Free Fatty Acids/NEFA and Arrhythmia

From:  Circulating Nonesterified Fatty Acid Level as a Predictive Risk Factor for Sudden Death in the Population

 In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study.
Above is the abstract for the study.  Something that might not be alarming to some.  The association could be due to a co-correlation with insulin resistance, for example.

In the discussion section, the DIRECT effect of NEFA are elaborated:

Sudden death remains a critical problem in industrially developed countries, and treatment of sudden death victims frequently is unsuccessful.1,2 Therefore, early identification of subjects at high risk of sudden death is essential to preventive treatment strategies. Circulating nonesterified fatty acids (NEFA), also called free fatty acids, have been described as responsible for ventricular arrhythmias and sudden death after myocardial infarction.36 However, a possible arrhythmogenic role of NEFA has not been investigated in nonischemic patients. The main source of circulating NEFA is release from adipose tissue. A higher frequency of premature ventricular complexes was found to be associated with increased circulating NEFA concentration in patients with non-insulin-dependent diabetes mellitus.7 A recent study observed an association between high NEFA concentration in offspring and increased risk of cardiovascular disease in their parents.8 Additionally, direct arrhythmogenic action of an experimental high concentration of NEFA was described in nonischemic isolated perfused rat hearts.9

If elevated circulating NEFA concentration has a direct arrhythmogenic effect in asymptomatic subjects, these subjects may be predisposed to sudden death. We used the long follow-up period of the Paris Prospective Study I (>20 years) to assess the role of circulating NEFA concentration as a risk factor for sudden death in middle-aged men without known cardiovascular disease.  

This graphic of the results is interesting.  Notice the almost normal distribution of MI (heart attack) v. NEFA while SCD & NEFA show a pretty stark correlation.

Some more from the Discussion:

Proarrhythmic Mechanisms of Increased Circulating NEFA
Proarrhythmic mechanisms of toxicity of increased NEFA are numerous and complex.17 NEFA have been shown to modulate the ATP-sensitive K+ channel and to activate ATP-insensitive K+ channels in rat heart cells.18 This may contribute to extracellular K+ accumulationand shortening of action-potential duration observed during early ischemia and anoxia. Even in absence of ischemia, a perfusion of high molar ratios of albumin-bound NEFA in isolated rat hearts has been shown to have a direct arrhythmogenic effect that could be mediated by Ca2+ overload in myocardial cells.9,19 Increased intracellular Ca2+ concentration induces uncoupling between cells, which supports occurrence of electrical reentry.

NEFA also may inhibit the Na+,K+ ATPase pump, thereby leading to high intracellular sodium and calcium,20 activating protein kinase and affecting Na+, K+, and Ca2+ currents.21 Arrhythmogenic effects of lysophospholipids, derived from the breakdown of membrane lipids during ischemia, and of acylcarnitine, derived at least in part from circulating NEFA, may be added. Accumulation of acylcarnitine can activate Ca2+ channels directly21 to produce arrhythmias through Ca2+ overload.22

Suspected Hyperadrenergic Tone
Level of circulating NEFA is mediated largely by adrenergic stimulation, which may enhance its arrhythmogenic effect. A rise in plasma catecholamine concentration leads to increased release of NEFA from adipose tissue stores13; in the present study, NEFA were relatively strongly correlated with heart rate and blood pressure. After inclusion of NEFA concentration into the multiadjusted model, heart rate was no longer an independent risk factor for sudden death. However, suspected hyperadrenergic tone is likely to play a direct role in arrhythmogenicity beyond causing a possible proarrhythmic effect of NEFA.

Presented without comment at this time.


Anonymous said…
"This graphic of the results is interesting. Notice the almost normal distribution of MI (heart attack) v. NEFA while SCD & NEFA show a pretty stark correlation."

It's actually even more interesting if you look at it carefully. The top three quintiles show decreasing MI deaths as SCD deaths increase. The total deaths among the top three quintiles from cardiac events are therefore showing little significant change after the 2nd to 3rd quintile jump. That tells you that going from the third to 5th quintile, where the biggest increase in SCD is seen, means you are just exchanging an immediate death from CAD (SCD) for a less quick one in the next day or so (MI) - you are just as dead either way.

To be consistent, shall we recommend elevated NEFA as being protective against MI once we are above the 2nd quintile?

So despite alleged mathematical independence of NEFA as a variable, common sense and review of the data they present both argue that NEFA is not independent, unless you want to say that NEFA are "protective" against MI at the same time they kill you with SCD.

As diabetes severity correlates with elevated NEFA, and severity of diabetes correlates with risk of death from CAD (much more than a mere 70% increase, more like 500%), this study just shows that the worse your diabetes, the more CAD you have, and the more likely that when you pop an unstable plaque you will die instantly of arrythmia instead of making it to the hospital.

And it is quite possible that NEFA levels are just a marker for severity of diabetes, extent of CAD at the event, prior silent infarcts, infarct size, etc, etc...

I assume you understand that lack of known CAD does not mean these people with SCD were not dying of CAD, it only means they had not yet been diagnosed.

But let's for fun stipulate that NEFA elevation is not confounded by diabetes and overall CAD risk (as I just suggested) and let's assume that if one has CAD, they will do well to avoid elevated NEFA, preferring a death from MI in 24 hrs to a death from SCD in 20 minutes.

The NEFA, if they do initiate the arrythmia, are doing it because the myocardium is ischemic - it is abnormal - you are having a heart attack!. If lipotoxicty is to blame it has may have something to do with serum levels of NEFA. But the really big issue is there is no oxygen delivered to the cardiomyocyte! Again lipotoxicity is not passively caused by elevated NEFA in this case, it is in the context of a heart attack. NEFA are associated with a massive surge in epi as the body tries to maintain cardiac output and keep your brain perfused. If epi and NEFA levels were low, you would be having circulatory collapse or watershed infarcts in your brain instead.

So perhaps your fear is that you have undiagnosed CAD, and WHEN you have a heart attack you will die instantly instead of getting an ambulance ride first. Are you avoiding all the other things that might elevate your sympathetic response and are know to put you at risk if you have CAD, like vigorous exercise, or emotional and mental stress?

Your admonition to avoid VLC only makes as much sense as totally avoiding exercise because it "might" trigger an MI in case you have cryptic CAD. Only less, though, as VLC if you have metS or DM is a powerful way to get glucoregulatory control NOW, before your liver and other tissues have recovered from dietary damage.

Does it not make more sense to eat a diet that minimizes your risk of CAD in toto, than worry about what type of cardiac death you will have when it comes?
CarbSane said…
Kurt, do you think it might be possible for you to comment without implying that you're the only one capable of carefully reading something?

VLC may be a way to gain glucoregulatory control now. Great. But doing so seems to be at the expense of liporegulatory control. Persistently elevated NEFA will lead to higher levels in ectopic tissues. This lipid accumulation or the byproducts of it, absent an increase in oxidation has deleterious effects in all sorts of tissues whether you want to acknowledge it or not. We don't have many examples at all of VLC cultures, and we really have none that are relevant to the diets of modern day adherents.

Long term low carbers are hard to come by to look to for outcomes. To me, never being able to eat a normal serving of any carb is evidence of a persisting metabolic dysfunction.

What of the outcomes in Shai?

If I'm diabetic (I'm not thankfully) and I lose some weight and my FBG goes down 30 points and my pancreas functions normally enough to handle the carbs in the common Mediterranean diet I would say that's a pretty good long term outcome.
Melchior Meijer said…
CarbSane, a 'paleo diet' - sans grains, legumes, dairy - performs even better in restoring glucose tolerance and insulin sensitivity, as per Staffan Lindeberg and Lydia Frassetto. Lindeberg's trial was quite low carb, if you ask me. The case against wheat (and fructose and n-6 and, now I'm swearing in the church, dairy) becomes stronger and stronger. The 'mediteranean diet' is a crutch, an overrated, grain laden alternative. Ever visited Greece or Italy? More obesity there than in Holland!

I recently figured out that our traditional Dutch evening meal is actually pretty paleo. Potatoes, vegetables and meat ;-). Unfortunately we are also addicted to bread and bovine tits.
Anonymous said…
"Great. But doing so seems to be at the expense of liporegulatory control."

I understand that it seems that way to you, but you have presented no evidence at all here that the NEFA elevations with VLC are "loss of liporegulatory control." As I and Stephan and Peter have all pointed out, the NEFA elevation and failure to suppress lipolysis are textbook normal physiology and entirely predictable, as is the lack of suppression with a meal that is less than 10% CHO. It is no more pathology than the glucose and insulin spikes with a high carb meal that are absent without carbohydrate feeding. Loss of liporegulation with inappropriate elevation of NEFA is part of diabetes, but it is simply not true that NEFA elevation when burning mostly fat and almost no CHO is pathological.

Neither this paper nor any you have presented gives any evidence that NEFA elevation in VLC is pathologic or will lead to lipotoxicity.

" Persistently elevated NEFA will lead to higher levels in ectopic tissues."

Persistently elevated NEFA are "associated" with lipotoxicity when inapprropriate - when on a high carb diet. In the context of VLC, where much more of baseline metabolism is running on fatty acids and ketones, the elevated NEFA is physiologic and in response to demand. You have presented no evidence that it leads to cellular damage in this context. This paper in particluar is irrelevant to NEFA levels with VLC.
CarbSane said…
The paleo diet used was not anywhere near a high fat very low carb version:
1 or fewer eggs/day, lean meats, a lot of fish, nearly 500g fruit/day?!! on average and over 300g veggies/day. The Mediterranean diet used was dairy intensive which is not what I've understood the diet to be.

The Paleo diet was also considerably lower in calories - 1344 vs. 1795 - that's 451 cal/day deficit. Comparable in protein (~90 g ) but actually slightly lower in fat than the Med diet (42 vs. 50g) and as a percent would be described by many low carbers as almost dangerously low fat (~27%). Carbs were 134g/day on average. Overall they compared a P/F/C 28/27/40 diet to a 21/25/52 diet providing 450 cal more/day. The paleo group lost more weight in 12 weeks.

So anyway, all that fruit didn't send them into the throes of hyperglycemia after all. This was also a 3 month study. Shai was 2 years, and granted their version of LC wasn't VLC either, but carb consumption improved glucose tolerance in the long term.
CarbSane said…
(I would add that the above compositions do not add to 100% due to rounding and omitting alcohol consumption)
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