the normally beating heart at around 22 days after conception.

Cardiac fibroblasts, cardiomyocytes, smooth muscle cells, endothelial cells and a range of embedded immune cells recognize each other, develop the extra-cellular matrix and/or function within it, talk to each other, work together and finally dance together, while building and maintaining the heart’s micro- and macro-structure until the last waltz plays out to its very last beat.

In this dynamic environment the interactions between different cell types and the nature of the ECM within which they are positioned are extensive, up to and including the re-programming of fully differentiated cells by the ECM when appropriate (21).

Various populations of cells in the myocardium clearly retain the potential to adapt to adult life (21), but in all likelihood this can only be positively manifested if the internal environment, including the local ECM, is providing the right chemical, electrical and mechano-transductive signals. Like all tissues the atrium – fibrillating or not – is essentially fibrillar (21\2).

To sum up, we experience atrial fibrillation as inherently progressive. However, the conventional development of this condition may be more artefactual than we realize, and one that is shaped by the currently degraded and pro-inflammatory exposome. It seems that AF does not need to progress; in former times it did not do so (1), and in my own case it did not do so. After 15 years of enforced stability, it appears to have regressed.

We cannot ignore the economic aspects. The current road map, which generally leads in short order from anti-arrhythmics via anti-coagulants to expensive surgery, is unsustainable in a dietary environment that has, in the last 2 decades, raised the lifetime risk of atrial fibrillation from one in four to one in three (23).

I don’t know yet whether I am cured or in recovery. Fibrillation might return at any moment. With each passing day, however, I feel a little more open to the possibility that positive atrial remodeling may have occurred; and that there might be a road map to helping the heart to heal.

Postscript, day 71. Due to occasional ectopic beats and one brief episode of fibrillation I have decided to revert, for the moment, to 50 mg flecainide / b.i.d. The underlying condition appears to have improved. The investigation, and la luta, continues.

Next week: Perhaps scattered white horses.

References

1. https://whitesmoke-heron-286383.hostingersite.com/blog/your-cheating-heart/
2. Vinter N, Cordsen P, Johnsen SP, Staerk L, Benjamin EJ, Frost L, Trinquart L. Temporal trends in lifetime risks of atrial fibrillation and its complications between 2000 and 2022: Danish, nationwide, population based cohort study. BMJ. 2024 Apr 17;385:e077209.
3. Tieleman RG, Van Gelder IC, Bosker HA, Kingma T, Wilde AA, Kirchhof CJ, Bennekers JH, Bracke FA, Veeger NJ, Haaksma J, Allessie MA, Crijns HJ. Does flecainide regain its antiarrhythmic activity after electrical cardioversion of persistent atrial fibrillation? Heart Rhythm. 2005 Mar;2(3):223-30. 
4. Kerr CR, Humphries KH, Talajic M, Klein GJ, Connolly SJ, Green M, Boone J, Sheldon R, Dorian P, Newman D. Progression to chronic atrial fibrillation after the initial diagnosis of paroxysmal atrial fibrillation: results from the Canadian Registry of Atrial Fibrillation. Am Heart J. 2005 Mar;149(3):489-96.
5. De Vos CB, Breithardt G, Camm AJ, Dorian P, Kowey PR, Le Heuzey JY, Naditch-Brûlé L, Prystowsky EN, Schwartz PJ, Torp-Pedersen C, Weintraub WS, Crijns HJ. Progression of atrial fibrillation in the REgistry on Cardiac rhythm disORDers assessing the control of Atrial Fibrillation cohort: clinical correlates and the effect of rhythm-control therapy. Am Heart J. 2012 May;163(5):887-93.
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10. Rog-Zielinska EA, Norris RA, Kohl P and Markwald R. The living scar-cardiac fibroblasts and the injured heart. Trends Mol Med. 22:99–114. 2016.
11. Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest. 127:1600–1612. 2017.
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13. Smorodinova N, Bláha M, Melenovský V, Rozsívalová K, Přidal J, Ďurišová M, Pirk J, Kautzner J, Kučera T. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLoS One. 2017 Feb 22;12(2):e0172691.
14. Trentin AG, De Aguiar CB, Garcez RC, Alvarez-Silva M. Thyroid hormone modulates the extracellular matrix organization and expression in cerebellar astrocyte: effects on astrocyte adhesion. Glia. 2003 Jun;42(4):359-69.
15. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421. 
16. van den Berg NWE, Neefs J, Kawasaki M, Nariswari FA, Wesselink R, Fabrizi B, Jongejan A, Klaver MN, Havenaar H, Hulsman EL, Wintgens LIS, Baalman SWE, Meulendijks ER, van Boven WJ, de Jong JSSG, van Putte BP, Driessen AHG, Boersma LVA, de Groot JR; PREDICT-AF Investigators. Extracellular matrix remodeling precedes atrial fibrillation: Results of the PREDICT-AF trial. Heart Rhythm. 2021 Dec;18(12):2115-2125.
17. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995 Oct 1;92(7):1954-68. 
18. Nattel S, Heijman J, Zhou L, Dobrev D. Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective. Circ Res. 2020 Jun 19;127(1):51-72.
19. De Bruyne T, Steenput B, Roth L, De Meyer GRY, Santos CND, Valentová K, Dambrova M, Hermans N. Dietary Polyphenols Targeting Arterial Stiffness: Interplay of Contributing Mechanisms and Gut Microbiome-Related Metabolism. Nutrients. 2019 Mar 8;11(3):578.
20. https://whitesmoke-heron-286383.hostingersite.com/blog/all-about-eva/                (Pending)
21. Ma SKY, Chan ASF, Rubab A, Chan WCW, Chan D. Extracellular Matrix and Cellular Plasticity in Musculoskeletal Development. Front Cell Dev Biol. 2020 Aug 25;8:781.
22. https://whitesmoke-heron-286383.hostingersite.com/blog/matrix-reloaded/
23. Vinter N, Cordsen P, Johnsen SP, Staerk L, Benjamin EJ, Frost L, Trinquart L. Temporal trends in lifetime risks of atrial fibrillation and its complications between 2000 and 2022: Danish, nationwide, population based cohort study. BMJ. 2024 Apr 17;385:e077209.