Part of my job as a specialist in preventive cardiology is to stay abreast of all the latest developments and share them with patients. Key developments in preventive cardiology in recent years have been:

- The stratification of risk using blood markers such as high sensitivity C reactive protein, fibrinogen, homocysteine, Lipoprotein (a), Apo b, plasminogen activator inhibitor 1 and so forth

- Measuring lipoprotein particle size, number and density (NMR, VAP)

- Using electron beam computed tomography to measure plaque. This is also known as the “heart scan.”

A new test has emerged over the last few years that may rival all other medical tests for heart disease risk. This new test measures the thickness of the blood, technically called blood viscosity.[1] This new test gives two numbers, one for blood moving very slowly (called low shear viscosity) and the other for blood that is moving fast (called high shear viscosity). Whole blood is a fluid that behaves in a non-linear fashion similar to catsup or motor oil. It is thicker at rest and thinner when it is moving- much like catsup leaving the mouth of a bottle.

I have written previously on the role of blood viscosity in exercise performance and how blood viscosity may be related to heart disease in athletes. Accumulating evidence suggests that increased blood viscosity is an independent risk factor for atherosclerotic heart disease and its complications. [2] In this article I will discuss the entire topic as it relates to the work the heart must do and how elevated blood viscosity may be the real cause of atherosclerosis.

Atherosclerosis is an inflammatory response the body mounts to injurious insults at the artery wall. Think of it like a callus you might get on your skin in response to friction. A callus of this type is not detrimental, in fact it improves function. However, the body adapts to stress in various ways, not all of them are beneficial in the long term. Forming a callus in your artery is a good example of an adaptation that may protect the artery in the short term but decrease functionality in the long term.

After an artery wall becomes injured, it forms a scar and the scar can grow forming more extensive plaque over time. Plaque grows in size and shape over time depending on genetic, environmental and biochemical factors. Plaque can do two bad things. It can occlude (block) the artery and cause limitations to blood flow or it can rupture and cause a heart attack. The main cause of heart attacks is a plaque rupture. Gradually occluding coronary arteries limit blood flow to the heart and often the patient will have symptoms such as chest pain or shortness of breath, but not always.

Heart disease is a term the media likes to use to describe coronary artery disease (CAD)[3] but this is a general term that includes many disorders. To discuss all these is beyond the scope of this paper and includes prolapsed (leaky) valves, irregular heart beat, and heart failure.  The topic I am concerned with is preventing heart attacks, the main cause of death for Americans. To do this we must reverse or stabilize plaque.

Now that we know that plaque is the problem lets discuss how and why plaque forms.

Arteries have three layers starting from the inside out with the intima, then the media and finally the adventitia (Fig 1). The intima is composed of a single layer of endothelial cells. Endothelial cells are similar to skin cells. The intima is the one most involved in atherosclerosis, specifically a dysfunctional intima. Endothelial dysfunction is the term that describes an intima that is not functioning well. Endothielial dysfunction has been described as the cause of atherosclerosis.

When the intima is injured platelets adhere the injured area and release growth factors that lead to the growth of endothelial cells. These cells try to cover up the injured area. As a result, muscle cells move to the intima and the intima becomes thicker. This process is an adaptive response to injury that improves function in the short at the expense of long term function. In the end stage of atherosclerosis the plaque is so large that the center outgrows the blood supply and it becomes more susceptible to rupture.

Additionally, there are three basic types of plaque, soft, and hard plaque. These are also referred to as vulnerable and stable plaque, respectively. Mixed plaque is a combination of the two.  Researchers are still trying to determine the exact characteristics that make a plaque unstable. Plaque generally starts with a thin fibrous cap and progresses as more calcium is deposited and a stronger cap is formed. Two features of plaque that make it more vulnerable are spotty calcium deposits and a lipid (fatty) core. Estimating one’s degree of vulnerable plaque subject to rupture is an inexact science. How much calcification occurs in an individual is variable and depends on certain factors. Vitamin K and D imbalances, coumadin therapy and existing kidney disease are a few factors that increase calcification.

Endothelial dysfunction

The endothelium controls constriction and expansion of the artery (think blood pressure), coagulation (clotting), and inflammatory responses. The endothelium is the layer of cells right next to where the blood flows.  When healthy, the endothelial layer keeps plaque from forming, maintains good blood flow, and controls blood pressure. Endothelial dysfunction leads to hypertension and plaque. Many researchers think that endothelial dysfunction is the final common pathway in heart disease. Through proper treatment, endothelial function can be restored.

Endothelial dysfunction precedes plaque formation in the artery wall and often gets worse as the plaque becomes more extensive. An improvement in endothelial function is associated with a decreased risk of future cardiovascular events.

But what causes endothelial dysfunction? Causes include smoking, diabetes, high blood pressure, LDL cholesterol, homocysteine, oxidative stress and shear stress. Interesting, all these factors also cause elevated blood viscosity. Elevated blood viscosity is the reason why plaque is often site specific.

In exploring how and where plaque forms we can see why cholesterol alone can not be the main cause of atherosclerosis and here why:

1.    Premenopausal women have less risk of heart disease than men because they have lower blood viscosity. Estrogen may play a role but the monthly menstrual cycle is more important. Menstruation causes a monthly loss of blood which keeps viscosity down and also lowers iron levels. Iron is a potent but necessary free radical promoting metallic ion but the reason women have less atherosclerosis is not due to lower iron alone. Studies have been done comparing heart attack incidence in groups of men who do and do not donate blood that support my argument.

2.    When veins are used in bypass surgery they form plaque and “arterialize” because they are subject to more shear stress and mechanical stress. The shear stress is a function of velocity and viscosity. Mechanical stress is determined by how forcefully the heart beats and how high the peak systolic and pulse pressures are.

3.    Veins do not form plaque because the blood pressure, pulse pressure, and shear stress are low. If cholesterol alone were the main determinant of atherosclerosis we would see in veins.

4.    Arteries subject to the highest mechanical stress and shear stress have the most plaque.

5.    Healthy adults with normal blood pressure and normal cholesterol can have sudden heart attacks. How can this be? It’s Because of blood viscosity.

6.    Heart attacks occur more frequently in the morning because blood viscosity and clot formation is at its highest.

Why lowering your blood viscosity through therapeutic phlebotomy is a very good idea:

1.    Therapeutic phlebotomy is the medical term for removing blood. In practical terms you just donate blood. Sometimes your blood may not be eligible for donation and in that case we will do it for you. The blood is then discarded and picked up by a medical waste company. Your body makes new red blood cells to replace of the ones lost. Think of this as “blood rejuvenation.” Old cells are stiff and don’t deform well when they need to get through a vessel that is narrower then the width of the cell. New cells deform much better and are able to deliver oxygen to tissues more efficiently. The net effect is improved cardiovascular efficiency because the work of the heart is reduced and oxygen delivery improves.

2.    Donating blood decreased the number of old rigid cells. Because old rigid cells can not deform well, they cause frictional damage to the artery wall at high velocities. The callus of atherosclerosis is an adaptive response to this frictional damage.

3.    Lowering you blood viscosity reduces the wear and tear on your arteries. Also known as shear stress, this slow continuous damage accelerates atherosclerosis.

4.    Lowering your blood viscosity through donating blood makes your heart more efficient. Decreasing your blood viscosity lowers peripheral resistance to flow and lowers the “contractility” of the heart’s left ventricle. This, in turn, lowers the pulse pressure and peak systolic pressure. Less pressure = less damage to the artery wall and less work for the heart.

5.    In the human body, blood viscosity dictates how hard the heart must work to pump blood. Any increase in the work of the heart absorbed by the arterial system either by stretching or by friction on the inner artery wall (the endothelium).

What are some other factors that affect blood viscosity?

Red blood cell volume also known as hematocrit is the largest determinant of blood viscosity.  The following affect blood viscosity:

1.    HDL: Low HDL increases blood viscosity high HDL decreases it

2.    LDL cholesterol: LDL is inversely related to blood viscosity.

3.    Triglycerides: Triglycerides are a type of fat in the blood that can raise viscosity.

4.    Smoking

5.    Diabetes and elevated blood sugar

6.    Exercise: Exercise reduces blood viscosity, a sedentary lifestyle increases it.

7.    Obesity increases blood viscosity

8.    Sex: Premenopausal women have lower blood viscosity than men of the same age

9.    Elevated plasma proteins (IgA, IgG, IgM). This can be seen with a special blood test.

10.                       Fibrinogen: Fibrinogen forms fibrin a component of blood clots. Fibrinogen increases blood viscosity and increases risk of heart attack.

11.                       Loss of red blood cell deformability as seen in sickle cell anemia and diabetes. Red blood cell size is about 7.5 um while the inside diameter is most capillary vessels is 4 to 9 um. Thus, red blood cells must alter their shape or deform to get through these tiny vessels. Fish oil help improve red blood cell deformability.

What evidence is there that lowering whole blood viscosity (WBV) helps prevent heart attacks and stroke?

1.    Koenig et al. conducted a study on the relationship between blood viscosity and heart attacks in 1998. He examined 933 males between the ages of 45 and 64 years of age. The researchers reported that subjects with viscosity in the highest quintile were three times more likely to have fatal and non fatal cardiac events compared with those subjects in the lowest quintile (A quintile is one fifth or 20% of a given amount).

2.    Junker et al. compared the degree of vessel occlusion in 1142 male patients who had survived a heart attack in 1998. Patients were divided into two groups without any, and with one to three stenosed vessels. They found a positive relationship between plasma viscosity and the severity of coronary heart disease, even after adjusting groups for age, fibrinogen, and use of diuretics. Differences between the groups were significant.

3.    Yarnell et a. compared plasma viscosity, fibrinogen, and white blood cell counts in 4,860 middle aged men. The chances of dying or having a heart attack for men with viscosity measurements in the highest quintile (20%) were almost five times than for the men in the lowest tertile (20%).

4.    Ranier et al. measured blood viscosity in 17 patients with chest pain (angina). Compared to patients without chest pain the patients with chest pain all had elevated blood viscosity, hematocrit and red blood cell aggregation.

5.    Resch et al. looked at the association of blood viscosity and future cardiovascular events in stroke survivors. His team followed 625 stroke survivors for an average of two years. A total of 85 patients (13.6%) had a second stroke or heart attack. Whole blood viscosity and fibrinogen were higher in the patients who had cardiovascular events than in those who did not. Fibrinogen is a major contributor to elevated WBV. Others have found the same association. Di Perri et al. examined 106 patients with cerebrovascular disease and noted that symptoms were associated with increases in WBV, fibrinogen and red blood cell deformability. Acute symptoms regressed when the WBV was lowered. Other researchers including Fong and Chia, Coull et al., Grotta et al and Ernst et al support these findings.

High Blood pressure

Blood viscosity also affects blood pressure. Elevated blood pressure is a major risk factor for developing atherosclerosis and becomes a stronger risk factor after age 45. Remember that blood pressure depends on two factors; cardiac output and total peripheral resistance. Elevated blood viscosity increases peripheral resistance. Blood pressure must increase to maintain cardiac output when there increased resistance due to hyper-viscous blood (Stoltz et al.) Increased blood pressure then damages arteries further.

Koenig et al. found that plasma viscosity was more strongly associated with hypertension than smoking, cholesterol and alcohol. Fossum et al. reported that WBV was directly related to systolic blood pressure, total cholesterol triglycerides, body mass index. Subjects with blood pressure over 130 all had higher blood viscosity.

In summary, blood viscosity may be the final common pathway to atherosclerosis. Elevated WBV increases arterial mechanical stress due to increased pulsitile forces and increased stretching of the vessel wall. Shear stress is damage caused by the frictional forces of thick blood on the arterial wall, causing endothelial dysfunction. I believe that treating elevated WBV can result in regression of plaque and a lower overall risk of stroke and heart attack. I recommend blood viscosity testing for all patients 35 and over with a positive family history of heart disease, anyone with atherosclerosis (or a positive heart scan) and for all patients with high blood pressure.

Aspirin is used for a wide variety of indications, and an analysis of randomized trials by Rothwell and colleagues, which was published in the January 1, 2011, issue of the Lancet, found that aspirin was effective in reducing the overall risk for death from cancer. Aspirin was particularly effective in reducing the risk for death from gastrointestinal tract cancer, and longer duration of aspirin therapy was associated with greater reductions in cancer mortality risks. However, the dose of aspirin did not appear to affect this outcome.

Nonetheless, many reviews have failed to provide a balance between the risks and benefits of aspirin as primary preventive therapy. A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1].

Senior author Dr Kausik Ray (St George's University of London, UK) commented: "On a routine basis I would not recommend aspirin use in primary prevention”.

The new analysis included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal myocardial infarction (MI), but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.

Effect of Aspirin on Vascular and Nonvascular Outcomes or Death (below I = benefit)

Possible Benefit in Those at High Risk

The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk.

1.    Seshasai SRK, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med 2012; DOI:10.1001/archinternmed.2011.628. Available at: http://archinte.ama-assn.org/cgi/content/short/archinternmed.2011.628.

My Comments:

1.    I only advise aspirin for patients at high risk for heart attack and stroke (as demostrated by high CIMT, high calcium score or previous history of MI or stroke).

2.    I never use it in patients with high blood pressure as it may cause a hemorrhagic stroke.

3.    I do like to use 81 mg in people with a strong family history of GI cancer.

4.    I use it when there is elevated blood viscosity along with natto and phosphatidylcholine.

Tocotrienols are effective in lowering serum total and LDL-cholesterol levels by inhibiting the hepatic enzymic activity of beta-hydroxy-beta-methylglutaryl coenzymeA (HMG-CoA) reductase through the post-transcriptional mechanism. alpha-Tocopherol, however, has an opposite effect (induces) on this enzyme activity. Since tocotrienols are also converted to tocopherols in vivo, it is necessary not to exceed a certain dose, as this would be counter-productive. The present study demonstrates the effects of various doses of a tocotrienol-rich fraction (TRF25) of stabilized and heated rice bran in hypercholesterolemic human subjects on serum lipid parameters. Ninety (18/group) hypercholesterolemic human subjects participated in this study, which comprised three phases of 35 days each. The subjects were initially placed on the American Heart Association (AHA) Step-1 diet and the effects noted. They were then administered 25, 50, 100, and 200 mg/day of TRF25 while on the restricted (AHA) diet. The results show that a dose of 100 mg/day of TRF25 produce maximum decreases of 20% (total cholesterol), 25% (LDL-cholesterol), 14% (apolipoprotein B)  and 12% (triglycerides), respectively, suggesting that a dose of 100 mg/day TRF25 plus AHA Step-1 diet may be the optimal dose for controlling the risk of coronary heart disease in hypercholesterolemic human subjects.

TRF25 works in similar way to a statin but withmuch fewer if any side effects. Also, there is no inhibition of CoQ10 synthesis. 

Atherosclerosis. 2002 Mar;161(1):199-207. Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Qureshi AA, Sami SA, Salser WA, Khan FA.

Background  

Exhausting exercise induces muscle damage associated with high production of free radicals and pro-inflammatory mediators.

Aim  

The objective of this study was to determine for the first time and simultaneously whether oral coenzyme Q₁₀ (CoQ₁₀) supplementation can prevent over-expression of inflammatory mediators and oxidative stress associated with strenuous exercise.

Methods  

The participants were classified in two groups: CoQ₁₀ group (CG) and placebo group (PG). The physical test consisted in a constant run (50 km) that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing.

Results  

Exercise was associated with an increase in TNF-α, IL-6, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and isoprostane levels, revealing the degree of inflammation and oxidative stress induced. Oral supplementation of CoQ₁₀ during exercise was efficient reducing oxidative stress (decreased membrane hydroperoxides, 8-OHdG and isoprostanes generation, increased catalase, and total antioxidant status), which would lead to the maintenance of the cell integrity. Data obtained also indicate that CoQ₁₀prevents over-expression of TNF-α after exercise, together with an increase in sTNF-RII that limits the pro-inflammatory actions of TNF. Moreover, CoQ₁₀ supplementation reduced creatinine production.

Conclusions  

CoQ₁₀ supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.

Study: Coenzyme Q₁₀ supplementation ameliorates inflammatory signaling and oxidative stress associated with strenuous exercise. EUROPEAN JOURNAL OF NUTRITION DOI: 10.1007/s00394-011-0257-

A new analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) shows that changes in coronary artery calcium (CAC) (as measured by the heart scan) may lag behind changes in coronary disease risk factors. 

CAC is a common measure of subclinical coronary disease, but the association between changes in coronary disease risk factors and progression of CAC is not clear. So Arguelles and colleagues analyzed data from 6800 participants of the MESA study. All participants underwent a CAC imaging test with computed tomography at baseline and either 1.6 or 3.2 years later. A quarter of the study subjects also underwent a third CAC test at an average of 4.9 years after baseline.

Reason: Individuals who come in with a very high risk-factor profile and are the most likely to be placed on medications already have a very high underlying level of pathology that could be driving that calcification process independent of declines in risk factors, including blood pressure, lipid levels, and blood glucose. 

The authors analyzed if the changes in CAC over time were associated with changes in blood pressure and lipid levels. The analysis was adjusted for age, ethnicity, smoking status, family history of cardiovascular disease, total income as a marker of socioeconomic status, and previous use of hypertension, lipid, and glucose-lowering drugs.

Among men who had detectable CAC at baseline, CAC increased an average of 57 Agatston units/year. In women, CAC progressed by 39 Agatston units/year. In all patients, the risk-factor measures went up or down depending on whether they were taking antihypertensivse, statins, or other medications. 

The researchers said that CAC "occurs in a time-lagged fashion" such that a longer study would have eventually seen CAC progression stop or reverse many years after the reversal in risk factors in patients taking medication. Whether risk factors such as high blood pressure and hyperlipidemia are more important to the initiation of calcification--or if they have more of a role in the progression of existing disease--is not clear yet.

I like to use CAC for a baseline before treatment or to monitor progress. I aslo require all chelation patients to get one. I have seen this time lag in my practice many times now but it took me about three years to notice it. It typically takes two to three years to see a reversal of plaque after initiating aggressive treatment. This is a very important thing to explain to patients. I typically see less calcium deposition per year the above numbers because I use combination therapy.  A moderate to high risk patient in my office would typically be on some or all of the following: fish oil, Coenzyme Q10, statins, vitamin K2, vitamin D, blood pressure meds, antioxidants, superoxide dismutase, pomegranate, phosphatidylcholine, lipoic acid, vitamin C, niacin and tocotrienols. After all, the goal is to reverse plaque or stop its progression. Sometimes patients do intravenous treatments as well.

Vitamin D deficiency is traditionally associated with bone and muscle weakness, but in recent years a number of studies have shown that low levels of the vitamin may predispose the body to high blood pressure, congestive heart failure, and chronic blood vessel inflammation leading the increased risk of heart attack.. It also alters hormone levels to increase insulin resistance, which raises the risk of diabetes. Several large studies have shown that people with low vitamin D levels were twice as likely to have a heart attack, stroke, or other heart-related event during follow-up, compared with those with higher vitamin D levels.

In a review article published in the Journal of the American College of Cardiology, researchers surveyed recent studies on the link between vitamin D deficiency and heart disease to come up with practical advice on screening and treatment. 

They concluded that vitamin D deficiency is much more common than previously thought, affecting up to half of adults and apparently healthy children in the U.S. 

Researchers say higher rates of vitamin D deficiency may be due in part to people spending more time indoors and efforts to minimize sun exposure through the use of sunscreens. Sunscreen with a sun protection factor (SPF) of 15 blocks approximately 99% of vitamin D synthesis by the skin. An hour in the sun without sunblock at the beach in mid summer will cause the skin to produce about 10,000 iu of vitamin D. 

We are outside less than we used to be, and older adults and people who are overweight or obese are less efficient at making vitamin D in response to sunlight. A little bit of sunshine is a good thing, but the use of sunscreen to guard against skin cancer is still a good idea for prolonged sun exposure.

Vitamin D levels can be measured with a blood test that looks at a specific form of vitamin D called 25-hydroxy vitamin D (25(OH)D). Vitamin D deficiency is defined as a blood 25(OH)D level below 20 ng/dL. Normal levels are considered to be above 30 ng/dL. Optimal evels are between 50 and 80ng/dL.

Low serum testosterone is associated with increased adiposity, an adverse metabolic risk profile, and atherosclerosis. However, few prospective studies have demonstrated a protective link between endogenous testosterone and CV events. Polymorphisms in the SHBG gene are associated with risk of type 2 diabetes, but few studies have addressed SHBG as a predictor of CV events.

Results

During a median 5-year follow-up, 485 CV events occurred. Both total testosterone and SHBG levels were inversely associated with the risk of CV events (trend over quartiles: p = 0.009 and p = 0.012, respectively). Men in the highest quartile of testosterone (≥550 ng/dl) had a lower risk of CV events compared with men in the 3 lower quartiles (hazard ratio: 0.70, 95% confidence interval: 0.56 to 0.88). This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline (hazard ratio: 0.71, 95% confidence interval: 0.53 to 0.95). In models that included both testosterone and SHBG, testosterone but not SHBG predicted CV risk.

Conclusion

High serum testosterone predicted a reduced 5-year risk of CV events in elderly men.

Study: Journal of the American College of Cardiology, Volume 58, Issue 16, 11 October 2011, Pages 1674-1681

http://www.medscape.com/viewarticle/751263?src=mpnews Absolute garbage study, seriously. Regression analysis studies are notoriously inaccurate and the supplement use was self-reported. Why would a postmenopausal woman need iron anyway? Of course, iron should not be taken unless needed otherwise it can increase oxidative stress and risk of heart attack and stroke. Also, associating vitamin use with overall mortality is a pretty poor endpoint. Quality of life should be the endpoint.

Zinc can be toxic at high doses and zinc deficiency is associated with macular degeneration, low SOD function and low metalloproteinase activity in adults. Zinc and iron can be measured in the blood to determine if supplemental use is needed. As far as the calcium is concerned I question any association at all with overall mortality. It helps bone density and prevents colon cancer but increases heart attack risk (maybe). Possibly the benefits and risks cancel each other out.