Forcing The Heart To Burn Glucose Instead Of Fat May Cure Heart Failure

haidut

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One of the blockbuster studies I have seen over the last 12 months. It reads as if written by Peat himself and discusses tissue regeneration, Randle cycle, dietary control of metabolism, etc. AFAIK this is the first study brave enough to demonstrate that simply switching fuel types in an organism can have profound structural effects, and reverse pathological changes (e.g. heart fibrosis / failure) officially considered irreversible. Another important finding of the study was that the beneficial effects on heart failure could be elicited both by pharmacologically inhibiting fatty acid oxidation (FAO), as well as by simply lowering dietary fat intake and increasing carbohydrates. The pharmacological intervention that decreased FAO and increased glucose oxidation was aimed at inhibiting the enzyme PDK (PDK4 specifically). That enzyme is the master brake of another crucial respiratory enzyme known as pyruvate dehydrogenase (PDH). PDH is the rate-limiting step in glucose oxidation. Anything that activates PDK results in PDH inhibition and thus glucose oxidation. Increased FAO just so happens to be one of the most powerful activators of PDK (PDK4 specifically) and as such (due to the Randle cycle) an inhibitor of glucose oxidation. Conversely, anything that inhibits PDK will release the "brakes" on PDH and result in increased glucose oxidation. Interestingly, the study used tamoxifen to inhibit PDK4, which directly implicates estrogen in pathologies such as heart disease, cancer, and neurological disturbances, mental disorders, etc as all of them are characterized by increased FAO and decreased glucose oxidation. This suggests that the therapeutic effects of tamofixen in breast cancer are likely metabolic (by inhibiting excessive FAO) and that tamofixen may be therapeutic in many other conditions too. It also suggests that any other chemical/intervention that decreases FAO and increases glucose oxidation will likely have broad therapeutic effects for virtually all chronic conditions that plague the developed world nowadays.

However, tamoxifen is not without its risks. It is, after all, a synthetic estrogen (even though the corrupt drug industry calls it a SERM) and has potent estrogenic effects in various tissues except the breast. As such, tamofixen is not really a safe option for people who want to inhibit PDK. It just so happens that vitamin B1 is both a co-factor (and as such an activator) of PDH and also an inhibitor of PDK. This dual beneficial property of B1 has been extensively studied and, as the study below demonstrates, its potency as a PDK inhibitor is actually higher than the well-known PDK inhibitor DCA, which has shown so much promise as a treatment for cancer.

High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate. - PubMed - NCBI

While the study above does not mention specific doses for B1, in-vivo studies with both animals and humans have demonstrated that a HED of 100mg-300mg daily is sufficient to elicit a potent PDK inhibition and PDH activation effect. Adding 300mg-500mg niacinamide (vitamin B3) will likely potentiate the effects of B1 as a result of the anti-lipolytic effects of niacinamide as well as its direct FAO inhibition effects due to SIRT blockade. So, as hard as it is to believe that an "irreversible" condition such as heart failure may be curable it looks like the solution may not only be simple but cheap, safe, and widely available as well. Now, the only thing remaining to demonstrate so that the picture is complete is that not only does increased FAO (probably due to estrogen) prevent proper heart regeneration beyond infancy, it may be THE actual cause of heart failure to start with (at any age).

Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression | Nature Metabolism

"...Importantly, increased fatty acid oxidation perpetuates dependence on fatty-acid utilization by inhibiting glucose oxidation via the Randle cycle, in which acetylCoA generated from fatty-acid oxidation inhibits the mitochondrial enzyme pyruvate dehydrogenase (PDH) 36. Cardiac PDH activity is regulated by various isoforms of pyruvate dehydrogenase kinases (PDK1, PDK2 and PDK4) and phosphatases (PDP1 and PDP2), with phosphorylation resulting in enzyme inhibition37–39. Of the PDK isoforms, PDK4 is largely responsible for inhibiting PDH in the presence of fatty acids and increasing the reliance of the heart on fatty-acid oxidation for energy production 37,39–41. Intriguingly, our group and others have shown that mitochondria produce H2O2 at an elevated rate when using fatty acids rather than pyruvate as a respiratory substrate."

Changing what heart cells eat could help them regenerate: New study suggests that encouraging cardiomyocytes to consume glucose instead of fatty acids could help treat heart failure

"...Current pharmaceutical treatments for heart failure -- including ACE inhibitors and beta blockers -- center on trying to stop a vicious cycle of heart muscle loss as strain further damages remaining heart muscle, causing more cells to die, explains UT Southwestern physician-researcher Hesham A. Sadek, M.D., Ph.D., the J. Fred Schoellkopf, Jr. Chair in Cardiology. There are no existing treatments for rebuilding heart muscle. Nine years ago, Sadek and his colleagues discovered that mammalian hearts can regenerate if they're damaged in the first few days of life, spurred by the division of cardiomyocytes, the cells responsible for a heart's contractile force. However, this capacity is completely lost by 7 days old, an abrupt turning point in which division of these cells dramatically slows. Subsequent research has shown that this change in regenerative capacity appears to stem, at least in part, from damaging free radicals generated by organelles known as mitochondria, which power cells. These free radicals damage cells' DNA, a phenomenon called DNA damage, which prompts them to stop dividing. The shift in free radical production appears to be spurred by a change in what mitochondria in the cardiomyocytes consume for energy, Sadek explains. Although mitochondria rely on glucose in utero and at birth, they switch to fatty acids in the days after birth to utilize these energy-dense molecules in breast milk. Sadek and his colleagues wondered whether forcing mitochondria to continue to consume glucose might stymie DNA damage and, in turn, extend the window for heart cell regeneration. To test this idea, the researchers tried two different experiments. In the first, they followed mouse pups whose mothers were genetically altered to produce low-fat breastmilk and that fed on low-fat chow after they weaned. The researchers found that these rodents' hearts maintained regenerative capacity weeks later than normal, with their cardiomyocytes continuing to express genes associated with cell division for a significantly longer window than those fed a diet of regular breastmilk and chow. However, this effect didn't last into adulthood -- their livers eventually made up the deficit by synthesizing the fats that their diets were missing, which significantly reduced their hearts' regenerative capacity. In the second experiment, the researchers created genetically altered animals in which the researchers could delete an enzyme, known as pyruvate dehydrogenase kinase 4 (PDK4), necessary for the heart cells' mitochondria to digest fatty acids. When the researchers delivered a drug to turn off PDK4 production, the animals' cardiomyocytes switched to consuming glucose instead of fatty acids, even in adulthood. After researchers simulated a heart attack, these animals experienced improvement in heart function, which was accompanied by markers in gene expression that suggested their cardiomyocytes were still actively dividing. Sadek notes that these findings provide proof of principle that it's possible to reopen the window for heart cell regeneration by manipulating what cardiomyocyte mitochondria consume for energy. "Eventually," he says, "it may be possible to develop drugs that change what cardiomyocytes eat to make them divide again, reversing heart failure and representing a true cure."
 

Murtaza

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It also suggests that any other chemical/intervention that decreases FAO and increases glucose oxidation will likely have broad therapeutic effects for virtually all chronic conditions that plague the developed world nowadays.
So something like mildronate can be taken?
 

maillol

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Yes i know its an anti ischemic drug. Ive been wanting to try it since i think my body has been oxidizing fat for as long as i can remember
Just read up about Mildronate and it sounds like a good drug.
Does it raise nitric oxide?
What happens to the fat you consume while taking it?
Are there any potential issues after taking it for a while and then stopping?
 

Murtaza

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I dont th
Just read up about Mildronate and it sounds like a good drug.
Does it raise nitric oxide?
What happens to the fat you consume while taking it?
Are there any potential issues after taking it for a while and then stopping?
I dont think peat would mention a drug if it raised nitric oxide
 

mangoes

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Just read up about Mildronate and it sounds like a good drug.
Does it raise nitric oxide?
What happens to the fat you consume while taking it?
Are there any potential issues after taking it for a while and then stopping?
I dont think peat would mention a drug if it raised nitric oxide

it does raise vascular endothelial nitric oxide according to the studies in rats
 

ken

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I took A and B happened is tricky. As reading this forum teaches us. I'm still taking it a year later. the 500mg capsules are rather cheap and you can buy it on Amazon. I sometimes cut it in halve with niacin amide. Wish i had it back in my tennis playing days.
 

Broken man

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@haidut ....good one man but there Is one thing I dont understand, I know about masai tribe that consume Milk and meat only and dont have diseases, do you have any idea why? Thank you.
 

maillol

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I took A and B happened is tricky. As reading this forum teaches us. I'm still taking it a year later. the 500mg capsules are rather cheap and you can buy it on Amazon. I sometimes cut it in halve with niacin amide. Wish i had it back in my tennis playing days.
How do you feel when you're not taking it?
 

ken

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First person short term use article she describes the effects as subtle. There's a suggestion in studies that it trains the heart to properly burn sugars and of course other cells too. In my situation, valve replacement and heart failure 3 years ago I'm planning to take it for the foreseeable future. It does seem that I have much less edema.
 

Murtaza

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First person short term use article she describes the effects as subtle. There's a suggestion in studies that it trains the heart to properly burn sugars and of course other cells too. In my situation, valve replacement and heart failure 3 years ago I'm planning to take it for the foreseeable future. It does seem that I have much less edema.
Facial edema?
 

maillol

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I found this video by the manufacturers Grindex They say mildronate does increase nitric oxide.
This seems odd for a drug that increases glucose oxidation and decreases lactic acid.
 

ken

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over the last year my general level of liquid in tissues has decreased. Peat also recommends Urea to control energy balance/ water balance in cells. I don't know what the increased N.O. means, possibly the increased co2 allows the NO to used more correctly.
 

maillol

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What a fascinating drug.

I wonder if it would help with Corona seeing as people with diabetes and breathing issues are more at risk.

It seems that carnitine deficiency can be problematic however which I don't quite understand. Symptoms include cardiomyopathy (confusing as mildronate is used as a treatment for this), skeletal-muscle weakness, and hypoglycemia (makes sense). Maybe if you're consuming a lot of fat and can't oxidise it.

Do natural carnitine inhibitors exist?
 

LeeLemonoil

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mujuro

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Interesting. The owner of a private bodybuilding forum I frequented years ago recommended trimetazidine for anyone on long term high dose AAS to attenuate any negative cardiac changes effected by the hormones.
 

mujuro

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I found this video by the manufacturers Grindex They say mildronate does increase nitric oxide.
This seems odd for a drug that increases glucose oxidation and decreases lactic acid.

Maybe it doesn’t, at least in any significant way. I can see why they would put the manufacturers would put that in. Keep in mind “nitric oxide” is basically buzzword in athletic circles. It implies improved blood flow, better oxygenation, more nutrients, etc. Most athletes don’t have a clue to its negative consequences, only that it gives you sick pumps.
 
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