Heart Muscle Favors Ketones?

ejalrp

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Dr. Thomas Cowan claims in his book that the heart prefers ketones and fatty acids to glucose. In fact, he claims that heart attacks are caused by the heart being forced to switch over from ketones to glucose ( glycolysis) resulting in the build-up of lactic acid in the heart muscles which can then lead to necrosis and heart attack.

Has RP ever addressed the issue of what fuel the heart "prefers"?
 

haidut

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Yes, he has. He has said that heart and skeletal muscle preferentially oxidize fat at rest but under duress start incorporating glucose as well and if there is not enough oxygen (i.e. when overexercising for example) or excess levels of lipolysis then the anaerobic glycolysis / Randle cycle result in lactate buildup. Inhibiting fatty acid oxidation has been shown to dramatically improve survival in heart attacks and other ischemic events. That's the main impetus for the development of drugs like Mildronate.
Ray Peat, PhD on Low Blood Sugar & Stress Reaction – Functional Performance Systems (FPS)
"...If you do not eat enough of the necessary nutrients your body will convert your muscles to sugar to keep feeding the brain what it needs and if you are eating enough sugar or things that will turn into sugar your body doesn’t have to break down its own tissues to make the necessary glucose for your blood cells and brains. In that condition, your muscles at rest don’t require practically any glucose and they will do fine on a pure fat diet but that’s the resting muscle.”

How to Burn Fat and Why You Shouldn't - 180 Degree Health
"...“Healthy” fat loss is most likely a combination of keeping the metabolic rate up, consuming a nutrient-dense diet, and getting sufficient calories per your needs (e.g., stress and activity levels) – the basic message of Diet Recovery 2 and most of the material on this site. Suppressing lipolysis doesn’t mean that you will never burn fat for energy. In fact, large skeletal muscles prefer saturated fats as a source of fuel while at rest, as does the heart’s myocardium."

Heart and hormones
"...Stress, in the form of pressure-overload (Zhabyeyev, et al., 2013), or overactivity of the renin-angiotensin system (Mori, et al., 2013) and sympathetic nervous system or adrenergic chemicals (Mori, et al., 2012), or a failure of energy caused by diabetes, insulin deficiency, or hypothyroidism, causes a shift of energy production from the oxidation of glucose to the oxidation of fatty acids, with the release, rather than oxidation, of the lactic acid produced from glucose. This sequence, from reduced efficiency of energy production to heart failure, can be opposed by agents that reduce the availability of fatty acids and promote the oxidation of glucose. Niacinamide inhibits the release of free fatty acids from the tissues, and thyroid sustains the oxidation of glucose. This principle is now widely recognized, and the FDA has approved a drug that inhibits the oxidation of fatty acids (raloxazine, 2006), but which has serious side effects. Glucose oxidation apparently is necessary for preventing the intracellular accumulation of free calcium and fatty acids (Jeremy, et al., 1992; Burton, et al., 1986; Ivanics, et al., 2001). The calcium binding protein which is activated by thyroid and inhibited by estrogen seems to be activated by glucose and inhibited by fatty acids (Zarain-Herzberg and Rupp, 1999). "

So, inhibiting fatty acid oxidation actually lowers lactate levels and is especially beneficial when under duress but can help even a non-stressed person metabolize better. It is not the presence of glucose that harms the heart, rather the inability to metabolize it (due to hypoxia or excess lipolysis) results in turning it into lactic acid and that can contribute to the ischemia.
 

800mRepeats

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...
So, inhibiting fatty acid oxidation actually lowers lactate levels and is especially beneficial when under duress but can help even a non-stressed person metabolize better. It is not the presence of glucose that harms the heart, rather the inability to metabolize it (due to hypoxia or excess lipolysis) results in turning it into lactic acid and that can contribute to the ischemia.

Wait! I really want to understand this.

Inhibiting fatty acid oxidation can lower lactate levels?
Excess lipolysis inhibits ability to metabolize glucose and thus turns it into lactic acid?
(Also - what is "excess" and what might cause an "excess"?)

S0 ... If a highly "efficient" ultra endurance athlete (i.e., an excellent fat burner) were to take niacinimide (say, 100 mg x 3 / day, as mentioned in a thread recently?), what would likely happen?
 

haidut

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Wait! I really want to understand this.

Inhibiting fatty acid oxidation can lower lactate levels?
Excess lipolysis inhibits ability to metabolize glucose and thus turns it into lactic acid?
(Also - what is "excess" and what might cause an "excess"?)

S0 ... If a highly "efficient" ultra endurance athlete (i.e., an excellent fat burner) were to take niacinimide (say, 100 mg x 3 / day, as mentioned in a thread recently?), what would likely happen?

Yes, taking something like Mildronate or niacinamide would reduce fatty acid oxidation (Mildronate due to inhibiting carnitine synthesis and niacinamide due to decrease in lipolysis) and as a result of the Randle cycle the cells have better ability to metabolize glucose, so it does not get "wasted" into lactic acid. This has been discussed many times on the forum and Peat's articles. There is no official definition of excess lipolysis but some studies say any lipolysis level resulting in providing more FFA than muscle ability to oxidize it would be excessive as it would lead to elevated lactic acid due to glucose wasting. Most effective fatty acid oxidation inhibitors result in drop of blood glucose due to improved glucose utilization. That is why they are considered as treatment for diabetes.
Fatty acid oxidation inhibitors - Wikipedia
Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys. - PubMed - NCBI
"...Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyl-transferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of > or = 70%, as measured by beta-hydroxybutyrate levels, the end product of beta-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of beta-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy."

As far as endurance athletes, not sure what would happen if they take niacinamide but studies in mice show it increases endurance since it improves ability to metabolize glucose. Just because somebody is adapted to run very efficiently (i.e. low RMR) on fat does not mean they are at optimal performance/health. See below.
Nicotinamide-rich diet improves physical endurance by up-regulating SUR2A in the heart
 
Last edited:

Lejeboca

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And, to add two cents to @haidut very thorough replies, Peat and here, at "PTA", noted that excess glucose, if any, will be converted to SFAs. So not too worry about "not enough fatty acids" ;)
 

Koveras

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S0 ... If a highly "efficient" ultra endurance athlete (i.e., an excellent fat burner) were to take niacinimide (say, 100 mg x 3 / day, as mentioned in a thread recently?), what would likely happen?

As far as endurance athletes, not sure what would happen if they take niacinamide but studies in mice show it increases endurance since it improves ability to metabolize glucose. Just because somebody is adapted to run very efficiently (i.e. low RMR) on fat does not mean they are at optimal performance/health. See below.
Nicotinamide-rich diet improves physical endurance by up-regulating SUR2A in the heart

Eur J Appl Physiol. 2016 Apr;116(4):781-90. doi: 10.1007/s00421-016-3333-y. Epub 2016 Feb 5.
Carbohydrate dependence during prolonged simulated cycling time trials.
Torrens SL1, Areta JL2, Parr EB1, Hawley JA3,4.

PURPOSE:
We determined the effect of suppressing lipolysis via administration of Nicotinic acid (NA) and pre-exercise feeding on rates of whole-body substrate utilisation and cycling time trial (TT) performance.

METHODS:
In a randomised, single-blind, crossover design, eight trained male cyclists/triathletes completed two series of TTs in which they performed a predetermined amount of work calculated to last ~60, 90 and 120 min. TTs were undertaken after a standardised breakfast (2 g kg(-1) BM of carbohydrate (CHO)) and ingestion of capsules containing either NA or placebo (PL).

RESULTS:
Plasma [free fatty acids] were suppressed with NA, but increased in the later stages of TT90 and TT120 with PL (p < 0.05). There was no treatment effect on time to complete TT60 (60.4 ± 4.1 vs. 59.3 ± 3.4 min) or TT90 (90.4 ± 9.1 vs. 89.5 ± 6.6 min) for NA and PL, respectively. However, TT120 was slower with NA (123.1 ± 5.7 vs. 120.1 ± 8.7 min, p < 0.001), which coincided with a decline in plasma [glucose] during the later stages of this ride (p < 0.05). For TTs of the same duration, the rates of whole-body CHO oxidation were unaffected by NA, but decreased with increasing TT time (p < 0.05). CHO was the predominant substrate for all TTs contributing between 83 and 94 % to total energy expenditure, although there was a small use of lipid-based fuels for all rides.

CONCLUSION:
(1) NA impaired cycling TT performance lasting 120 min, (2) cycling TTs lasting from 60 to 120 min are CHO dependent, and (3) there is an obligatory use of lipid-based fuels in TTs lasting 1-2 h.
 

Koveras

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Also this one

Altering fatty acid availability does not impair prolonged, continuous running to fatigue: evidence for carbohydrate dependence

We determined the effect of suppressing lipolysis via administration of nicotinic acid (NA) on fuel substrate selection and half-marathon running capacity. In a single-blinded, Latin square design, 12 competitive runners completed four trials involving treadmill running until volitional fatigue at a pace based on 95% of personal best half-marathon time. Trials were completed in a fed or overnight fasted state: 1) carbohydrate (CHO) ingestion before (2 g CHO·kg−1·body mass−1) and during (44 g/h) [CFED]; 2) CFED plus NA ingestion [CFED-NA]; 3) fasted with placebo ingestion during [FAST]; and 4) FAST plus NA ingestion [FAST-NA]. There was no difference in running distance (CFED, 21.53 ± 1.07; CFED-NA, 21.29 ± 1.69; FAST, 20.60 ± 2.09; FAST-NA, 20.11 ± 1.71 km) or time to fatigue between the four trials. Concentrations of plasma free fatty acids (FFA) and glycerol were suppressed following NA ingestion irrespective of preexercise nutritional intake but were higher throughout exercise in FAST compared with all other trials (P < 0.05). Rates of whole-body CHO oxidation were unaffected by NA ingestion in the CFED and FAST trials, but were lower in the FAST trial compared with the CFED-NA trial (P < 0.05). CHO was the primary substrate for exercise in all conditions, contributing 83-91% to total energy expenditure with only a small contribution from fat-based fuels. Blunting the exercise-induced increase in FFA via NA ingestion did not impair intense running capacity lasting ∼85 min, nor did it alter patterns of substrate oxidation in competitive athletes. Although there was a small but obligatory use of fat-based fuels, the oxidation of CHO-based fuels predominates during half-marathon running.
 

Koveras

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...and these

I wonder if the increase in growth hormone in the first study here is an attempt by the body to increase fat availability when suppressed by NA ...or something peculiar to NA versus niacinamide.

Med Sci Sports Exerc. 1995 Jul;27(7):1057-62.
Physiological and performance responses to nicotinic-acid ingestion during exercise.
Murray R1, Bartoli WP, Eddy DE, Horn MK.

The purpose of this study was to assess how selected physiological and performance responses are affected when the normal increase in plasma free fatty acid concentration during exercise is blunted by ingesting nicotinic acid. On four occasions, 10 subjects cycled at 68 +/- 1% VO2peak for 120 min followed by a timed 3.5-mile performance task. Every 15 min during exercise, subjects ingested 3.5 ml.kg LBM-1 of one of four beverages: 1) water placebo (WP), 2) WP + 280 mg nicotinic acid.l-1 (WP + NA), 3) 6% carbohydrate-electrolyte beverage (CE), and 4) CE + NA. Ingestion of nicotinic acid (WP + NA and CE + NA) blunted the rise in FFA associated with WP and CE; in fact, NA ingestion effectively prevented FFA from rising above rest values. The low FFA levels with NA feeding were associated with a 3- to 6-fold increase in concentrations of human growth hormone throughout exercise. The mean performance time for CE (10.7 min) was significantly less than for WP (12.2 min) and WP + NA (12.8 min), but did not differ from CE + NA (11.4 min). The results indicate that blunting the normal rise in FFA alters the hormonal response to exercise and reduces the capacity to perform high-intensity exercise.

Int J Sports Med. 1997 Feb;18(2):83-8.
The effect of substrate utilization, manipulated by nicotinic acid, on excess postexercise oxygen consumption.
Trost S1, Wilcox A, Gillis D.

Increased fat oxidation during the recovery period from exercise is thought to be a contributing factor for excess postexercise oxygen consumption (EPOC). In an attempt to study the effect of serum free fatty acid (FFA) availability during exercise and recovery on the EPOC, nicotinic acid, a potent inhibitor of FFA mobilization from adipose tissue, was administered to five trained male cyclists prior to, during, and after a bout of cycling at 65% VO2max. In the nicotinic acid trial, a 500 mg dose of nicotinic acid was ingested prior to exercise, and 100 mg doses were ingested at 15, 30, and 45 min exercise, and 30 min recovery. The cyclists also completed a trial under control conditions. Serum FFA, serum glycerol, RER and VO2 were monitored during rest, exercise, and recovery, each of which was 1-h in duration. Nicotinic acid ingestion prevented the increase in serum FFA that occurred during exercise in the control trial. FFA levels during the nicotinic acid trial were significantly lower than control values during both exercise and recovery. Serum glycerol levels were also significantly lower during exercise in the nicotinic acid trial, indicative of a reduction in lipolysis. RER was not significantly different at rest or during exercise; however, RER values were significantly lower during recovery in the control trial, indicative of greater fat oxidation. For both treatments, postexercise VO2 remained elevated above resting levels at the completion of the 1-h recovery period. However, the magnitude of EPOC was significantly reduced after FFA blockade with nicotinic acid (3.4 +/- 0.61 vs 5.5 +/- 0.71). These results support the hypothesis that increased FFA metabolism during exercise and recovery is an important contributing factor to the magnitude of EPOC.
 

haidut

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...and these

I wonder if the increase in growth hormone in the first study here is an attempt by the body to increase fat availability when suppressed by NA ...or something peculiar to NA versus niacinamide.

Med Sci Sports Exerc. 1995 Jul;27(7):1057-62.
Physiological and performance responses to nicotinic-acid ingestion during exercise.
Murray R1, Bartoli WP, Eddy DE, Horn MK.

The purpose of this study was to assess how selected physiological and performance responses are affected when the normal increase in plasma free fatty acid concentration during exercise is blunted by ingesting nicotinic acid. On four occasions, 10 subjects cycled at 68 +/- 1% VO2peak for 120 min followed by a timed 3.5-mile performance task. Every 15 min during exercise, subjects ingested 3.5 ml.kg LBM-1 of one of four beverages: 1) water placebo (WP), 2) WP + 280 mg nicotinic acid.l-1 (WP + NA), 3) 6% carbohydrate-electrolyte beverage (CE), and 4) CE + NA. Ingestion of nicotinic acid (WP + NA and CE + NA) blunted the rise in FFA associated with WP and CE; in fact, NA ingestion effectively prevented FFA from rising above rest values. The low FFA levels with NA feeding were associated with a 3- to 6-fold increase in concentrations of human growth hormone throughout exercise. The mean performance time for CE (10.7 min) was significantly less than for WP (12.2 min) and WP + NA (12.8 min), but did not differ from CE + NA (11.4 min). The results indicate that blunting the normal rise in FFA alters the hormonal response to exercise and reduces the capacity to perform high-intensity exercise.

Int J Sports Med. 1997 Feb;18(2):83-8.
The effect of substrate utilization, manipulated by nicotinic acid, on excess postexercise oxygen consumption.
Trost S1, Wilcox A, Gillis D.

Increased fat oxidation during the recovery period from exercise is thought to be a contributing factor for excess postexercise oxygen consumption (EPOC). In an attempt to study the effect of serum free fatty acid (FFA) availability during exercise and recovery on the EPOC, nicotinic acid, a potent inhibitor of FFA mobilization from adipose tissue, was administered to five trained male cyclists prior to, during, and after a bout of cycling at 65% VO2max. In the nicotinic acid trial, a 500 mg dose of nicotinic acid was ingested prior to exercise, and 100 mg doses were ingested at 15, 30, and 45 min exercise, and 30 min recovery. The cyclists also completed a trial under control conditions. Serum FFA, serum glycerol, RER and VO2 were monitored during rest, exercise, and recovery, each of which was 1-h in duration. Nicotinic acid ingestion prevented the increase in serum FFA that occurred during exercise in the control trial. FFA levels during the nicotinic acid trial were significantly lower than control values during both exercise and recovery. Serum glycerol levels were also significantly lower during exercise in the nicotinic acid trial, indicative of a reduction in lipolysis. RER was not significantly different at rest or during exercise; however, RER values were significantly lower during recovery in the control trial, indicative of greater fat oxidation. For both treatments, postexercise VO2 remained elevated above resting levels at the completion of the 1-h recovery period. However, the magnitude of EPOC was significantly reduced after FFA blockade with nicotinic acid (3.4 +/- 0.61 vs 5.5 +/- 0.71). These results support the hypothesis that increased FFA metabolism during exercise and recovery is an important contributing factor to the magnitude of EPOC.

All of these a great! Peat referred to a few studies where giving endurance athletes a sugary drink and asking them to just wash their mouth with it but not ingest was enough to reduce fatigue. In addition to the critical role of carbs in exertion I think they also affect CNS and serotonin, and this has a role in fatigue as well. Carb drinks after exhaustive exercise have been shown to lower serotonin. The mechanism is through carbs lowering FFA, because FFA displace tryptophan from albumin and allow it to accumulate in the brain. So, a potentially highly effective endurance drink would be BCAA+phenylalanine/tyrosine+niacinamide+carbs.
Btw, that first study you posted used really high doses niacin - 15mg/kg before the race and then 5mg/kg every 30min during the race. So, most people probably got in excess of 2.5g niacin in a very short time period. In doses higher than 500mg niacin has been shown to increase ammonia and this may have contributed to the worsening of performance. I think naicinamide dose not have this effect in doses of under 1,500mg.
 

Wagner83

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If the heart and muscles consume fat at rest then isn't it less than ideal to supplement with compounds that inhibit fatty acids oxidation? It's not like muscles and heart are negligeable, it also means that they get rid us of fat and we don't store as much poofa on a high-carbohydrates diet, and the fact they burn fat means glucose/fructose is spared for the brain and what not.
 

haidut

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If the heart and muscles consume fat at rest then isn't it less than ideal to supplement with compounds that inhibit fatty acids oxidation? It's not like muscles and heart are negligeable, it also means that they get rid us of fat and we don't store as much poofa on a high-carbohydrates diet, and the fact they burn fat means glucose/fructose is spared for the brain and what not.

Not really, as the studies show that drugs Mildronate improve metabolism/health even at rest.
 
OP
E

ejalrp

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Yes, taking something like Mildronate or niacinamide would reduce fatty acid oxidation (Mildronate due to inhibiting carnitine synthesis and niacinamide due to decrease in lipolysis) and as a result of the Randle cycle the cells have better ability to metabolize glucose, so it does not get "wasted" into lactic acid. This has been discussed many times on the forum and Peat's articles. There is no official definition of excess lipolysis but some studies say any lipolysis level resulting in providing more FFA than muscle ability to oxidize it would be excessive as it would lead to elevated lactic acid due to glucose wasting. Most effective fatty acid oxidation inhibitors result in drop of blood glucose due to improved glucose utilization. That is why they are considered as treatment for diabetes.
Fatty acid oxidation inhibitors - Wikipedia.
Thanks Haidut!
 

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