Table salt was not a "thing" until recently.

Catching dinner catching salts at a salt lick

Endogenous Ouabain And Diabetic Heart Failure: Damned if you do, damned if you don't

Ouabain is synthesized by the kidney in mammals, perplexing some scientists worldwide but creating a field unto itself for others.  What confuses some people is that the dogma was that it was a poison only made by plants. What all this reveals is fundamental and profound in understanding heart failure.  Global cardiology often focuses on norepinephrine, phenylephrine, dopamine, angiotensin II or ACE, but not endogenous ouabain.  It could be the fact that ouabain is both extremely lethal and also simultaneously critical to sustaining extra-oceanic life.  While nature has perfected the tight-rope balance as an automation, "humans" can only begin to monkey around with what is often lethal in their 5-digit hands.

The problem is that with too much ouabain, you overdrive cardiomyocytes to eventual failure, but after renal failure, you do not have enough Endogenous Ouabain (EO), causing decompensated heart failure with structural defects and reduced fractional shortening for a large abnormal diastolic dimension, a weak systolic dimension, and weak ejection fraction.  At this point, EO is strangely lower than before it was very high when it caused heart failure through a period of chronic excess.  You don't have to use ouabain itself. You may use a similar agonist molecule or even a very different one to stimulate the same calcium overdrive.  Of course, this causes problems, but at least it won't be IMMEDIATE death from hypotension, the "dying in your sleep" type of heart failure from thromboses caused by stagnated blood as well as the bulky peripheral resistance of edema.  A concomitant problem in diabetic heart failure is no GLUT receptors, therefore no glucose intake, and therefore no ATP synthesis.  You can allay this malady with insulinomimetics, many of which have no resemblance to insulin but have potent insulin effects.  Polyphenol class molecules can often display impressive insulin receptor pathway stimulation despite having no structural resemblance to insulin.   This would re-display glucose receptors for ingestion of glucose into heart cells, restoring the missing ATP synthesis in heart failure.  Using insulin is a futile effort as there are no working insulin receptors in diabetic heart failure.

Diabetes mellitus causes dangerous hyponatremia not compensated by endogenous ouabain. Exogenous ouabain rescues diabetic hyponatremia.

The human ouabain synthesis system is to preserve salt at all cost.  Sodium chloride, NaCl, is a precious electrolyte, which would be traded for acute and chronic hypertension without reservation via ouabain excretion when salt is available.  This is the evolutionary value of NaCl for all creatures that live outside the ocean.  Before table salt, sodium chloride availability was sporadic above ocean.  This drove our mammalian evolution to conserve salt even if it caused systolic overdrive and hypertension.  In the cause of non-diabetes 2 heart failure, AngII or NE  and/or ouabain are probably causal.  In the cause of IDDM or DM heart failure, the conjoining of reduced ATP synthesis, and renal dysfunction, as well as mildly increased ouabain, suggests that ouabain type agonists could be therapeutic in this scenario to restore cardiac function alone without addressing underlying cardiac insulin resistance as well as renal hormone and electrolyte function impairment.

(above graphic source)

In diabetes, ouabain (sodium conservation) synthesis is deranged:

The sodium pump, an ancestral enzyme with conserved ability to bind ouabain, plays a key role in salt conservation and is regulated by aldosterone and endogenous ouabain (EO). Plasma EO is elevated in about 45% of patients with essential hypertension and correlates with blood pressure. The relationship of EO with Na+ balance is complex. Na+ depletion raises circulating EO, whereas acute saline loads have no effect on EO in essential hypertension, and ambient levels of EO are unrelated to the saline sensitivity of blood pressure. Short-term periods of high dietary salt elevate EO and the relationship with salt balance in normal individuals is V-shaped, whereas the long-term relationship is likely to be L-shaped. Normal individuals suppress the high EO transient triggered by high-salt diets and avoid hypertension. In contrast, patients with elevated EO on normal Na+ intakes have hypertension related to poor modulation of EO biosynthesis, clearance, or both.

Diabetic Hyponatremia

Of course, this is just one problem of many.

Is the association of serum sodium with mortality in patients with type 2 diabetes explained by copeptin or NT-proBNP? (ZODIAC-46).

With chronic hyponatremia, adrenal production of sodium regulating cardiotonic compounds are reduced thereby causing aberrant muscle calcium.

But that is just one problem of several, including a lack of mitochondrial ATP from no glucose import.

Vitamin K2, CoQ10, "High" Cholesterol, and Schnyder Corneal Dystrophy

This is a new discovery, quietly making its way through the internet of knowledge in 2016, but probably no less profound than Brown and Goldstein's uncovering active LDL feedback and control mechanisms.  This is more contemporary evidence that those wonk heads who honestly think they have put an end to new discovery are usually wrong.  While ascorbate is important to prevent the damage that apo(a) repairs, it is not the only thing you need to prevent atherosclerosis.  Huge amounts of ascorbate can cover for a UBIAD1 deficiency as I will explain later on here, but probably you will never recover what you could gain by augmenting the loss-of-function from not having enough menaquinone-4 vitamin K2..and CoQ10.

UBIAD1, the vitamin K2 generating enzyme, is necessary in its un-mutated form to chaperone HMG CoA reductase as a steric protease inhibitor.  When encountering geranylgeraniol in the mevalonate pathway, UBIAD1 dissociates from the reductase, removing the steric hindrance to proteolysis and then the reductase is degraded, and cholesterol synthesis goes down.

The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase.

When the UBIAD1 enzyme is mutated, it does not dissociate from the mevalonate pathway enzyme and it does not degrade and so over-functions in constitutive cholesterol synthesis.

Not only this, but mutated UBIAD1 can be rescued by the administration of its gene product, menaquinone-4, a molecular species of Vitamin K2, making this a very solvable problem for people if they understand what it is they have.  If they do not understand what they have, they will get Schnyder Corneal Dystrophy and eventual coronary and renal calcifications if not also calcium deposits in all the arterial bifurcations and curvatures.

Role of UBIAD1 in Intracellular Cholesterol Metabolism and Vascular Cell Calcification

Looks like someone already beat me to the punch here:

Vitamin K2 biosynthetic enzyme, UBIAD1 is essential for embryonic development of mice.

So there is a bonafide conjunction, not coincidental or supplemental, but an essential conjoining of function between HMG CoA reductase, UBIAD1, cholesterol levels, and prevention of vascular calcification.  Not having K2 or CoQ10 will raise intracellular cholesterol levels directly at the enzymatic level, not at a degradation or accumulation aspect.

As I speculated, massive doses of vitamin C can cover some of the defects of a UBIAD1 defect by virtue of it being an electron donor and labile redox molecule, but won't fully rescue the UBIAD1 defect.  "In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements."

Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects

Of these compounds, you make CoQ10 until age 20 when the enzymatic synthesis starts to run down (sad but true) until age 80 when the synthesis levels are very low to nil.  Vitamin K is needed in the micrograms quantity per day, qualifying it as a classical "MICRO" nutrient.  I will argue that ascorbate IS NOT a micronutrient but a millinutrient.  For some bubble headed quackademic to claim that you can get by on micrograms of ascorbate is not paying attention and will cause a massacre by scurvy.  Leave it to a quack (mal) nutritionist to have only two blunt categories:  Macro and micronutrients, ignoring millinutrients.  It is like a person saying there is only 2 hours in a day when there are 12 or spring and winter, forgetting summer and autumn.  Nobody ever makes vitamin C, so if you had to supplement only 1 out of 3 things, I would most definitely choose vitamin C.









 

Unlike Vitamin C (Ascorbate), Humans Make Their Own Sufficient CoQ10 Until Age 20:

In the same way we need to always take vitamin C in order to prevent death, we also need to start taking CoQ10 after the age of 20 to prevent death.

In a picture, why CoQ10 is so important to preserving cardiovascular integrity.

Without CoQ10, as provided by the UBIAD1 protein, we incur constant free radical damage to our arteries and heart cells.  It is not as important to ingest reduced Ubiquinol as to replenish the level of Ubiquinone lost to age related decrease in synthesis.

The weird English language

When you say "ascent," you don't pronounce the silent c.  When you say "descend," you don't say "dee-skend."  When you say ascorbate, you transcend normal rules of speaking English and say "a-skorbate."  Sure, whatever.  If I say "asorbate," people know that I am referring to ascorbate, the same way that Americans understand a Brit when he says "toe-mah-toe." Miniscule irrelevant trifle.  Of course I mean the anion of vitamin C, ever linkable to a cationic 2+ mineral.  Duh!