Metabolic Syndrome and Cardiovascular Disease: Aa Look at the Mechanism tThat Drives This Inflammatory Process.

Part 1: – Understanding the Metabolic Problem.

Submission by Gary Huber, D.O., AOBEM

As a board -certified emergency medicine physician for 20 years I have treated more acute MIs (myocardial infarctions) MI’s than I care to remember. The devastation that an ischemic event causes to the individual, the family and the community at large is overwhelming. With todaystoday’s new paradigm that cardiovascular disease is the result of inflammation we can lay old myths aside and now realize a great opportunity to impaaffect the course of inflammation, the direction of plaque formation and retard the progression of this disease long before the first chest pain is ever felt.

I propose a linear thought:, which is that inflammation from any source follows a simple path of cytokine emergence to cardiovascular disease. Our lifestyle in this country has chronically been the source of inflammation even dating back to the time of the Korean conflict. In 1953 a study of our fallen soldiers revealed that upon autopsy, 77.3% of these young men (average age 22 years old) had gross evidence of coronary plaque.¹ Since then our use of wheat and its hybridization has only gotten worse, as Dr. William Davis reports in his book “Wheat Belly” that 20% of Amercia’sAmerica’s present caloric intake comes from wheat alone. Our American diet and lifestyle of stress and over commitment continually contributes to inflammation as we watch metabolic syndrome rise at an alarming rate.

Metabolic Synsyndrome now affects more than a third of all Americans. NHANES data reports a rise in Metmetabolic Synsyndrome from 29% in 1994, to 34% in 2006. This is an age and weight related occurrence. Above age 40 you are 3 times more likely to meet criteria for Metmetabolic Synsyndrome. Overweight males increase their risk 6- fold and obese males have a 32- fold rise in risk. With 70% of the American population presently being overweight or obese, this represents a huge burden medically, financially, and emotionally.
There is ample data showing that metabolic syndrome is an inflammatory state that leads to MI’s, stroke, and dementia. The mechanism is clear, as cytokine inflammation from multiple inflammatory triggers is generated from suboptimal lifestyle choices. This is an epigenetic phenomenon, and as such there are very real solutions that we can employ to divert this pathophysiology towards a healthfuly path, avoiding the all too common vascular insult.
Metabolic syndrome represents run away inflammation with excess insulin production representing the first domino to fall in a chain reaction that results in eventual vascular plaque formation. Anything that reduces this process will ultimately reduce cardiovascular risk. So how do we define inflammation in this current age to aggressively reduce the occurrence of vascular disease?

GRAPHIC: Lifestyle choices, habits, and diet lead to inflammation in the form of IL-1, IL-6, TNFaTNF-α , which cause acute phase reactants such as fibrinogen and, PAI-1, leading to endothelial dysfunction and cellular damage representing the end points of Metmetabolic Synsyndrome that over time lead to myocardial infarction, stroke, and general decay.

As an integrative care physician, I offer this view:

1. Lifestyle choices provide the genesis of inflammation – food, sleep, stress, etc.and so on – generate inflammatory cytokines. Admittedly, this list of inflammatory etiologies could be endless (toxins, gum disease, allergies, etc.), but let us focus on these 3 three common and primary movers.
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2. Cytokine generation causes Metmetabolic Synsyndrome as a progressive disorder typically starting with insulin resistance.
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1. Metabolic syndrome is the pathway to cardiovascular disease. It is also the source of cerebrovascular disease, dementia, and cancer as inflammatory end points; but our focus here is cardiovascular.
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1. Cardiovascular disease in an inflammatory disorder, not simply a dysfunction of cholesterol. It can be measured and quantified long before an MI occurs.²
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As physicians we need to talk with our patients about epigenetics and help foster understanding that what we become in our lifetime is dominantly (95%) the result of choices, not genes (5%). LetsLet’s look at a few lifestyle factors that generate inflammation in the body: sleep, diet, and stress (cortisol).

Sleep

As a culture, American’s have lost our understanding of the importance of sleep. We give it away as if it were an inconvenient extravagance in exchange for activities that ramp up our stress levels. A look at recorded national sleep questionnaires over the last few decades show that in the 1960s the average sleep cycle lasted 8 to -8.9 hours nightly. In fact, less than 15% reported sleeping less than 7 hours per night.³ From the 1970’s to the early 2000’s sleep duration dropped to only 7 hours nightly on average.⁴ From 2004 to present further reductions are seen, as most Americans report netting approximately 6 hours per night.

In the Kobayashi study of 44,452 patients, sleeping 6 hours or less a night significantly increased risk for developing Metmetabolic Synsyndrome.⁵ As sleep decreased the risk of metabolic syndrome rose to 42% occurrence and the risk for myocardial infarction was more than 4 times normal for those sleeping less than 6 hours.⁵

The risk of metabolic syndrome rose by 45% in patients sleeping less than 7 hours in a study by Hall.⁶ Another study demonstrated that sleep of 5 hours per night or less on a regular basis results in an increased risk for obesity of 73%.⁷
Experimental restriction of sleep to 4 hours per night for 6 nights resulted in impaired glucose tolerance (IGT) in healthy young adults.⁸ Loss of sleep below 7 hours consistently leads to diabetes, hypertension, increased mortality rates, as well as and cardiovascular disease regardless of age and prior health history.^6–-12

A study which followed 1,741 men and women for 14 years reported that those individuals who slept 6 hours of less had a significantly greater mortality rate than those sleeping 7 to -8 hours.¹³ American Academy of Sleep medicine states: “25 years of research has irrevocably proven that 65-70% of CV disease, MI’s, stroke, hypertension, can be attributed to sleep disordered breathing.”. Certainly we can move forward comfortable with the concept that as sleep deteriorates, we expect to see elevated or disordered cortisol production, abnormally elevated sympathetic tone, and a nidus for the generation of inflammatory cytokines.

Food and& Sugar

Simply observing the quantitative amounts of processed food intake relative to intake of whole foods will offer a significant clue to levels of inflammation in the body. Processed foods offer less nutritional value, reduced fiber content, and increased levels of sugar. This chronic intake of high- glycemic, low- fiber, processed foods provide greater risk for the development of insulin resistance and diabetes.

The medical profession’s recognition of risky behavior is blunted by a guideline that states any fasting blood sugar under 100 is “normal.”. A study from Kaiser Permanente of 46,000 patients followed over the course of 10 years showed us that insulin resistance, the precursor to diabetes and metabolic syndrome, starts long before our blood sugars rise over 100.¹⁴ In this study, for each point above 84 shown on a fasting blood glucose test, the risk of developing diabetes over the next 10 years rose by 6%. Thus a fasting blood glucose of 94, clearly read as “normal” by traditional standards, reflects an increased risk of 60% for the development of diabetes. This result is actionable now, not in 10 years. That rise in glucose is being echoed by a rise in insulin, which we know is causing cytokine induction and plaque formation. Essentially, a patient’s blood glucose and insulin are far more predictive of heart disease than traditional lipid panels. We will discuss the newer tests such as LDL-particle number and size as well as myeloperoxidase, CRP, homocysteine, and others but keep sight of glucose and insulin, as this is the fatal first flaw that drives inflammation.

The consumption of an inflammatory diet of sugar and grains has been shown in numerous studies to contribute to the risk for IBS, dysbiosis, altered immune response, cognitive insult, loss of probiotics, and chronic inflammation.^15-–19 This proven conclusion requires us to be proactive for our patients and guide them to better comprehension of the dangers of their present diet. We cannot afford to be vague and need to provide fully actionable step- by- step solutions if we are to complete our mission as health- care providers.

There are many contributing factors that result in the development of tType 2 diabetes, but diet plays the most significant role. The diagnosis of T2DM is synonymous with systemic inflammation and the elevation of cytokine levels resulting in a rise in CRP, PAI-1, fibrinogen, and other acute phase reactants, which ultimately lead to vascular disease and plaque. Elevated CRP and IL-6 rise and fall in response to insulin.²⁰ These inflammatory pathways, modulated by insulin, are infinitely responsive to diet and lifestyle features, including nutraceutical manipulation. We can discuss the pros and cons of drug therapy but food is far more powerful in its ability to create both healing or destruction.

Insulin’s effect on lipids and vascular tissue:

¥ Insulin halts the use of fat as cellular fuel, leading to triglyceride elevation
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¥ Triglycerides accumulate and VLDL rises
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¥ Insulin stimulates LDL production from the liver
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¥ Insulin increases LDL particle number
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¥ Insulin increases cytokine levels, which in turn oxidize LDL
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¥ Elevates vascular adhesion as well as ICAM-1, provoking plaque risk
¥ .

Consequently, offering drugs that simply promote greater production of insulin in a vain attempt to lower glucose is not going to lead to good long-term results. Our efforts are better directed at restoring altered cellular physiology to lower the need for excessive insulin or the efficiency of insulin at the receptor.

We can truly predict who is actively developing plaque based on simple lab parameters such as CRP, fasting glucose, and postprandial insulin. Angina, atherosclerosis, diabetes and even simple insulin resistance patients all show consistent inflammatory pathway elevation with enhanced acute phase response.^21-–23

Inflammation regardless of source, (aging, smoking, obesity, oral infections, etcetc.) leads to increased cytokine production producing chronic subclinical inflammation. Cytokines retard insulin receptor function and leads to HTN, dyslipidemia, and obesity, which all coalesce into risk for atherosclerosis disease.²⁴

The consistent link is “inflammation” reflected by elevation in CRP. As our new paradigm dictates, an elevated CRP is a warning of impending cardiovascular events even when cholesterol levels are completely normal.²⁵ The majority of myocardial infarctions occur in the face of normal cholesterol levels. If you haven’t addressed CRP then you have not reduced risk.

Our Iintake of dairy products and milk in particular has been correlated with an increased risk for the development of both type 1 and type 2 diabetes.²⁶ The presence of antibiotics and hormones in dairy foods have also contributed to general inflammation from our diet.

Wheat represents the greatest inflammatory risk in the American diet. Wheat is the single most common food allergen and represents a full 20% of our caloric intake. We are instructed by governmental agencies and even ill-advised health resources to eat 6 to 10 servings of grains per day. The American Heart Association recommends 6 to 8 servings of grain per day. The number one grain in this country is wheat, and wheat represents one of most consistent paths to digestive pathology, resulting in inflammation and cytokines. Wheat is a high- glycemic food, leading to elevated blood glucose, insulin, diabetes, and eventual heart disease.

Stress and& Cortisol

The normal inflammatory cascade has TNFaTNF-α response, leading to stimulation of IL-1. Both TNFaTNF-α and IL-1 stimulate the production of IL-6, which in turn acts as negative feedback to inhibit TNFaTNF-α and IL-1. IL-6 goes on to stimulate the acute phase reactants in the liver (fibrinogen, CRP, serum amyloid A, complement factors). Glucocorticoids (cortisol) inhibits the production of all 3 cytokines in a balanced physiology; but when balance has been disturbed, resulting in an altered function such as elevated HPA axis secondary to chronic stress, then this down-regulation does not occur.²⁷ Now we are left with run-away inflammation and table is set for vascular disease.

How significant is IL-6 in this cortisol- driven inflammatory response? IL-6 is produced by immune cells, endothelial cells, fibroblasts, myocytes, and adipose tissue. IL-6 stimulates the central and sympathetic nervous system, leading to HTN and autonomic imbalance; and in fact the presence of hypertension is an independent predictor of elevated IL-6 concentrations. Further exacerbating the picture, IL-6 can lead to increased collagen in the vessel wall, increase blood viscosity via elevated fibrinogen levels, and aeffects angiotensinogen expression, leading to higher concentration of angiotensin II.^28-–30

Cortisol excess induces increased TNF-α levels, which block the action of insulin
in vitro and in vivo. TNF-α results in serine phosphorylation of insulin receptor substrate 1, decreasing the tyrosine kinase activity of the insulin receptor rendering the cell incapable of proper insulin signaling.^31-–32 The result is the first step towards T2DM and the anticipated vascular insult.

Cortisol stimulates mass glucose mobilization via:

¥ liver gluconeogenesis
¥ blocks protein synthesis to push amino acids into sugar
¥ fatty acid liberation increases glucose
¥ stimulates visceral fat storage if this excess glucose is not quickly utilized, resulting in weight gain

Cortisol contributes to weight gain through multiple mechanisms. Abdominal obesity constitutes a low-grade inflammatory state, which, as we are well aware, produces inflammatory cytokines. Adiponectin levels are inversely related to weight. Adiponectin exhibits anti-inflammatory actions and favorable affects on insulin signaling and sensitivity. As weight rises and adiponectin falls, this further increases TNF-α activity. TNF-α is overexpressed in the adipose tissue of obese individuals compared to lean individuals. This increased expression of TNF-α blocks the action of insulin.³³ Studies show that weight loss directly increases adiponectin plasma levels, and adiponectin administration reverses insulin resistance associated with obesity.^34-,35

With weight comes biochemical alterations (adiponectin, TNFaTNF-α , IL-6, etcetc.) that result in cytokine inflammation and it’s associated endothelial dysfunction. The inflammatory attack on the endothelium has been shown to be reversible with weight loss. In a study of 56 obese pre-menopausal women, a body weight reduction of 10% was associated with a significant reduction in cytokine levels and an improvement in endothelial dysfunction.³⁶ A return toward normal physiology was evidenced by the fact that vascular response to arginine administration improved after loss of 10% body weight. The presence of cytokines had adversely altered nitric oxide physiology.

Stress as a source of inflammation is omnipresent. The very nature of the American lifestyle is to be plugged into all things at all times. Being over scheduled and overcommitted is common and catastrophic to good health. As our cortisol levels rise in response to poor sleep, bad diets, and excessive stress, we see cytokine production lead to dysfunction across all organ systems.

Thyroid function is adversely affected by excess cortisol, which inhibits the efficiency of T4 conversion to T3 and instead promotes greater conversion to reverse T3. Suboptimal thyroid function hampers cardiovascular performance, increasing risk for ischemia. Risk of death from CVD was 68% greater in patients with subclinical hypothyroid. Compared to with age matched controls, subclinical hypothyroid patients demonstrate greater occurrence of hypertension, diabetes, & and hyperlipidemia.³⁷ The effects of subclinical hypothyroidism results in a poor lipid profile with triglyceride elevation, small LDL particle size, and low levels of HDL.³⁸

Healthy thyroid presence is critical for homeostasis and, gene expression, and impacts affects cardiovascular contractility and remodeling. Thyroid stimulation of myocardial tissue regulates angiogenesis and favorably impacts affects myocyte regeneration, and improved left ventricular remodeling post infarction.^39-–41

Subclinical hypothyroidism increases risk for development of congestive heart failure.^42-–43 One of the repeated shortcomings of these studies is the lack of freeT3 measurement, which if included would identify an even broader pool of patients that who would benefit from appropriate thyroid assessment and treatment in an effort to normalize cellular function in the fight against ongoing inflammatory changes.

Metabolic Syndrome

Those with Metmetabolic Synsyndrome incur greater cardiovascular risk and increased occurrence of MI. Once again, this is just a continuation of our simple paradigm, which is that any inflammation from any source causes cytokine elevation leading to damage that results in insulin resistance leading to diabetes, resulting in weight gain that simultaneously impaaffects blood pressure and the lipid profile. This cumulative ball of inflammatory change is gaining momentum and causing vascular damage along the way. Plaque is developing whether we choose to become aware or not. Identifying these inflammatory signals and taking action will slow or reverse the progression and avert the immanent ischemic event.

Cytokines naturally elevate over time with aging leading to progressive inflammation.⁴⁴ In our youth we tend to get more sleep, we are not abusing caffeine and alcohol, stress isn typically minimal, and our hs-CRP -hs measures are most likely less than 1.0. As we age, we gain toxic exposures as well as accumulate toxic habits that are reflected in a subtle rise in CRP. Even if our CRP rises to a mere 1.5, this may reflect a 3- fold rise in inflammation when compared to with our youthful measures. This will only worsen with time. So waiting for CRP to elevate above 3.0 before engaging in a preventive approach will produce a suboptimal result. The Ferrucci study showed that CRP naturally rises with each successive decade of life.⁴⁵ Between the ages of 20 and -39, men and women average a CRP of 1.05, but by age 49 it rises to 1.5, representing a 50% increase. It doubles by age 64, triples in our 70’s, and by age 85 the typical CRP is 4.35 on average.⁴⁵ There is a step wise progressive increase in CRP, reflecting the cumulative affectseffects of aging; and with it comes graduating increase of cardiovascular risk. Since cardiac disease is by definition an inflammatory process as described in the literature, ^46-47 then monitoring and addressing this rise should net far greater return in healthy function and avoid progressive cardiovascular decline.^46,47

CRP is a surrogate marker of IL-6 activity. IL-6 is secreted from adipose tissue and contributes 33% of all IL-6 in the circulation. Abdominal (omental) adipose tissue produces 3-fold time more IL-6 than subcutaneous adipose tissue, so there is a positive association between obesity and plasma IL-6 levels.⁴⁸

IL-6 plays a key role in CAD as a procoagulant and source of damage to endothelium. This damage to the vessel wall and endothelial disruption exposes the underlying vascular smooth muscle cells. Monocytes and lymphocytes accrue in the intima secondary to cytokine release, an essential step in the disease process. Increased levels of IL-6 levels and CRP predicted cardiovascular mortality and future myocardial infarction.^49-–50

IL-10 is a cytokine with strong anti-inflammatory properties that acts to inhibit the production of IL-6 and TNF-α. Elevated IL-10 levels improve the lipid profile as serum concentrations of total cholesterol, LDL cholesterol, triglycerides, glucose, and hemoglobin A1c all decrease, thus reducing cardiovascular risk. In a study by Van Exel, IL-10 production was measured and low levels correlated with increasing risk for type 2 diabetes.⁵¹ This study demonstrates IL-10 as an important regulator of the inflammatory immune response. This in turn elevates the significance of possessing proper gut flora that work to enhance both T_-reg cell populations and their production of IL-10. Sublingual immune modulation therapy (SLIT) has also been shown to greatly stimulate IL-10 and T-reg_reg cells. Discussion of SLIT is beyond the scope of this article but represents an excellent therapeutic process for reducing overall body inflammation, reducing CRP, and stabilizing the inflammatory immune response, which acts as one of the primary drivers of cardiovascular disease.

So we have a spiraling inflammatory cycle where stress and cortisol drive both insulin production and cytokine elevation, making the exact mechanism less than clear. Do cytokines drive insulin dysfunction or vice versa? Both have been provedn and are infinitely interrelated. Insulin is one of the primary regulators of the cytokine-associated acute-phase reaction. The liver is targeted by the inflammatory process resulting in altered production of inflammatory proteins (acute phase mediators).⁵² This perpetual inflammatory drive creates a growing stress on the body that further exacerbates cortisol, all of which leads to endothelial damage and heart disease.

The CARDIA Study looked at diurnal change in cortisol in over 700 patients and found that the flatter the slope of the diurnal cortisol curve, the greater the odds of coronary calcium change.⁵³ A relatively flat diurnal pattern is associated with the risk of coronary calcification. Excessive cortisol expression drives TNF-α as sited above. TNF-α contributes to plaque rupture, as it decreases collagen synthesis and increases matrix metalloproteinase activity.⁵⁴ Human atherosclerotic lesions have been found to contain TNF-α mRNA.⁵⁵

So this endothelial dysfunction, fueled by high oxidative stress secondary to insulin resistance, oxidizes LDL that in turn is targeted by monocytes that then migrate into the subendothelial space stimulating macrophages to form foam cells.

Both high levels of LDL and ox-LDL increase endothelial production of oxygen free radicals, which bind to and inactivate N.O. Superoxide dismutase is the major antioxidant enzyme system of the vessel wall, and without it’s activity we see increased free radicals and lower N.O. Glucose and IR reduce N.O. formation. Any acute inflammatory reaction that is capable of can produceing CRP elevation is capable of can createing endothelial dysfunction via this mechanism. Furthermore, asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and a known risk factor for coronary events. Oxidized LDL increases ADMA production by endothelial cells and decreases its enzymatic degradation.

Identifying endothelial dysfunction through understanding of all of the mechanisms detailed above allows us to take action early with confidence. The study by Kuvin and Patel⁵⁶ drives that point home, as they it used non-invasive means to identify at- risk patients with a high degree of reliability.⁵⁶ Their study of 94 patients with risk factors for coronary heart disease were tested using
brachial artery ultrasound to predict coronary artery disease as it reflects endothelial dysfunction.⁵⁶ Exercise radionuclide myocardial perfusion imaging was then performed to demonstrate who had true disease. Presence of endothelial dysfunction as identified via ultrasound had a high sensitivity (91 percent%) for predicting the finding of coronary heart disease on perfusion imaging.
The absence of endothelial dysfunction as defined by ultrasound, had a high negative predictive value (95 percent%).

It is my hope that this discussion has shed light on a few basic concepts that allow us to simplify our future course of action and therapeutic options. We need to identify inflammation in all of its’ various presentations as a broad but highly specific marker for heart disease risk. Understanding that seemingly simple issues like such as poor sleep or a diet full of processed food is pointing an accusatory finger at silent biochemistry that will lead to vascular insult. This opens a great opportunity to protect our patients from bad outcomes long before they express any symptoms. I will continue this discussion in part 2 as I highlight what tests are most productive in quantifying the risk of cardiovascular disease and what therapeutic options warrant your consideration as you devise a treatment plan.

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