Newly Identified Risks Of Excess Homocysteine

Few debates expose the inability of mainstream medicine to recognize disease causation more than the homocysteine controversy.

No one disputes that homocysteine is toxic to our inner arterial lining.^1,2

No one disputes that arterial disease is the leading cause of disability and death.^3,4

If we are to achieve healthy longevity free from heart failure,^5-8 stroke,^9-11 and dementia,^12,13 we cannot allow our bodies to be poisoned by excess homocysteine blood levels.

The debate about homocysteine and atherosclerosis dates back to 1968. Compared to previous medical controversies, this 47-year time interval may appear trivial.¹⁴

For instance, bloodletting began around 500 B.C. and became near universal standard of care before the medical establishment rejected it in the early 20^th century. The number of deaths caused by physician-induced bloodletting was astronomical, yet it took 2,500 years to figure this out.^15,16

The problem today is that doctors are overlooking health risks associated with elevated homocysteine, despite new scientific studies documenting dangers that extend beyond increased heart attack risk.^17-21

A significant proportion of Americans have a genetic defect that predisposes them to high homocysteine.^22-25 The exciting news is that proper blood testing can readily identify these individuals so they can take one simple step to slash their homocysteine down to a safe range.

In 1981, we advised our members to keep their homocysteine levels low to protect against heart attack and stroke. At the time, there were only 12 published studies available to make this recommendation, yet we were confident in the strength of the data 34 years ago.^{1,2,7,8,26-33}

Move forward to the year 2015 and more than 2,000 published studies are found when searching “homocysteine and heart disease” on the National Library of Medicine database.

What happened between 1968 and 2015 shows how challenging it can be for the medical establishment to adopt new concepts into standard practice. When studies were conducted on high-risk patients using standard B vitamins to modestly lower homocysteine and anticipated benefits did not occur, doctors declared that homocysteine was not a risk factor for vascular disease.

The problem with these studies is that they were seriously flawed. In 2010, we meticulously exposed defects in these studies to demonstrate how meaningless they were to individuals who took steps to properly lower their homocysteine levels.¹⁷

Since our original rebuttals to the flawed homocysteine reports, newly published research further corroborates our long-standing position about the risks posed by excess homocysteine.

For example, a study published in 2014 took a closer look at previous work that proclaimed no benefit to lowering homocysteine. This more detailed analysis revealed a 24% reduced risk of stroke, heart attack, and death in patients older than 67 years given high-dose B vitamins to lower homocysteine.³⁴ This finding makes sense based on the fact that modestly elevated homocysteine does not usually create arterial disease early in life; i.e. it takes decades for damage to our endothelial lining to manifest as frank vascular disease.

A more striking risk reduction occurred in a clinical trial of elderly individuals published in 2014 who received a statin drug (pravastatin) to lower their cholesterol levels versus placebo. Patients in the placebo group with high homocysteine showed a 1.8-fold higher overall risk of developing fatal and nonfatal coronary heart disease.³⁵

Role Of Homocysteine In Vascular Dementia

The scientific community now largely accepts the role of homocysteine in heart disease. What’s overlooked is the adverse impact of elevated homocysteine on short-term memory and dementia risk.

A study published in 2014 evaluated a group of people (average age 64) with vascular cognitive impairment, but who were not demented. After only one year, patients with high homocysteine showed a 4.2-fold increased rate of clinically diagnosed dementia.³⁶

High blood pressure was an even greater determinant of who progressed to vascular dementia, which led the authors of this study to conclude that patients with vascular cognitive impairment “should receive vigorous controls of hypertension and high homocysteine.”³⁶

Another 2014 study looked at people with high homocysteine and uric acid and found a startling 10.5-fold greater risk of vascular dementia.¹² The authors of this study noted that elevated levels of homocysteine and uric acid are both well-known risk factors for cardiovascular disease, so it is not surprising that they also contribute to vascular dementia (neurovascular disease).

A 2013 study found that patients with vascular dementia “exhibit particularly elevated levels of plasma total homocysteine” and suggested that homocysteine may serve as a marker for the disease in addition to it being a contributing factor.¹³

When entering the term “homocysteine and vascular dementia” into the National Library of Medicine database, more than 240 published studies can be found dating back to the year 1992.

Does Homocysteine Increase Alzheimer’s Risk?

As we have published in this magazine over the years, vascular dementia and Alzheimer’s disease are often intertwined.^37-40 What happens is that capillary blood flow is impaired as a result of the endothelial damage caused by excess homocysteine. Beta-amyloid plaques then appear in these blood flow-deprived areas of the brain.^41,42 The result in many cases is clinically diagnosed Alzheimer’s disease.^9,18,43,44

Studies show that homocysteine may be toxic to brain cells, in addition to disrupting cerebral blood flow. A systematic review of published studies starting in 1990 and extending to 2012 found that high homocysteine increased Alzheimer’s risk by 1.93-fold, whereas physical activity and omega-3 fatty acids conferred a protective effect.⁴⁵

A 2013 review looked at the effects of lowering homocysteine for the purposes of protecting against mild cognitive impairment and Alzheimer’s. Based on findings from several previous studies, these researchers concluded that treating patients with B vitamins to lower homocysteine could “prevent or delay cognitive decline and Alzheimer’s disease.”⁴⁶

Homocysteine alone is not the sole cause of age-associated cognitive decline or Alzheimer’s, but it appears to be a significant contributory factor.

There remains an open controversy as to whether mere treatment with B vitamins will protect against Alzheimer’s. You’re going to learn later in this article why conventional B vitamins don’t always provide necessary homocysteine-lowering effects.

Homocysteine Worsens Diabetic Complications

Based on a recent report from the CDC, 86 million Americans age 20 and older were found to have prediabetes.⁴⁷ This is diagnosed when fasting blood glucose levels are in the 100 to 125 mg/dL range.⁴⁸ Optimal fasting glucose is under 86 mg/dL.

During the prediabetic period before frank type II diabetes is diagnosed, substantial damage to the arterial lining occurs.^49,50 This is attributed to the widely fluctuating levels of after-meal glucose and insulin suffered by prediabetics and explains why diabetic complications often manifest before frank type II diabetes is diagnosed.

A 2014 study looked at cardiovascular risk factors beyond glucose and hemoglobin A1C in prediabetics and found that homocysteine and blood thickness are significantly higher in prediabetic patients compared to controls.⁵¹ The authors suggested that homocysteine and blood viscosity be used as markers in prediabetics to identify subclinical cardiovascular disease and take preventive measures before a heart attack or stroke manifests.

Another 2014 study cited previous research showing that high homocysteine levels are correlated with increased mortality in type II diabetic patients.⁵² The researchers then looked at the impact of high homocysteine and type II diabetes in experimental models and found that endothelial damage inflicted by high glucose is worsened by high homocysteine blood levels.

Peripheral neuropathy is a common complication of diabetes that is associated with poor glycemic control.⁵³ Recent clinical studies reveal that high homocysteine exaggerates the prevalence of peripheral neuropathy in diabetics and exacerbates preexisting diabetic neuropathy.^54-57

In a community-based study of 483 adults, a high prevalence of peripheral neuropathy was observed among undiagnosed diabetics.⁵⁴ After an analysis that controlled for age, it was found that low education, hemoglobin A1C, smoking, and elevated homocysteine were independently associated with peripheral neuropathy.⁵⁴ The role of high homocysteine as an independent risk factor associated with increased prevalence of diabetic neuropathy has been supported by other clinical studies.^55,56,58,59

The take-home lesson for anyone with glycemic control issues is that aggressively lowering homocysteine is of the utmost importance. Just as important are comprehensive blood tests to evaluate vascular markers (like C-reactive protein) that doctors today don’t normally associate with diabetic complications.

Cerebral Circulatory Deficit

Normal aging results in diminished capillary blood flow to the brain. The medical term for reduced blood flow is “hypoperfusion” and it has been implicated in premature brain aging and neurodegenerative disease.^60-64

A 2014 study identified excess homocysteine as a specific marker for reduced cerebral perfusion in a group of healthy subjects aged 50 to 75 years.⁶⁵ The findings corroborate previous research associating high homocysteine with diminished capillary blood flow in the brain.⁹

Another 2014 study looked at the carotid arteries, which are the largest blood vessels feeding the brain. When factoring in other independent variables such as LDL-cholesterol, hemoglobin A1C, and C-reactive protein, homocysteine was the strongest predictor of carotid blood flow resistance in men older than 65.⁶⁶ This finding is corroborated by previous research showing elevated homocysteine to be significantly associated with carotid artery disorders.^67-69

Aging robs the brain of vital blood flow through occlusion of the large carotid arteries extending from the base of the neck into the brain. Cerebral circulation is further impaired by blockage of microscopic capillaries that feed individual brain cells. Elevated homocysteine damages the carotid arteries^69,70 and cerebral capillaries, thus depriving the brain of critical blood flow in two lethal ways.^71-73

Our Shrinking Brains

An increased rate of brain atrophy (shrinkage) is often observed in elderly people, especially in those who suffer from cognitive decline.^74,75

A study published in 2010 evaluated a group of people over age 70 with mild cognitive impairment to ascertain if lowering homocysteine with B vitamins would reduce the rate of brain shrinkage measured by MRI scans. The results showed that compared to the placebo arm of the study, those taking the B vitamins showed almost 30% less brain shrinkage.⁷⁴

In patients in this study with higher baseline homocysteine levels (>13 µmol/L), treatment with B vitamins resulted in a remarkable 53% lower rate of brain atrophy. What this finding suggests is that those with higher homocysteine levels suffer greater brain atrophy and derive greater benefit when homocysteine levels are brought down. This study showed that greater rate of brain atrophy resulted in lower cognitive test scores.⁷⁴ The authors of the study concluded:

“The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins…
Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.”⁷⁴

Move forward four years to 2014 and a study was published whereby researchers looked at the impact of homocysteine on hippocampal volume in a group of elderly patients with varying degrees of cognitive function. After ruling out other known causes of brain atrophy, homocysteine was deemed to be independently associated and significantly involved with hippocampal volume shrinkage.⁷⁶ This led the researchers to conclude that high homocysteine has a “direct adverse effect” on hippocampal volume.

The hippocampus is the part of the brain that is involved in forming,⁷⁷ organizing,⁷⁸ and storing memories.^79,80 Based on these findings, the adverse impact of elevated homocysteine on hippocampal volume is depriving aging individuals of the ability to form new memories and connect emotions and senses with past memories, and is placing individuals with high homocysteine at greater risk of dementia.

Yet homocysteine blood testing is still not being routinely done in the clinical setting, which is needlessly condemning large segments of the aging population to cognitive impairment, dementia, and loss of independence.

Surviving A Stroke

Homocysteine is a risk factor for suffering a stroke,^117,118 but the impact of high homocysteine on the neurological deterioration that occurs after a stroke was not known until recently.

Recovery from an ischemic stroke is highly dependent on the brain’s ability to survive the temporary loss of blood flow. Without recovery, the outcome is paralysis or death.

A 2014 study assessed whether an association existed between elevated homocysteine and neurological deterioration in patients with acute ischemic stroke. A total of 396 stroke patients were studied. The results showed that high homocysteine levels were independent predictors for poor outcomes in these acute stroke victims.¹⁰

Most striking about this study was what the researchers defined as “high” homocysteine blood levels. In patients with homocysteine levels above 10.3 µmol/L, there was a 3.45-fold increase in independent predictors of early neurological deterioration.¹⁰

Conventional medicine does not believe homocysteine poses a health problem until blood levels exceed 15 µmol/L.¹¹⁹ Yet this randomized double-blind, multicenter trial showed that homocysteine levels over 10.3 µmol/L markedly worsened outcomes for stroke victims. The conclusion by the authors of this study was simple and to the point:

“Patients with acute stroke with elevated serum homocysteine levels are at an increased risk for early neurological deterioration.”¹⁰

Life Extension^® has long urged members to keep their homocysteine blood levels below 7 to 8 µmol/L whenever possible. This study on acute stroke patients and other recent studies show that homocysteine levels considered “safe” by the medical establishment are quite injurious to the brain, heart, kidneys, and other tissues.^120-127

What Causes High Homocysteine?

Homocysteine forms in the body from the amino acid methionine.¹¹⁵ Foods such as cereals, legumes, seafood, meat, and dairy products are rich in methionine¹²⁸ so it is difficult for most people to consistently consume a methionine-deficient diet.

Fortunately, your body has detoxification enzymes that keep homocysteine levels in safe ranges. These homocysteine detoxification enzymes are dependent on the B vitamins, primarily folate, B12, and B6.^128-136

Cigarette smoking depletes folic acid in the body, causing smokers to have notoriously high levels of homocysteine.^137-139

As we age, our homocysteine detoxification mechanisms become impaired, often resulting in sharply higher homocysteine levels¹⁴⁰ in elderly individuals¹⁴¹ that can be accompanied by accelerated atherosclerosis.¹⁴²

Genetic Defect Causes High Homocysteine

For the majority of people, the proper intake of folic acid, vitamins B12, and B6 and other nutrients will keep their homocysteine levels in safe ranges.

A surprisingly high proportion of Americans,^25,143 however, suffer a genetic defect that impairs their ability to convert folic acid into its biologically active form called 5-methyltetrahydrofolate (5-MTHF).^144-147

Folic acid itself will not adequately rid the body of excess homocysteine. It needs to be converted to 5-MTHF. The chart on the following page shows the advantage of 5-MTHF over synthetic folic acid.

Fortunately, there is now a high-dose dietary supplement that contains the enzymatically active 5-MTHF form of folate. The advantage of 5-MTHF is that it does not require conversion in the body to slash homocysteine blood levels.^147,148 Another plus to 5-MTHF is that it readily crosses the blood-brain barrier to facilitate cognitive function.¹⁴⁹

Aging individuals with rising homocysteine levels now have a potent new weapon to reduce their homocysteine level even if they don’t have a defect in their folate-converting genes.

Efficient Way To Determine Who Needs 5-MTHF

There are several variations of genotypes that could hinder one’s ability to convert folic acid into biologically-active 5-methyltetrahydrofolate (5-MTHF).^144-147

Rather than pay for these expensive genetic tests, it is far more efficient to have one’s homocysteine blood level tested once a year.

Anyone with a homocysteine reading substantially over 8 µmol/L should take at least one 5,000 micrograms tablet of 5-MTHF daily. Those with homocysteine readings above 12 µmol/L might need to take a 5-MTHF 5,000 micrograms tablet twice daily.

The objective in taking 5-MTHF is to reduce homocysteine levels to optimal safe ranges. If your homocysteine blood test results come back in the low range, then you don’t need to take 5-MTHF.

For optimal homocysteine reduction, adequate amounts of other B vitamins are also required, especially vitamins B2 (50 mg), B6 (75 mg), and B12 (300 micrograms). Sufficient doses of these B vitamins can be found in high-potent multivitamins. In rare cases of B12 absorption problems, vitamin B12 shots (1,000 micrograms) several times a week are needed.

Critical Importance Of Comprehensive Annual Blood Tests

As you can see on page 6, there are 17 independent risk factors for vascular disease. What this means is that if just one of these markers is out of balance, it can lead to a heart attack or stroke.

The reality for individuals as they age is that they might develop multiple imbalances in their blood such as elevated glucose, LDL, triglycerides, and homocysteine that conspire to sharply increase vascular risks.^93,151-153

This is why comprehensive annual blood testing is so critical to protecting against today’s leading killers. Standard blood tests omit the majority of independent vascular risk factors, which explains why arterial disease continues at epidemic levels despite widespread testing for glucose and lipids.

What we have observed in reviewing our members’ blood test results for the past four decades is how quickly a lethal blood marker can elevate over a year’s period of time. For example, it is not unusual for homocysteine levels to spike over a 12-month period as aging wears down detoxification processes.

The good news is that when elevated homocysteine is detected, it can easily be brought down with low-cost 5-methyltetrahydrofolate (5-MTHF).¹⁵⁰

Discount Blood Testing

Since the early 1980s, Life Extension^® has advised its members to have annual blood tests to identify disease risk factors that can be reversed before serious illness develops.

A barrier some members face is that their conventional doctor still doesn’t recognize the dangers of elevated homocysteine and refuses to test for it. Another problem is that even when doctors order all the blood tests requested, the phlebotomist often fails to check off the appropriate codes on the laboratory requisition form or does not properly draw the blood. When the results come back incomplete, another blood draw becomes necessary, thus inconveniencing the patient.

Even today, most doctors fail to routinely test a patient’s blood for important cardiovascular risk factors such as homocysteine and C-reactive protein. Life Extension^® resolved this problem 19 years ago by offering comprehensive blood test panels directly to its members.

Once a year we discount the prices of all our blood tests to a fraction of the price charged by commercial labs. For example, the many tests included in our comprehensive Male or Female Panels can cost around $1,000 at commercial laboratories. Yet members obtain these identical tests during the annual Blood Test Super Sale for only $199.

In addition to the cost savings, members benefit by the convenience of walking into a blood drawing station in their neighborhood, usually without an appointment required. Results come back within a few days and are mailed and/or emailed directly to you. If you have questions about your blood test results, our health advisors are available seven days a week to assist.

Based on what I have discovered as a result of having my blood tested regularly, I am convinced that I have corrected the risk conferred by a number of genetic risk factors that would otherwise have predisposed me to a premature illness or death.

I hope no serious health enthusiast will neglect their annual pilgrimage to a local blood draw station to ensure their homocysteine and other disease risk markers are maintained in optimal safe ranges.

To order a Male or Female Panel, call 1-800-208-3444.

For longer life,

William Faloon

References

1. Wall RT, Rubenstein MD, Cooper SL. Studies on the cellular basis of atherosclerosis: the effects of atherosclerosis risk factors on platelets and the vascular endothelium. Diabetes. 1981;30(Suppl 2):39-43.
2. Wall RT, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. 1980 Apr 1-15;18(1-2):113-21.
3. Murphy SL, Xu JQ, Kochanek KD. Deaths: Final data for 2010. Natl Vital Stat Rep. 2013;61(4).
4. Available at: http://www.who.int/mediacentre/factsheets/fs310/en. Accessed February 18, 2015.
5. Vasan RS, Beiser A, D’Agostino RB, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA. 2003 Mar 12;289(10):1251-7.
6. Vizzardi E, Bonadei I, Zanini G, et al. Homocysteine and heart failure: an overview. Recent Pat Cardiovasc Drug Discov. 2009 Jan;4(1):15-21.
7. McCully KS. Homocysteinemia and arteriosclerosis. Am Heart J. 1972 Apr;83(4):571-3.
8. McCully KS. Macromolecular basis for homocystein-induced changes in proteoglycan structure in growth and arteriosclerosis. Am J Pathol. 1972 Jan;66(1):83-96.
9. Feng C, Bai X, Xu Y, Hua T, Huang J, Liu XY. Hyperhomocysteinemia associates with small vessel disease more closely than large vessel disease. Int J Med Sci. 2013 10(4):408-12.
10. Kwon HM, Lee YS, Bae HJ, Kang DW. Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke. Stroke. 2014 Mar;45(3):871-3.
11. Narang AP, Verma I, Kaur S, Narang A, Gupta S, Avasthi G. Homocysteine--risk factor for ischemic stroke? Indian J Physiol Pharmacol. 2009 Jan-Mar;53(1):34-8.
12. Cervellati C, Romani A, Seripa D, et al. Oxidative balance, homocysteine, and uric acid levels in older patients with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci. 2014 Feb 15;337(1-2):156-61.
13. Nilsson K, Gustafson L, Hultberg B. Elevated plasma homocysteine level in vascular dementia reflects the vascular disease process. Dement Geriatr Cogn Dis Extra. 2013 Jan;3(1):16-24.
14. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56:111–28.
15. Greenstone, G. The history of bloodletting. BCMJ, 2010; 52(1), page(s) 12-14.
16. Ulvik RJ. Bloodletting as medical therapy for 2,500 years. Tidsskr Nor Laegeforen. 1999 Jun 30;119(17):2487-9.
17. Available at: https://www.lifeextension.com/magazine/2010/12/why-reading-mainstream-magazines-can-be-detrimental-to-your-health/page-01. Accessed December 15, 2014.
18. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
19. Cho NH, Lim S, Jang HC, Park HK, Metzger BE. Elevated homocysteine as a risk factor for the development of diabetes in women with a previous history of gestational diabetes mellitus: a 4-year prospective study. Diabetes Care. 2005 Nov;28(11):2750-5.
20. Cahill M, Karabatzaki M, Meleady R, et al. Raised plasma homocysteine as a risk factor for retinal vascular occlusive disease. Br J Ophthalmol. 2000 Feb;84(2):154-7.
21. Enneman AW, Swart KM, Zillikens MC, et al. The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons. Bone. 2014 Jun;63:141-6.
22. Kraus JP, Janosik M, Kozich V, et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mut. 1999;13:362–75.
23. Adinolfi LE, Ingrosso D, Cesaro G, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology. 2005 May;41(5):995-1003.
24. Li XM, Wei YF, Hao HL, et al. Hyperhomocysteinemia and the MTHFR C677T mutation in Budd-Chiari syndrome. Am J Hematol. 2002 Sep;71(1):11-4.
25. Peng F, Labelle LA, Rainey BJ, Tsongalis GJ. Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. Int J Mol Med. 2001 Nov;8(5):509-11.
26. Gupta VJ, Wilcken DE. The detection of cysteine-homocysteine mixed disulphide in plasma of normal fasting man. Eur J Clin Invest. 1978 Aug;8(4):205-7.
27. Grieco AJ. Homocystinuria: pathogenetic mechanisms. Am J Med Sci. 1977 Mar-Apr;273(2):120-32.
28. Wilcken DE, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest. 1976 Apr;57(4):1079-82.
29. McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis. 1975 Sep-Oct;22(2):215-27.
30. McCully KS. Growth disorders and homocysteine metabolism. Ann Clin Lab Sci. 1975 May-Jun;5(3):147-52.
31. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia. Am J Pathol. 1970 Oct;61(1):1-11.
32. McCully KS. Importance of homocysteine-induced abnormalities of proteoglycan structure in arteriosclerosis. Am J Pathol. 1970 Apr;59(1):181-94.
33. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969 Jul;56(1):111-28.
34. Towfighi A, Arshi B, Markovic D, Ovbiagele B. Homocysteine-lowering therapy and risk of recurrent stroke, myocardial infarction and death: the impact of age in the VISP trial. Cerebrovasc Dis. 2014 37(4):263-7.
35. Drewes YM, Poortvliet RK, Blom JW, et al. Homocysteine levels and treatment effect in the PROspective Study of Pravastatin in the Elderly at Risk. J Am Geriatr Soc. 2014 Feb;62(2):213-21.
36. Tan C, Peng W, Deng Y. Risk factors and predictive factors of cognitive deterioration in patients of vascular cognitive impairment no dementia with subcortical ischemic vascular disease. Zhonghua Yi Xue Za Zhi. 2014 Feb 11;94(5):352-5.
37. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord. 1999 Oct-Dec;13 Suppl 3:S115-23.
38. Román G. Diagnosis of vascular dementia and Alzheimer’s disease. Int J Clin Pract Suppl. 2001 May;(120):9-13.
39. Wallin A. The overlap between Alzheimer’s disease and vascular dementia: the role of white matter changes. Dement Geriatr Cogn Disord. 1998 Jul;9 Suppl 1:30-5.
40. Ravona-Springer R, Davidson M, Noy S. Is the distinction between Alzheimer’s disease and vascular dementia possible and relevant? Dialogues Clin Neurosci. 2003 Mar;5(1):7-15.
41. Zhang CE, Wei W, Liu YH, et al. Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am J Pathol. 2009 Apr;174(4):1481-91.
42. Irizarry MC, Gurol ME, Raju S, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology. 2005 Nov 8;65(9):1402-8.
43. Humpel C. Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol. 2011 Apr;46(4):225-32.
44. Muradashvili N, Tyagi R, Metreveli N, Tyagi SC, Lominadze D. Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia. J Cereb Blood Flow Metab. 2014 Sep;34(9):1472-82.
45. Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643.
46. Cacciapuoti F. Lowering homocysteine levels with folic acid and B-vitamins do not reduce early atherosclerosis, but could interfere with cognitive decline and Alzheimer’s disease. J Thromb Thrombolysis. 2013 Oct;36(3):258-62.
47. National Diabetes Statistics Report: Estimates of diabetes and tts burden in the United States, 2014 . Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 2014.
48. Xing FY, Neeland IJ, Gore MO, et al. Association of prediabetes by fasting glucose and/or haemoglobin A1c levels with subclinical atherosclerosis and impaired renal function: observations from the Dallas Heart Study. Diab Vasc Dis Res. 2014 Jan;11(1):11-8.
49. Suzuki K, Watanabe K, Futami-Suda S, et al. The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance. Cardiovasc Diabetol. 2012 Aug 14;11:98.
50. Lott ME, Slocomb JE, Shivkumar V, et al. Impaired retinal vasodilator responses in prediabetes and type 2 diabetes. Acta Ophthalmol. 2013 Sep;91(6):e462-9.
51. Nwose EU, Richards RS, Bwititi PT. Cardiovascular risks in prediabetes: preliminary data on “vasculopathy triad”. N Am J Med Sci. 2014 Jul;6(7):328-32.
52. Cheng Z, Jiang X, Pansuria M, et al. Hyperhomocysteinemia and hyperglycemia induce and potentiate endothelial dysfunction via µ-calpain activation. Diabetes. 2014 Oct 28.
53. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes. 2005;23:9-15.
54. Bruce SG, Young TK. Prevalence and risk factors for neuropathy in a Canadian First Nation community. Diabetes Care. 2008 Sep;31(9):1837-41.
55. Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001 Mar;18(3):185-92.
56. Cohen JA, Jeffers BW, Stabler S, Schrier RW, Estascio R. Increasing homocysteine levels and diabetic autonomic neuropathy. Auton Neurosci. 2001 Mar 23;87(2-3):268-73.
57. Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol. 2014 Oct;10(4):281-8.
58. González R, Pedro T, Martinez-Hervas S, et al. Plasma homocysteine levels are independently associated with the severity of peripheral polyneuropathy in type 2 diabetic subjects. J Peripher Nerv Syst. 2012 Jun;17(2):191-6.
59. Jianbo L, Yuche C, Ming S, et al. Association of homocysteine with peripheral neuropathy in Chinese patients with type 2 diabetes. Diabetes Res Clin Pract. 2011 Jul;93(1):38-42.
60. Farkas E, de Wilde MC, Kiliaan AJ, Luiten PG. Chronic cerebral hypoperfusion-related neuropathologic changes and compromised cognitive status: window of treatment. Drugs Today (Barc). 2002 May;38(5):365-76.
61. Bennett SA, Tenniswood M, Chen JH, et al. Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment. Neuroreport. 1998 Jan 5;9(1):161-6.
62. Kim HA, Miller AA, Drummond GR, et al. Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):953-9.
63. Fernández-Seara MA, Mengual E, Vidorreta M, et al. Cortical hypoperfusion in Parkinson’s disease assessed using arterial spin labeled perfusion MRI. Neuroimage. 2012 Feb 1;59(3):2743-50.
64. Fernando MS, Simpson JE, Matthews F, et al. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006 Jun;37(6):1391-8.
65. Henriksen OM, Jensen LT, Krabbe K, Guldberg P, Teerlink T, Rostrup E. Resting brain perfusion and selected vascular risk factors in healthy elderly subjects. PLoS One. 2014 May 19;9(5):e97363.
66. Okura T, Miyoshi K, Irita J, et al. Hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males. Sci Rep. 2014 Jul 11;4:5663.
67. Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation. 1993 Apr;87(4):1107-13.
68. Symons JD, Mullick AE, Ensunsa JL, Ma AA, Rutledge JC. Hyperhomocysteinemia evoked by folate depletion: effects on coronary and carotid arterial function. Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):772-80.
69. Voutilainen S, Alfthan G, Nyyssönen K, Salonen R, Salonen JT. Association between elevated plasma total homocysteine and increased common carotid artery wall thickness. Ann Med. 1998 Jun;30(3):300-6.
70. Demuth K, Drunat S, Girerd X, et al. Homocysteine is the only plasma thiol associated with carotid artery remodeling. Atherosclerosis. 2002 Nov;165(1):167-74.
71. Dayal S, Blokhin IO, Erger RA, et al. Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia. PLoS One. 2014 Sep 16;9(9):e107734.
72. Kloppenborg RP, Geerlings MI, Visseren FL, et al. Homocysteine and progression of generalized small-vessel disease: the SMART-MR Study. Neurology. 2014 Mar 4;82(9):777-83.
73. Hornstra JM, Hoekstra T, Serné EH, et al. Homocysteine levels are inversely associated with capillary density in men, not in premenopausal women. Eur J Clin Invest. 2014;44(3):333-40.
74. Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain at­­rophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010 Sep 8;5(9):e12244.
75. Scahill RI, Frost C, Jenkins R, Whitwell JL, Rossor MN, Fox NC. A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch Neurol. 2003 Jul;60(7):989-94.
76. Choe YM, Sohn BK, Choi HJ, et al. Association of homocysteine with hippocampal volume independent of cerebral amyloid and vascular burden. Neurobiol Aging. 2014 Jul;35(7):1519-25.
77. Preston AR, Eichenbaum H. Interplay of hippocampus and prefrontal cortex in memory. Curr Biol. 2013 Sep 9;23(17):R764-73.
78. Coras R, Pauli E, Li J, et al. Differential influence of hippocampal subfields to memory formation: insights from patients with temporal lobe epilepsy. Brain. 2014 Jul;137(Pt 7):1945-57.
79. Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol. 2004 Apr;14(2):198-202.
80. Teyler TJ, DiScenna P. The hippocampal memory indexing theory. Behav Neurosci. 1986 Apr;100(2):147-54.
81. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol. 1993 22 Suppl 4:S1-14.
82. Bolad I, Delafontaine P. Endothelial dysfunction: its role in hypertensive coronary disease. Curr Opin Cardiol. 2005 Jul;20(4):270-4.
83. Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010 Dec;12(6):448-55.
84. Rajendran P, Rengarajan T, Thangavel J, et al. The vascular endothelium and human diseases. Int J Biol Sci. 2013. Nov 9;9(10):1057-69.
85. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54.
86. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001 Nov 27;104(22):2673-8.
87. Chrissobolis S, Miller AA, Drummond GR, Kemp-Harper BK, Sobey CG. Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front Biosci. (Landmark Ed). 2011 Jan 1;16:1733-45.
88. Malyszko J. Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta. 2010 Oct 9;411(19-20):1412-20.
89. Chade AR, Zhu X, Lavi R, et al. Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation. 2009 Feb 3;119(4):547-57.
90. Asfar S, Safar HA. Homocysteine levels and peripheral arterial occlusive disease: a prospective cohort study and review of the literature. J Cardiovasc Surg (Torino). 2007 Oct;48(5):601-5.
91. Malinow MR, Kang SS, Taylor LM, et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation. 1989 Jun;79(6):1180-8.
92. Brattström L, Israelsson B, Norrving B, et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis. 1990 Feb;81(1):51-60.
93. Baszczuk A, Kopczyński Z, Thielemann A. Endothelial dysfunction in patients with primary hypertension and hyperhomocysteinemia. Postepy Hig Med Dosw (Online). 2014 Jan 30;68:91-100.
94. Chen Y, Zhao S, Wang Y, et al. Homocysteine reduces protein S-nitrosylation in endothelium. Int J Mol Med. 2014 Nov;34(5):1277-85.
95. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 suppl 1):III27-32.
96. Vuckovic BA, Cabarkapa VS, Ilic TA, Salatic IR, Lozanov-Crvenkovic ZS, Mitic GP. Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients. Croat Med J. 2013 Oct 28;54(5):480-8.
97. Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis. Thromb Res. 2008;122(6):727-35.
98. Riba R, Nicolaou A, Troxler M, Homer-Vaniasinkam S, Naseem KM. Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels. Atherosclerosis. 2004 Jul;175(1):69-75.
99. Woo KS, Chook P, Lolin YI, et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation. 1997 Oct 21;96(8):2542-4.
100. Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, S­­trongin RM. Homocystamides promote free-radical and oxidative damage to proteins. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):551-4.
101. Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal. 2007 Nov;9(11):1941-58.
102. Mujumdar VS, Aru GM, Tyagi SC. Induction of oxidative stress by homocyst(e)ine impairs endothelial function. J Cell Biochem. 2001;82:491-500.
103. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia isassociated with impaired endothelium-dependent vasodilation in humans. Circulation. 1997 Mar 4;95(5):1119-21.
104. Stühlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation . 2003 Aug 26;108(8):933-8.
105. Weiss N, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med. 2002 Aug;7(3):227-39.
106. Zhang C, Cai Y, Adachi MT, et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem. 2001 Sep 21;276(38):35867-74.
107. Outinen PA, Sood SK, Pfeifer SI, et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood. 1999 Aug 1;94(3):959-67.
108. Perła-Kaján J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids. 2007;32(4):561-72.
109. Harpel PC, Zhang X, Borth W. Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr. 1996 Apr;126(4 Suppl):1285S-9S.
110. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001 Mar;107(6):675-83.
111. Genoud V, Lauricella AM, Kordich LC, Quintana I. Impact of homocysteine-thiolactone on plasma fibrin networks. J Thromb Thrombolysis. 2014 Nov;38(4):540-5.
112. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr. 2000 Feb;130(2S Suppl):369S-372S.
113. Guthikonda S, Haynes WG. Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep. 2006;8:100–6.
114. Kim CS, Kim YR, Naqvi A, et al. Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc. Cardiovasc Res. 2011 Dec 1;92(3):466-75.
115. Hanratty CG, McGrath LT, McAuley DF, Young IS, Johnston GD. The effects of oral methionine and homocysteine on endothelial function. Heart. 2001 Mar;85(3):326-30.
116. Chambers JC, Obeid OA, Kooner JS. Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2922-7.
117. Zhong C, Lv L, Liu C, et al. High homocysteine and blood pressure related to poor outcome of acute ischemia stroke in Chinese population. PLoS One . 2014 Sep 29;9(9):e107498.
118. Goldstein LB. Novel risk factors for stroke: homocysteine, inflammation, and infection. Curr Atheroscler Rep. 2000 Mar;2(2):110-4.
119. Dankner R1, Chetrit A, Dror GK, Sela BA. Physical activity is inversely associated with total homocysteine levels, independent of C677T MTHFRgenotype and plasma B vitamins. Age (Dordr). 2007 Dec;29(4):219-27.
120. Liu XQ, Liu XQ, Jiang P, Huang H, Yan Y. Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof. Zhonghua Yi Xue Za Zhi. 2008 Aug 19;88(32):2246-9.
121. Matsui T, Nemoto M, Maruyama M, et al. Plasma homocysteine and risk of coexisting silent brain infarction in Alzheimer’s disease. Neurodegener Dis . 2005 2(6):299-304.
122. Prins ND, Den Heijer T, Hofman A, et al. Rotterdam Scan Study. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology. 2002 Nov 12;59(9):1375-80.
123. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation. 2004 Jun 8;109(22):2766-72.
124. Spence JD. Patients with atherosclerotic vascular disease: how low should plasma homocysteine levels go? Am J Cardiovasc Drugs. 2001 1(2):85-9.
125. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death, the Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial. JAMA. 2004 Feb 4;291(5):565-75.
126. Chao MC, Hu SL, Hsu HS, et al. Serum homocysteine level is positively associated with chronic kidney disease in a Taiwan Chinese population. J Nephrol. 2014 Jun;27(3):299-305.
127. Nerbass FB, Draibe SA, Feiten SF, et al. Homocysteine and its determinants in nondialyzed chronic kidney disease patients. J Am Diet Assoc. 2006 Feb;106(2):267-70.
128. Available at: https://www.lifeextension.com/protocols/heart-circulatory/homocysteine-reduction/page-01. Accessed December 29, 2014.
129. Selhub J, Jacques PF, Rosenberg IH, et al. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med. 1999 Sep 7;131(5):331-9.
130. Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J Cardiol. 1999 Mar 15;83(6):821-5.
131. Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004 Jul;11Suppl1:S56-64.
132. Lee H, Kim JM, Kim HJ, Lee I, Chang N. Folic acid supplementation can reduce the endothelial damage in rat brain microvasculature due to hyperhomocysteinemia. J Nutr. 2005 Mar;135(3):544-8.
133. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999 Dec;34(7):2002-6.
134. Oltean S, Banerjee R. Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J Biol Chem. 2003 Jun 6;278(23):20778-84.
135. Vermeulen EG, Stehouwer CD, Twisk JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet. 2000 Feb 12;355(9203):517-22.
136. Vermeulen EG, Stehouwer CD, Valk J, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial. Eur J Clin Invest. 2004 Apr;34(4):256-61.
137. Mannino DM, Mulinare J, Ford ES, Schwartz J. Tobacco smoke exposure and decreased serum and red blood cell folate levels: data from the Third National Health and Nutrition Examination Survey. Nicotine Tob Res. 2003 Jun;5(3):357-62.
138. Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. The associations between smoking, physical activity, dietary habits and plasma homocysteine levels in cardiovascular disease-free people: the “ATTICA” study. Vasc Med. 2004 May;9(2):117-23.3811.
139. O’Callaghan P, Meleady R, Fitzgerald T, Graham I. Smoking and plasma homocysteine. Eur Heart J. 2002 Oct;23(20):1580-6.
140. Sinha M, Saha A, Basu S, Pal K, Chakrabarti S. Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): implications in the pathogenesis of Alzheimer’s disease. Neurosci Lett. 2010 Oct 11;483(2):123-6.
141. McCully KS. Chemical pathology of homocysteine. III. Cellular function and aging. Ann Clin Lab Sci. 1994 Mar-Apr;24(2):134-52.
142. Agrawal A, Ilango K, Singh PK, et al. Age dependent levels of plasma homocysteine and cognitive performance. Behav Brain Res. 2015 Jan 16. pii: S0166-4328(15)00020-0.
143. Greenberg JA, Bell SJ, Guan Y, Yu YH. Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011 Summer;4(2):52-9.
144. Girelli D, Martinelli N, Pizzolo F, et al. The interaction between MTHFR 677 C-->T genotype and folate status is a determinant of coronary atherosclerosis risk. J Nutr. 2003 May;133(5):1281-5.
145. Cotlarciuc I, Malik R, Holliday EG, et al. Effect of genetic variants associated with plasma homocysteine levels on stroke risk. Stroke. 2014 Jul;45(7):1920-4.
146. Girelli D, Friso S, Trabetti E, et al. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction. Blood. 1998 Jun 1;91(11):4158-63.
147. Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol. 2004 Mar;141(5):825-30.
148. Prinz-Langenohl R, Brämswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009 Dec;158(8):2014-21.
149. Available at: http://www.cancer.gov/drugdictionary?cdrid=750726. Accessed February 19,2015.
150. Caruso R, Campolo J, Sedda V, et al. Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia. J Cardiovasc Pharmacol. 2006 Apr;47(4):549-55.
151. Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol. 1992 Aug;263(2 Pt 2):H321-6.
152. Yokoi T, Fukuo K, Yasuda O, et al. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells. Diabetes. 2006 Jun;55(6):1660-5.
153. Russo GT, Giandalia A, Romeo EL, et al. Lipid and non-lipid cardiovascular risk factors in postmenopausal type 2 diabetic women with and without coronary heart disease. J Endocrinol Invest. 2014 Mar;37(3):261-8.