Your Cheating Heart
OnAtrial fibrillation (AF), like a bad moon, is on the rise. Nutritional standards have fallen so low that within a single generation the age-adjusted prevalence of AF has quadrupled (1), a worrying trend that appears to be continuing (2-4). Even more concerning, the disease itself may be becoming more malignant.
Students of medical history and ethnobotany will know something about the Cinchona or fever tree, which provides the closely related alkaloids quinine and quinidine. Their pharmacological properties overlap; quinine is the more effective anti-malarial and quinidine is the more effective anti-arrhythmic.
Quinidine fell out of favour in the mid-60’s (5) and was largely replaced by synthetic analogues which are more effective and somewhat safer (although see 6). Its main use today is to treat and prevent electrical storms in patients with Brugada syndrome (7), a rare genetic condition which carries a high risk of fatal ventricular arrhythmias and the name of the three cardiologist brothers who characterized it.
My old anatomy professor was not entirely thrilled by the burgeoning pharmaceutical industry, and often talked about medicine past. A proponent of quinidine, he had served in WW2 and told us of veterans from the Great War he knew who took the natural compound to treat intermittent atrial fibrillation, and had done so for decades. The implication was that their arrythmias were stable over time.
Fast forward fifty years and the picture is rather different. AF is now seen as an inherently and often rapidly progressive condition, with between 9 and 30% of patients moving from paroxysmal (intermittent) to persistent and finally permanent fibrillation within a year of diagnosis (8); requiring increasing doses of anti-arrhythmic drugs and moving on, where indicated, to cardiac ablation (9, 10).
Given the rapidly increasing numbers of cases and the apparent worsening in disease profile, discovering the risk factors which promote AF and its progression has become a priority in cardiovascular research. If this search is successful, it should help to provide strategies for better patient management.
Hypertension, obesity, diabetes and age are all risk factors for developing AF. The first three are increasing due to the modern diet and lifestyle, and this helps to explain the increasing incidence of fibrillation.
Reducing them would result in fewer cases of AF. But there is more.
The comorbidities most likely to signal progression include hypertension, obesity and diabetes (as before), but also coronary artery disease, sleep apnea and age (10-14). While there are many confounding variables (ie diet, smoking, physical activity, psychological factors), the above mix signals that chronic inflammatory stress is involved in the pathoaetiology and progression of AF (ie 15, 16).
Other inflammatory conditions can also trigger fibrillation.
These range from local inflammation caused by myocarditis (17) to systemic diseases such as sepsis (18), pneumonia (19), and autoimmune conditions (20-22); with higher inflammatory biomarkers in blood predicting a higher risk of developing or progressing AF (23-26). Inflammatory changes can be seen in the atria themselves (ie 27).
To summarise, atrial fibrillation is increasingly being seen as an inflammatory condition, with inflammation a key factor driving its progression (27, 28).
This explains why the commonly used anti-arrhythmic drugs, while they improve the acute symptoms of AF, have relatively little effect on slowing progression (29) or on overall mortality (10, 30, 31). They treat symptoms but are not dealing with the underlying pathology. The anticoagulants, in contrast, are highly protective (32) because they correctly target intra-atrial thrombus formation.
Let us progress to a very basic overview of the pathophysiology of AF progression.
There is evidence that recurrent AF episodes promote the inducibility and stability of AF (ie progression) via an interaction between electrical and structural re-modelling (33, 34); with subsequent changes in the ongoing conversations between myocytes, fibroblasts and endothelial cells (35).
Chronic inflammation is a central part of this process. Chronic inflammation in the atria (and in any other tissue) degrades the extracellular matrix, a 3-D mesh of microfibers which acts as a soft skeleton for the myocytes and is involved in extra-cellular channeling of electrical and physical signals.
The inflammatory process drives fibrosis in the heart, involving fibroblast proliferation and the subsequent deposition of amyloid and improperly orientated bundles of microfibers (36-39). As these deposits grow they impede normal electrical flow and facilitate re-entry (36-39) in a process which resembles kindling. Activation of the inflammasome in immune cells infiltrating the myocardium is integral to this process (39), and therefore to atrial fibrillation (40, 41).
If this model is even partly accurate, anti-inflammatory drugs should provide some degree of protection – but the data are not very encouraging.
The nonsteroidal anti-inflammatory drugs are associated with a slightly increased risk of developing AF (42). This relationship is probably not directly causative. It is thought to be a sequel to these drug’s more familiar adverse effects, which include raising the risk of heart attacks. Prednisone and colchicine have anti-inflammatory and anti-arrhythmic effects (43-45), but are too toxic for long-term use.
Are the anti-inflammatory nutrients any better?
Key anti-inflammatory nutrients include the omega 3 HUFA’s and the polyphenols. The omega 3’s (46-48) and many polyphenols (49-55) including the amphiphilic polyphenols in marine algae (53) and olives (54, 55), down-regulate the inflammasome very effectively.
Intakes of these important anti-inflammatory compounds have steadily declined since the late 19th century (56), due to our increasing reliance on ultra-processed foods (57). This has left us more vulnerable to chronic inflammation and all of its manifestations; and it is logical to suppose that this has contributed to the increasing incidence of atrial fibrillation, and an increasing tendency to progression.
Might replacing the omega 3’s and the polyphenols in our diet be protective?
The omega 3’s stabilise cardiomyocyte membranes and offer protection against ventricular arrhythmias (58, 59), but their effect on A-fib is unclear. Omega 3 HUFA’s in commercial fish oil supplements have either no effect at all (60) or a tendency to increase AF in individuals with cardiovascular disease (61), depending on which paper you prefer.
As the inflammasome / inflammatory stress is profoundly involved in the development and progression of AF, and the omega 3’s are one of the key nutrient groups which have the ability to down-grade the inflammasome, these results appear paradoxical. But there is another way of looking at this.
Given that commercial and pharmaceutical fish oils do NOT confer the documented benefits of oily fish or omega 3’s combined with amphiphile polyphenols (ie 62-68), I suspect that the null / negative results reflect the fish oil industry’s decision to replace the phlorotannin chaperones originally contained in fish oil with the inappropriate antioxidant, d-alpha-tocopherol.
This formulation error leaves ingested omega 3’s prone to oxidation in the body, manifested as lower secondary bioavailability (69) and implying increased formation of lipid peroxidation products – some of which appear to be profibrillatory (70-72).
The polyphenols have anti-arrhythmic properties of their own (ie 73) which may extend to the alleviation of atrial fibrillation (74). Extra virgin olive oil, a rich source of amphiphile polyphenols, was found in the PREDIMED trial to reduce the risk of AF developing (75) and PREDIMAR, a follow-up study designed to look at the effects of olive oil on AF progression (76), will be reporting in late 2023.
I will continue to take Balance oil, which combines fish oil and extra-virgin olive oil, to manage my own AF. Originally triggered by Grave’s Disease and documented by the good doctors at Epsom Hospital in the UK, my AF has not progressed in 13 years.
It is controlled by the same low dose of flecainide (50 mg b.i.d.) that was originally prescribed.
This is not the whole story. Chronic and/or severe psychological stress is pro-inflammatory (77), and extreme stress, which re-wires circuitry in the hippocampus, parahippocampus and limbic system, is known to trigger Takotsuba syndrome (78, 79) which can cause AF directly. Psychological stress also increases the secretion of aldosterone (80), another factor implicated in AF (81).
Declining intakes of anxiolytic phytonutrients make us more vulnerable to stress (82, 83), and even to the memory of stress (84). Is loss of resilience, caused by the ultra-processed diet, contributing to the increase in AF? Here is another potential problem to lay at the doors of the food industry, and another avenue worth exploring.
A hat tip to the surgeons who developed maze and then closed chest maze surgery. This beautiful and very often curative technique has transformed many lives, and is still developing. And finally, my heartfelt gratitude for the healing power of music (85).
Next week: Only the Lonely. Hearts, minds and gut feelings.
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- https://www.youtube.com/watch?v=cIiTdsvCjYo