Positive Health Online

Abstract
Coronary artery calcification is highly prevalent in patients with coronary heart disease and is associated with an increase in major adverse cardiovascular events. It may also have prognostic significance for individuals with no evidence of coronary disease. Various studies have shown that the process of arterial calcification shares some features with skeletal bone formation, including chondrocyte and osteoblast differentiation, mineralization, as well as bone matrix deposition and resorption. It had been suggested over five decades ago that the body draws minerals from the bones to neutralize the effects of an acid ash diet. We propose that an increase in lactic acid/lactate production is a more important and unappreciated cause of atherosclerosis and coronary artery calcification. We will also discuss the risk factors that influence both bone loss and atherosclerosis that leads to coronary calcification, such as age, diabetes, hypertension, tobacco smoking, chronic kidney disease, rheumatoid arthritis and air pollution. In addition, warfarin, statins, metformin and other drugs can influence lactic acidosis that then leads to osteoporosis and coronary calcification. There is also good evidence that acidosis may be responsible for calcification in the aortic valve, brain and other tissues.

Introduction
Coronary artery calcification (CAC) is widespread in patients with coronary heart disease (CHD), and although previously considered a benign, asymptomatic, and age-related trait, it is now believed to be an active process that can result in atherosclerosis. Calcification forms within the intimal layer of the arterial wall and begins with spotty minuscule deposits that coalesce to form larger sheet-like accumulations that are readily visible on radiography, computed tomography and intravascular imaging.[1] Because there is a strong correlation between the extent of calcification and the degree of atherosclerosis, it has now been proposed that CAC may be the most accurate way to predict future cardiac events, especially in asymptomatic individuals.[2-4] The prevalence of CAC is age and gender related, since it occurs in more than 90% of men and 67% of women over the age of 70 years.[4]

Vascular calcifications can be classified into 2 separate types depending on whether they are located within the intimal or medial layer. Medial arterial calcification primarily affects the legs, and is prevalent in patients with peripheral vascular disease. Intimal calcification predominates in coronary vessels, and both types can be found in the carotid arteries.[5,6] The progression of medial arterial calcification is associated with renal failure, hypercalcemia, hyperphosphatemia, and parathyroid hormone. These abnormalities are not seen with intimal coronary calcification although both types of calcification share some risk factors, most of which are age related, as shown in Figure 1.

Figure 1: From Vos A et al[6]



Table 1: Modified from Goodman et al. [7]

There is no treatment to prevent arterial calcification or its progression, which is not surprising, since the cause is not clear. There are no satisfactory animal models, because in contrast to humans, rodents, rabbits and dogs do not spontaneously develop atherosclerosis with age. Patients with end stage renal disease or uremia also have increased coronary artery calcification[8] Calciphylaxis is a rare disorder that causes subcutaneous vascular calcification and cutaneous necrosis.  It is sometimes called calcific uremic arteriolopathy, since it also usually occurs in patients with severe kidney disease. Little is known about its etiology and pathogenesis other than more than 50 percent of those affected die within 12 months after the diagnosis is made. It was first described in 1898 by Bryant and White,[9] but it was not until 1962 that the term “calciphylaxis” was coined by Hans Selye. He defined it as a hypersensitivity disorder, since in his experimental animal model, it was necessary to administration both a “sensitizer” and a “challenger” to produce calcification in various structures.[10,11] Arterial calcification has been induced in rabbits and other herbivores with extremely elevated cholesterol levels due to a very high fat diet because cholesterol is a foreign substance for them and can elicit an inflammatory response. However, these lesions are mainly in the aorta and large arteries rather than the coronaries, differ under the microscope from atherosclerotic plaque in humans, and the identical high fat diet produces no lesions in carnivorous animals. Severe fat restriction and intensive statin therapy to lower cholesterol or LDL did not prevent or diminish coronary calcification in one study,[12] and in another review of over 1,000 patients with high calcium artery calcification scores who were randomized to receive a statin or a placebo, LDL was lowered in the treatment group but there was no reduction in coronary calcification progression.[13]

The severity of coronary artery calcification is usually assessed by ultrafast computerized tomography that measures the degree of density multiplied by the area of the coronary calcification to provide a calcium artery calcification (CAC) or Agatston score, after its originator.[14] The CAC score is an independent risk marker for cardiac events, cardiac mortality, all-cause mortality, provides prognostic information and helps to identify diabetics and others at greatest risk who could benefit from screening for silent ischemia and may require more aggressive treatment.[15] It has been suggested that the process of arterial intimal calcification shares some features with skeletal bone formation, including chondrocyte and osteoblast differentiation, as well as bone matrix deposition and resorption. In addition, a variety of bone related proteins have been identified in calcified arteries,[16,17] and calcium is in the form of calcium phosphate in both bone and arteries.[18] The extent of coronary artery calcification is a better indication of the degree of atherosclerotic plaque than a reduction in lumen,[19] and is also associated with an increase in all-cause mortality [20] It is believed that spotty and incomplete calcification is more likely to cause major adverse cardiac events because of unstable and vulnerable plaque, whereas extensive calcification is more stable.[21] Since statins increase calcification,[22,23] it has been proposed they would benefit patients by making plaque more stable via some pleiotropic effect, since it is not related to lowering cholesterol or LDL.[24] This creates a conundrum for clinicians, since high calcium artery scores are associated with an increased risk of heart attacks and deaths, and no benefits have been found with statins or other cholesterol lowering drugs.

The first clue that calcification might be due to acidosis came in 2006, during the development of the Acidity Theory of Atherosclerosis.[25] Numerous articles that had been retrieved led to the hypothesis there was a link between osteoporosis and atherosclerosis, as explained in my 2012 book Acidity Theory of Atherosclerosis: New Evidences [25] as follows:

Although the prevalence of both atherosclerosis and osteoporosis increase with age, evidence that has accumulated since these initial studies[26,27] suggest a more direct relationship between these two disorders. This is supported by other studies that show an increase in carotid intima-media thickness, a marker for atherosclerosis in women who develop osteoporosis.[28,29]

Hip fracture, a frequent complication of osteoporosis, is two to five times more common in patients with heart disease than in those with no history of cardiovascular problems.[30]  Other studies have shown that bisphosphonates not only decreased the progression of osteoporosis, but also inhibited the development of atherosclerosis, in addition to reducing  total mortality.[31]  In that regard, it is important to note that bisphosphonates also reduce the production of lactic acid,[32] which further supports the hypothesis that lactic acidosis may be involved in the etiology and pathogenesis of coronary heart disease.[33]  This also substantiates the role of stress in coronary atherosclerosis, since chronic stress increases lactate.[34]

Studies Linking Acidosis to Bone Loss

“Life is a struggle, not against sin, not against the Money Power, not against
malicious animal magnetism, but against hydrogen ions" - H.L. Mencken[35]

In commenting on Mencken’s statement 75 years later, Kraut and Coburn wrote, “These words, about the meaning of life and death, may also apply to the struggle of the healthy skeleton against the deleterious effects of retained acid.”[36] It had been known since the early 20th century, that systemic acidosis causes depletion of the skeleton, an effect assumed to result from physico-chemical dissolution of bone mineral. And, as noted previously, coronary calcification is no longer viewed as a benign, asymptomatic, age-related trait, but an active process that can predict risk of coronary atherosclerosis and calcification.[37]

In 1918, Kingo Goto, at the Rockefeller Institute for Medical Research, showed that feeding acid to rabbits resulted in depletion of skeleton minerals [38] This paper also includes an excellent review of pertinent 19th century publications. More recent reports over the last two decades suggest that even subtle chronic acidosis can cause appreciable bone loss if prolonged.[39] In 1968, Wachman and Bernstein postulated that bone mineral functioned as a mechanism to buffer the fixed acid load imposed by the digestion of an “acid ash” diet in man.[40]  

Lactic Acidosis Is Associated With Coronary Disease And Atherosclerosis

However, not everyone agrees,[41] and our alternative hypothesis is that autonomic dysfunction results in an increased secretion of catecholamines that accelerates glycolysis and raises lactic acid and lactate concentration in blood and tissues for the following reasons.

a.    In advanced plaques the existence of hypoxic areas in the arterial wall – with accumulation of lactic acid in atherosclerotic lesions – appears to be related to a decreased oxygen diffusion capacity and increased oxygen consumption by foam cells.[42]
b.    Macrophages and lymphocytes convert most of their glucose into lactate rather than oxidizing it completely to CO2, and macrophages possess a selective transporter in their plasma membranes for lactic acid. This lactic acid may make the extracellular space surrounding macrophages acidic in atherosclerotic lesions.[43]
c.    It has been demonstrated that approximately two-thirds of atherosclerotic plaques show lactate dehydrogenase isoenzyme shifts significantly above that of the media and intima.[44]  
d.    The association of increased lipid levels with abnormal lactate metabolism might provide a useful screening test for the detection of coronary artery disease.[45]
e.    Plasma lipid abnormalities and myocardial lactate production were significantly associated with subsequent arteriographic progression of coronary artery disease.[46]
f.    The amount of lactate released by the myocardium has been shown to be related to the severity of coronary artery disease.[47]
g.    Lactate levels are strongly associated with increased carotid atherosclerosis and the association is independent of traditional cardiovascular risk factors.[48]

Risk Factors For Atherosclerosis That Are Associated With Lactic Acidosis, Bone Loss And Coronary Artery Calcification

Age

1.    Lactic acidosis[49,50]
2.    Bone loss[51]
3.    Coronary artery calcification[52]

Increased brain lactate is the hallmark of ageing, which is associated with an elevation of brain lactate due to effects on lactate dehydrogenase.[49] In that regard, a 1989 study designed to obtain normal blood chemistry references in elderly subjects, reviewed pertinent laboratory data from 1822 male and 1870 females.  The values for most analyses except inorganic phosphorus and total protein were significantly higher in males than female when compared to subjects aged 21 to 50, The values for lactic dehydrogenase, albumin, sodium, and calcium were higher in females older than 50 years of age than in their counterpart. When males and females were combined, the normal reference ranges for lactic dehydrogenase, alkaline phosphatase, uric acid, blood urea nitrogen, creatinine and potassium tended to be elevated, while those for total protein, albumin and calcium declined with aging.[50] In the aging skeleton, bone volume and mass declines in both sexes and in people of all ethnic backgrounds, and is often associated with osteoporosis and an increased risk of fracture.[51]

As Leopold noted, “Vascular calcification, once considered a passive consequence of aging, is now recognized to be a highly regulated process akin to bone formation. Vascular calcification is prevalent across ethnicities and age groups and observational studies show an interaction with aging in asymptomatic adults and in individuals with established coronary artery disease.” [52]

Diabetes

1.    Lactic acidosis[53-55]
2.    Bone loss[56-58]
3.    Coronary artery calcification[59]
As noted in a 2016 study, “Elevated circulating lactate is a common occurrence in diabetes patients and this finding suggest it may contribute to the increased prevalence of vascular calcification in this population.” [53]

Hypertension

1.    Lactic acidosis[60]
2.    Bone loss[61]
3.    Coronary artery calcification[62,63]

Smoking

1.    Lactic acidosis[64,65]
2.    Bone loss[66]
3.    Coronary artery calcification[67]

Chronic Kidney Disease

1.    Lactic acidosis [68,69]
2.    Bone loss [70]
3.    Coronary artery calcification [71,72]

High Carbohydrate Diets

1.    Lactic acidosis [73-75]
2.    Bone loss [76]
3.    Coronary artery calcification [77,78]

“High levels of sugar-sweetened carbonated beverage consumption may be associated with a higher prevalence and degree of CAC in asymptomatic adults without a history of cardiovascular disease, cancer, or diabetes.” [77]
“Diets low in carbohydrate and high in fat and/or protein, regardless of the sources of protein and fat, were not associated with higher levels of CAC, a validated predictor of cardiovascular events, in this large multi-ethnic cohort.“ [78]

Rheumatoid Arthritis

1.    Lactic acidosis [79]
2.    Bone loss [80,81]
3.    Coronary artery calcification [82,83]

Air Pollution

1.    Lactic acidosis[84]
2.    Bone loss[85]
3.    Coronary artery calcification[86]

Drugs that are associated with lactic acidosis, bone loss and coronary artery calcification

Warfarin

1.    Lactic acidosis [87]
2.    Bone loss [88]
3.    Coronary artery calcification [89]

Metformin

1.    Lactic acidosis[91-93]
2.    Bone loss[94]
3.    Coronary artery calcification[95]

Several older studies showed that metformin was osteogenic in vitro. In contrast, recent research found no effect of metformin on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells. And a 2015 report on forty postmenopausal diabetic women found that metformin is neither osteogenic nor did it have anti-osteoporotic effects.[94] A more recent report found that there were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity.[95] However, according to the authors, there are several limitations in their study, since “Interpretation of the effect of the interventions was based on the assumption that there were no differences in baseline CAC given the randomization of subjects into intervention groups at baseline.” In addition, “We found no differences in cardiometabolic risk factors at baseline between treatment groups except for slightly lower HDL-C and higher smoking rates in women in the placebo group only”, and concluded that “Whether these findings translate into beneficial effects on CVD events will require follow-up”[95]

Statins

1.    Lactic acidosis [96-98]
2.    Bone loss [99, 117]
3.    Coronary artery calcification [100]

The 2015 JUPITER Trial in men and women with evidence of inflammation concluded that randomization to rosuvastatin did not reduce the risk of fracture and that, higher baseline high sensitivity C-Reactive Protein was not associated with an increased risk of fracture.[99] This is consistent with other statin trial results. The authors also state, “Baseline use of thiazide diuretics, bisphosphonates, calcium, vitamin D, and inhaled or oral steroids did not result in a change in effect estimates and thus were omitted from the multivariate model.”[99] However, it is important to emphasize that bisphosphonates reduce the increased production of lactic acid caused by statins, therefore offsetting their negative effects, which could have influenced the JUPITER statistics and conclusions.

A 2016 study[100] found that statin intake in subjects with an LDL cholesterol equal or greater than 115 milligrams per deciliter, was associated with lower CAC progression than statin intake in subjects with LDL cholesterol levels below 115 mg/dL. But guidelines suggest that individuals with an optimal LDL-C at or below 100 mg/dL have lower rates of heart disease and stroke, and some claim that LDL-C should be lowered as much as possible. This could pose a perplexing problem for physicians when prescribing statins.

A study published in 2019 concluded that the diagnosis of osteoporosis in statin-treated patients is dose-dependent[117]
The acidity theory of atherosclerosis theory may be helpful in this regard, because of the following findings.

a.    Lowering pH augments the oxidation of low-density lipoprotein (LDL) by releasing iron and copper radicals, and decreasing anti-oxidant defenses.[101,102]
b.    LDL oxidation occurs within lysosomes in macrophages of atherosclerotic lesions rather than the surrounding interstitial fluid. Most importantly, studies have shown that this oxidative process can be promoted by an acidic pH, and is inhibited by chloroquine, which increases lysosome pH. [103]

Coronary Artery Calcium is Associated With An Increase In Major Adverse Cardiovascular Events Over The Next 3 Months

A study presented at the American College of Cardiology Scientific Session on March 16, 2019, reported that patients whose scans revealed significant CAC scores were at higher risk of a cardiac event within 90 days compared with controls whose scans showed no CAC. The study involved 5,547 symptomatic patients without a history of coronary artery disease or elevated troponin, who underwent Rb-82 cardiac PET/CT scans from April 2013 to July 2016. CAC was associated with a statistically significant higher risk of 90-day coronary angiography, high-grade obstructive CAD, revascularization and long-term major adverse coronary events (p<0.0001).[104]

It is important to recognize that the heart is an organ that is always active and never rests, in contrast to other muscles in the body. Chronic or acute elevations of catecholamines can accelerate myocardial glycolysis and result in a significant increase in lactate production during coronary events.[105]

Stroke, Acidosis and Coronary Artery Calcification

Acidosis is also a hallmark of stroke[106] and the presence and severity of coronary artery calcification is an independent predictor of future stroke events in the general population.[107,108]

Cancer, Acidosis and Coronary Artery Calcification

Acidosis is another hallmark of cancer,[109] and the 2015 Multi-Ethnic Study of Atherosclerosis trial demonstrated an increase in the incidence of coronary artery calcification over time in individuals with cancer compared with non-cancer controls.[110] This relationship persisted even when other risk factors for atherosclerosis were excluded. A subsequent 2018 study revealed that cancer chemotherapy can also worsen CAC.[111] In that regard, it is important to note that Cisplatin, a popular chemotherapy drug in use for over four decades has recently been shown to cause acidosis.[112]
Conclusion

We have tried to demonstrate and explain how lactic acidosis increases coronary artery calcification and why various drugs and other factors also influence this process. Long-term and high dose statin therapy increase coronary artery calcification, which poses a problem for practitioners.[113] Statin proponents claim that spotty and incomplete calcification is more likely to cause major adverse events and that statins stabilize vulnerable plaque.[114] They also propose that PCSK9 inhibitors suppress coronary artery calcification by regulation of inflammation.[115]
However, we concur with A. Arbeb-Zadah and V. Fuster’s conclusion that:

“Despite major advancements in coronary artery imaging and identification of atherosclerotic lesion morphology associated with rupture, there is no conclusive evidence that individual plaque assessment better predicts acute coronary event risk than established risk factors, such as the extent and severity of coronary artery disease. Pathology and clinical studies consistently demonstrate that atherosclerotic plaques rupture without clinical symptoms much more frequently than is widely acknowledged, challenging the notion of a close association between plaque rupture and clinical events.”[116]

In addition to coronary artery calcification, lactic acidosis may also cause calcification in the aortic valve, brain, and other tissues.

The introduction of this article was developed by Prof. Dr. Paul J. Rosch, Chairman from The American Institute of Stress,  to whom I dedicate our present postulation on lactic acidosis as cause of coronary artery calcification, noting that this is not the first time I have been inspired by this brilliant teacher and researcher.

The postulation contained in the present article was first introduced during my lecture on March 27 at the “Fifth International Congress for Advanced Cardiac Sciences. King Of Organs, 2019”, occurred in Saudi Arabia (Schedule at https://bit.ly/2G5U3xe )

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