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  Return to CHC Home Page                                                                Integrative Approach to Atherosclerotic Vascular Disease

For additional information please review a) the heartfixer.com website, where these approaches are discussed in greater detail, in both print and audio-visual form, and b) Reverse Heart Disease Now by Drs. Roberts and Sinatra.

Atherosclerosis is a maladaptive response of the acquired immune system to perceived infection of the artery wall with oxidized LDL and Lp(a), coupled with an inappropriate response of the innate immune system to perceived danger posed by the presence of crystalline cholesterol within the vascular wall.  These processes are driven by oxidative and inflammatory stress. 

To prevent, stabilize, and potentially reverse atherosclerosis, we need to address all of these steps in plaque formation, progression, and destabilization.  Atherosclerosis begins with hyperlipidemia, a level of LDL inappropriate for your level of vascular wall permeability.  Elevated LDL is necessary, but not sufficient, to initiate plaque formation. Native LDL diffuses into and out of the vascular wall, and will be incorporated only into cells that need it (they express open LDL receptors).  LDL not needed for biosynthetic activity will diffuse back out into the circulation (unless it is trapped).

While risk factors are systemic, atherosclerosis is focal, occurring beyond vessel branch points.  Pulsatile, laminar flow, occurring within “straightaway” vessels (such as the Left Internal Mammary Artery, which never experiences atherosclerosis) leads to heighted endothelial function.  Nitric oxide (NO) and antioxidant enzyme generation (SOD and Catalase) is increased.  Vascular wall integrity is maximized; WBC infiltration, platelet aggregation, and lipid oxidation does not occur.

Beyond branch points (such as when the Left Main divides to give of the Left Anterior Descending and Circumflex), laminar flow gives way to oscillatory, shearing flow. In this situation NO and antioxidant enzyme generation cease and instead the vessel wall expresses oxidant generating enzyme system (Xanthine Oxidase and NADPH Oxidase).  Hypertension and systemic inflammation (from any cause - gingivitis, leaky gut, belly fat, etc.) contributes to this pro-oxidative process.  Focal “leaky artery” pathology follows. 

Our physiology and immune system, designed (by our creator over four million years of evolution) to protect us from microbial invasion, our natural predator, reacts to this focal oxidative stress as if infection is brewing.  White cells infiltrate the intima (the endothelial and smooth muscle inner layers of the vascular wall) and release oxidative and inflammatory mediators. Phospholipase enzymes, the activity of which are up regulated in the presence of systemic inflammation, oxidize the phospholipid coating of the LDL particle, rendering it “sticky”, promoting LDL clumping.  A scaffolding of ground substance (such as chondroitin sulfate) is generated.  The clumped, sticky LDL particles become trapped on the chondroitin scaffold.

So now we have clumped LDL molecules, unable to diffuse out of the intima.  Superoxide and downstream free radicals, churned out by now upregulated NADPH Oxidase and Xanthine Oxidase, lead to full oxidation of the trapped LDLs.  Trapped, oxidized LDL can no longer interact with an open LDL receptor (it no longer looks like food).  Rather the oxidized LDL particle is recognized by scavenging white cells as a microbial invader.  Immune cells will engulf (phagocytose) the oxidized lipid particles, and then die, to create the “fatty streak”, the initial manifestation of atherosclerosis that begins in our 20s.  Over the years, LDL particles will enter the activated, “leaky artery” in branch point zones, WBCs will chase them, and a boil-like structure will develop.  The “atheroma” is a pool of oxidized lipids covered by a fibrous cap, which grows silently, manifesting itself only in middle age, when it encroaches on the flow area such that the supply of oxygenated blood is insufficient to meet the needs of the heart muscle (» 80-90% narrowing).  Effort-related symptoms will then occur, prompting you to seek medical attention.  Or worse, in a fit of oxidative/inflammatory stress, the fibrous cap can rupture, releasing lipid gruel into the flow area, leading to sudden heart attack or stroke. A newly recognized, and critically important mechanism of plaque activation involves first line defense cells reacting to crystals of cholesterol (oxidized or non-oxidized) as a sign of danger, and this mechanism also leads to inflammation and plaque destabilization (akin to gout).

Let’s list the factors that play a role in atherosclerosis, and outline our options to deal with them.  Optimal diet, trim waistline, adequate sleep, regular exercise, and stress management are all important, and are discussed elsewhere in our educational materials. This document focuses more on testing and biological intervention.  This is only an outline, an intellectual check list for us, to make sure that each step in your individual anti-atherosclerosis program is covered.

LDL Cholesterol Management:  Our goal here is to achieve an LDL level appropriate for you.  Traditionally we have measured LDL mass (mg/dl), but we know that small, dense LDL is more problematic (it can wiggle in more readily) than large, fluffy LDL (which can’t get in easily).  Thus, a better measure of LDL risk is LDL particle number.  In primary prevention, our goal is a LDL £ 100 mg/dl and a LDL-P (LDL particle number) £ 1200 mg/dl.  If atherosclerosis is present, and thus our focus is on secondary prevention (keeping the situation from getting worse) then an LDL £ 70 mg/dl and an LDL-P £ 700 is more appropriate.

Increased LDL generation leads to an enhanced oxidative/inflammatory response, just what you want when dealing with infection (as did primitive Man, over and over).  Genomic hyperlipidemia is thus Mother Nature’s response to recurrent infection (particularly peri-natal sepsis, the leading cause of death in the history of Mankind).  Age related, acquired hyperlidemia (95% + of us) relates to our physiology misrecognizing cumulative oxidative/inflammatory cues of modern living (overweight, leaky gut, toxin exposure, sleep apnea, etc.) as signs of recurrent infection.  Diet/life style modification can prevent all of this, but once atherosclerosis has been established, you will likely need additional help (to turn the ship around).  LDL reduction is covered within the HMG Co-A Reductase section on heartfixer.com, but we can outline our strategy as follows:

A. By inhibiting HMG Co-A Reductase, the rate-limiting step in cholesterol generation, we lower cholesterol and lower oxidative/inflammatory stress (stated otherwise, CRP levels fall, endothelial function improves, etc.). Statin drugs and like-acting plant-derived substances (RYRE, Bergamot, Amla, and Danshen) all achieve this goal.

B. PCSK9, which degrades the liver LDL receptor, thus raising LDL, is induced whenever we inhibit HMG Co-A Reductase.  We can blunt PCSK9 generation with Berberine (an agent that also improves insulin sensitivity), which I uniformly prescribe whenever a HMG Co-A Reductase inhibitor is used.  We can also sequester PCSK9 with either of the two currently available subcutaneous injectable agents (Repatha or Praluent).

C. Tocotrienols (Vitamin E with a double bond in its side chain), powerful, plaque penetrating antioxidants are structurally similar to cholesterol and trick the liver into sensing cholesterol excess, leading to feedback inhibition of HMG Co-A Reductase.

D. Pantethine inhibits Acetyl-CoA Carboxylase (involved in triglyceride generation), with a weaker effect on HMG Co-A Reductase, and serves as an additional nutriceutical approach.

E. Plant sterols, also acting as cholesterol lookalikes, indirectly decrease cholesterol generation.

F. Niacin (discussed in Medical Topics section) lowers LDL and triglycerides while concomitantly increasing HDL.  Niacin depletes P-5-P recycling, raising homocysteine (so we co-supplement with P-5-P) and often leads to bothersome flushing (for which we can usually creat a work around).

G. (Zetia) and Cholestyramine block cholesterol uptake from the GI tract and can contribute to cholesterol reduction, but these agents do not directly reduce oxidative/inflammatory mediator generation (and are thus second line interventions).

H. If we are not able to lower your LDL values, a fallback position is to supplement with Chondroitin Sulfate (see website AV presentation).  The idea here is that exogenous chondroitin will interfere with LDL trapping onto vascular wall chondroitin, allowing the LDL to diffuse back out into the circulation.

Lipoprotein (a) Management (please see our website AV presentation for a detailed discussion). Lp(a) is a “repair particles”, one molecule of LDL bound to one molecule of apoprotein (a).  Lp(a) will bind to collagen lysine and proline residues within a damaged vascular wall, creating a micro-clot repair patch, while providing LDL for cell wall regeneration.  This was adaptive for primitive man during periods of Vitamin C deficiency (without Vitamin C arteries will crack, leading to blood loss anemia).  The Ice Age is over, but the genes for high Lp(a) have been retained in many of us, and our problem here is that circulating Lp(a) cannot differentiate atherosclerotic plaque from vessel damage due to Vit C deficiency.  Lp(a) thus binds to plaque, or to sites of vascular trauma, “pilling on”. Elevated Lp(a) is an independent risk factor for atherosclerosis, particularity when LDL is high, and it is a predictor and mediator of restenosis post-angioplasty and premature closure of vein grafts.  Estradiol deficiency in females and testosterone deficiency in males may increase Lp(a), as may thyroid deficiency in both genders. Curiously, statin drugs will raise Lp(a) as well. As no drugs are available to lower or neutralize Lp(a), this key risk factor is ignored in standard medicine. My approach, patterned after the wisdom of Double Novel Laureate Dr. Linus Pauling, is to:
A. Measure Lp(a) in all patients (in some labs the upper reference limit is 30 and in others 75).
B. In the absence of atherosclerosis or an elevated risk factor burden, supplementing with Vitamin C 500-1000 mg twice a day, should suffice.
C. In the presence of atherosclerosis, and particular in the setting of unstable atherosclerosis or a recent anatomic intervention, our metabolic intervention to neutralize elevated Lp(a) will involve supplementation with lysine 1000 mg and proline 500 mg, both twice a day, along with Vit C 1-2000 mg twice a day, to blunt Lp(a) binding to the vascular wall. 
D. I cannot back these recommendations up with a clinical trial (who would fund such a study?) but my 25-year experience with this approach has been quite positive. In the pre-stent days, high Lp(a) patients nearly always experienced restenosis following balloon angioplasty. Restenosis was greatly attenuated when we placed these patients on a Lp(a) neutralizing program. Also, this approach is low in cost and without risk (if diarrhea occurs you can back off of the Vit C dose).  E.  What constitutes an “elevated” Lp(a) level relates to your risk factor burden and clinical status (the same thinking as with LDL).  In an unstable or otherwise high-risk patient, I may recommend Lp(a) binding even if the level is well within the reference.  Conversely, in a young, healthy individual with clear vessels (with nothing to “repair”) specific attention to Lp(a) becomes less important.

Oxidative Stress (please see Atherosclerotic Oxidative Stress on our website for a detailed discussion) is the driving force underlying atherosclerosis, heart failure, and essentially all of the age-related disease states that plague Modern Man.  Simply put, oxidative stress occurs when superoxide (SO) generation outpaces the ability of our innate antioxidant enzyme systems to neutralize it.  Our physiology interprets this imbalance as a sign that “another” infection is occurring, and thus we ramp up our innate inflammatory response. All effective drug and non-drug approaches to the treatment of atherosclerosis directly or indirectly target oxidative stress.  Our approach here is to assess the level of oxidative stress that you are experiencing, identify and remove the causative factors (this will take years), and to apply drug and non-drug measures to down regulate SO generation and up regulate SO neutralization.

A. Measurement can involve one or more of the below listed studies:
Oxidized LDL, MPO (myeloperoxidase), and uric acid (Cleveland Heart – CH Panel).
Precision Pont oxidative stress panel.
Genova Labs NutrEval measures of glutathione, lipid peroxides, and 8-OHDG.
CRP, fibrinogen, and PLA2, markers of inflammation, rise secondary to oxidative stress (CH). Endothelial function (EndoPAT test) is inversely related to vascular wall oxidative stress.
Genomic testing identifies specific predispositions to impaired SO neutralization.

B. Resolving acquired causes of Oxidative Stress:
Weight loss, clean diet, adequate sleep, and regular exercise decrease SO and increase NO.
Resolving or control sleep apnea and diabetes.
Removing metals and fat-soluble organic toxins from your body.
Blood donation as needed to keep ferritin below 200 mg/dl.
Dietary change and supplementation as needed to lower TMAO.

C. Augmenting our first line (mineral dependent) antioxidant enzymes defenses:
GliSODinÔ to provide exogenous SOD (Superoxide Dismutase).
Pomegranate to stimulates Paraonoxidase (the antioxidant enzyme associated with HDL).
Nrf-2 translocators (e.g., sulforaphane) to increase generation of antioxidant and detox enzymes.
Glutathione (liposomal or IV). and/or glutathione precursors (N-Acetyl Cysteine or Lipoic Acid).
Mineral repletion (selenium, zinc, copper, iodine) as needed.

D. Pharmaceutical/nutraceutical measures to blunt upregulated ROS generating systems:
1) HMG Co-A Reductase (drug and non-drug statins + Berberine +Tocotrienols).
2) NADPH Oxidase (HMG inhibition, ACEI/ARB, Spironolactone, Nebivolol, Hydralazine, Berberine, Colchicine, and Polyphenols).
3) Xanthine Oxidase (Allopurinol).
4) NLRP3 (Colchicine).
5) b-Adrenergic Blockade (Carvedilol and Nebivolol provide additional antioxidant support).
6) Pentoxifylline to shunt the immune response away from Th1 and towards Treg.

E. Antioxidant supplementation to “scarf up” residual SO and downstream oxidants:
1) N-acetyl cysteine and taurine (generate protective hydrogen sulfide and improve endo fn).
2) Tocopherols/tocotrienols and bioflavonoids vs. fat soluble oxidants.
3) Vitamin C and bioflavonoids vs water soluble oxidants.
4) PPC to “sop up” fat soluble oxidants at the level of the cell membrane.

F. Periodically remeasure Oxidative Stress markers and adjust your program as needed.

Endothelial Function (please see corresponding entry on our website for more information).  Endothelial dysfunction (vascular wall Nitric Oxide Synthase generating SO free radical as opposed to Nitric Oxide), is a key, oxidative driver of hypertension, ED, heart failure, plaque formation, and plaque destabilization.  Conversely, optimal endothelial function ameliorates the disease-producing effects of other risk factors.
Our plan here involves:
A. EndoPAT endothelial function testing.
B. If sub-par, begin one or more treatments as listed on the Endothelial Function entry.
C. Periodically re-test to ensure that endothelial tone remains optimal.

Hypertension is a consequence and a cause of vascular wall oxidative stress, and thus is far easier to prevent than to reverse.  Excessive BP down regulates Nitric Oxide Synthase and induces Xanthine Oxidase and NADPH Oxidase.  Mild hypertension can be reversed by removing its pro-oxidant causes.  Fixed hypertension will require drug therapy, ideally with agents that also improve endothelial function and block superoxide generation (see above).

Insulin Insensitivity, Diabesity, and Metabolic Syndrome all refer to the expanding waist line and blood sugar values characteristic of Western populations. This condition involves cellular resistance to the metabolic actions of insulin.  Insulin promotes burning of glucose to generate energy.  The insulin insensitive cell instead converts glucose into triglyceride and cholesterol.  Fatty liver and fat cell accumulation follows.  While subcutaneous fat is not particularly problematic, visceral fat (fat surrounding our internal organs) generates oxidative and inflammatory mediators, interpret by our physiology as a sign of persistent infection.  Insulin insensitivity is a cause and consequence of oxidative stress, which as you now understand mediates hypertension, inflammation, endothelial dysfunction, and thus atherosclerosis.  Early insulin insensitivity can be reversed with dietary modification, nutritional support, and weight loss; fixed diabetes is difficult to reverse and will likely mandate life-long drug intervention – don’t let things get to this point!

Measurement/Quantification of Insulin Insensitivity can involve:
1) Fasting glucose, insulin, and triglycerides all reflect your current level of insulin sensitivity.
2) HbA1c reflects average glucose control over the preceding three months.
3) Looking at you – if belly fat is present, we know that insulin insensitivity is present or will later develop.

Treatment/Prevention will involve:
A. Dietary change, which is 100% your responsibility.  While in trim individuals with atherosclerosis we recommend a plant-based diet (the Ornish/McDougal/ Esselstyn/Campbell approach), to address insulin insensitivity, which involves glucose intolerance, our approach is to minimize or preferably eliminate dietary glucose intake.  The Paleo (be a hunter-gather and not a farmer) or Gundry (avoiding pro-inflammatory grains) and Mediterranean diets serve this purpose, while strict carbohydrate avoidance (Ketogenic diet) will lead to more rapid wight loss and control of insulin resistance.  The best diet for you is one that you can follow, and I encourage all of you with insulin insensitivity to read up on these approaches and change your diet (and thus your health trajectory).  Intermittent Fasting (taking in all of your calories within an eight-hour window) also promotes insulin sensitivity and helps with weight loss. 

B. Insulin Sensitizer therapy:
1) Berberine (see Chronicles of Berberine AV presentation) improves insulin sensitivity (and lowers LDL and oxidative stress).  The standard dose is 500 mg twice a day, which can be advanced to 1000 mg twice a day. Berberine can cause diarrhea or constipation which is dose-related; should these occur don’t stop berberine but rather decrease the dose to a tolerable level.

2) Metformin and Pioglitazone (Actos) promote insulin sensitivity at the level of the liver and skeletal muscles, respectively. Metformin can cause diarrhea (less so with its long-acting form) and B12 deficiency and Pioglitazone may cause edema formation (more so at 30 mg as opposed to 15 mg/day). These are useful first line drugs.

3) Exercise increases muscular glucose uptake and will dependably lower your blood sugar. Resistance training increases muscle mass and tonic glucose uptake while aerobic exercise pulls sugar into your cells. Glucose falls, insulin sensitivity improves, and weight loss follows.

 C. Nutritional therapy – Insulin insensitivity and the oxidative/inflammatory stress it creates leads to the loss of key nutrients, which in turn aggravate these conditions – a viscous cycle. Supplementation thus makes sense and has been demonstrated to help:
1) Chromium picolinate 500-1000 mcg/day will lower A1c and is risk-free.  GlucoA1c combines chromium with Bitter Mellon, essentially a plant-based insulin.
2) B Vitamins, especially biotin and thiamine, are lost in insulin insensitivity/diabetes.
3) The intracellular antioxidant pool, especially glutathione, is compromised and rectification with lipoic acid (keep the dose £ 600 mg/day to avoid adverse thyroid effects) is helpful. 
4) Herbal insulin sensitizers and anti-inflammatory agents are available.  My patients have benefited from GlucoSupreme Herbal (Designs for Health) which provides berberine and related herbal agents, and Incinase (Metagenics) which breaks the inflammatory link between belly fat the liver.
5) All of the major nutraceutical firms provide mutinutritional  programs designed to meet the nutritional needs of the insulin insensitive individual, such as Metagenics Wellness Essential Health Balance, Designs for Health Metabolic Synergy, or Biotics GlucoBalance, which we can chose from in relation to your individual nutritional status and preferences.

D. Other drug approaches
1) Sulfonylureas (Glimepiride) stimulate the pancreas to kick our more insulin.  This makes sense when insulin output is poor, but this approach will not improve insulin insensitivity.  These drugs will lower your blood sugar, but will also lead to weight gain (the underlying problem) and these agents will decrease your tolerance to oxygen deficiency in the event of a heart attack (acting in a fashion opposite to that of Ouabain).  Endocrinologists may use these agents within a comprehensive treatment program, but otherwise we use them only when cost is the key constraint (these drugs are inexpensive), or when our first line approaches are not getting the job done.

2. Insulin is critical in childhood diabetes, and will lower glucose values in individuals with type II (adult-onset of insulin insensitivity induced hyperglycemia).  Insulin, however, does not address the underlying problem of insulin insensitivity and its use may lead to weight gain, and thus we turn to insulin only when all else fails.  Long-acting insulins provides tonic blood glucose control while short-acting insulin covers for post-meal glucose spikes.

3. SLGT (sodium-glucose co-transport) inhibiters (Jardiance, Invokana, Farxiga) prevent the kidneys from resorbing glucose from the blood stream.  Insulin insensitivity is not improved, but diabetes control does, and these agents have been shown to be of significant values in heart failure, in diabetics and in non-diabetics. They may cause volume depletion (water and sodium follow the glucose excretion) and they may increase risk urinary track and cutaneous fungal infection.

4. GLP-1 agonists (Ozempic, Bydureon – injectable agents) mimic a molecule that mediates pancreatic insulin release, and will lower glucose values and may help with weight maintenance.

5.DPP-4 Inhibitors (Januvia, Alogliptin, Tradjenta, Onglyza – oral agents) block the breakdown of GLP-1, thus supporting pancreatic insulin release, and improve insulin sensitivity without inducing weight gain.

Reverse Cholesterol Transport with PPC (please see our Phosphatidylcholine write up and AV presentation):  If our physiology allows for increased LDL cholesterol generation and subsequent tissue deposition in response to infection (or perceived vascular wall infection as is the case in atherosclerosis) then there must be a compensatory mechanism to allow for lipid egress.  Cholesterol is stored within the atheroma as an ester (one molecule of cholesterol bound to one molecule of a fatty acid).  Cholesterol esters cannot be mobilized out of the vascular wall and into the circulation. Cholesterol esterase splits off the fatty acid, such that the now free cholesterol is free to move out.  The free cholesterol can be acted upon by HDL-associated LCAT (Lecithin-Cholesterol Acyl-Transferase), which tacks on an unsaturated fatty acid to the now free cholesterol, such that it can be loaded into an HDL molecule and transported back to the liver for degradation.  PPC (Polyenylphosphatidylcholine) stimulates cholesterol esterase and LCAT, and thus removes lipids from the vascular wall.  IV (Plaquex, Lipostabile) and oral (Plaquex, PhosChol) PPC have been shown to reverse atherosclerosis and attenuate ischemic symptoms.  Other forms of phosphatidylcholine will improve cell membrane function and thus provide benefit, but they will not stimulate reverse cholesterol transport.

 Reverse Cholesterol Transport with Cyclodextrin (please see the Cyclodextrin to Rapidly Reverse Atherosclerosis write-up). Cyclodextrin (trade name CavadexÔ) will “pluck” a cholesterol molecule from the cell membrane of a vascular wall cell, and then “hand it off” to an HDL particle, where it is esterified (by LCAT, which is stimulated by PPC), and then transported back to the liver.  Cell membrane cholesterol depletion stimulates dissolution of intracellular lipid droplets (also stimulated by PPC).  Cyclodextrin can enter the activated vascular wall, where it solubilizes crystalline cholesterol.  This creates a class of compounds termed oxysterols, which potently increase expression of cholesterol egress pumps (ABCA1 and ABCG1) which also stimulate HDL maturation and functionality.  Cyclodextrin also removes diacylglycerols from the cell membrane, and this action improves endothelial function and NO generation. Anginal symptoms typically attenuate within weeks and we feel that longer term use of Cyclodextrin, particularly in combination with PPC, will lead to plaque volume reversal.

Our integrative approach thus involves measures to blunt LDL cholesterol generation, combined with PPC and Cyclodextrin to pull lipids out of the vascular wall.  HDL cholesterol provides two beneficial functions, mediating reverse cholesterol transport (via HDL-associated LCAT), as just discussed, and by reversing LDL oxidation (via HDL-associated Paraoxonase), discussed in the oxidative stress section.  HDL levels are directly related to one’s level of insulin sensitivity.  If you are diabese and inflamed, HDL will be low.  Exercise, moderate alcohol intake (especially red wine) and fish oil have beneficial effects on HDL expression. 

Homocysteine, the metabolism of which is B Vitamin dependent, is both a cause and consequence of oxidation stress, and is a key mediator of atherosclerosis.   An elevation in Homocysteine also reflects impaired methylation, a key process that governs the activity of 300 methylation dependent enzymes, including catecholamine (adrenalin) neutralization, fatty acid metabolism, and the silencing of cancer stimulating onco-genes.  Many prescription drugs raise homocysteine and there are no drugs that lower this risk factor; thus, this key mediator of ill health is typically ignored.  Homocysteine and Methylation are discussed in detail on our website.  Our initial approach to elevated homocysteine is broad-spectrum B vitamin supplementation (such as Designs for Health B Supreme or Homocysteine Supreme).  If this initial, non-specific approach does not get the job done, we then assess specific B vitamin status with the Genova Labs NutrEval study, and we can also look for genomic predispositions to impaired methylation and target any weak links identified. Many drugs (especially “purple pills”, oral estrogens, and thiazide diuretics) deplete B vitamins and lead to elevated homocysteine and impaired methylation, creating new disease states (and no none tells you about this).

Inflammation Reduction:  Inflammation, the activity of inflammatory cytokines (immune system effector molecules), is an appropriate response to trauma or real infection.  In contrast, chronic inflammation on the basis of “pseudo-infection” cues such as visceral fat, leaky gut, and vascular wall oxidized lipids directs Mother Nature against us (please see Immune Mechanisms of CV Disease AV presentation).  As a general rule, inflammation is a consequence, and a cause, of oxidative stress.  Dealing with one will attenuate the other.  While we cannot directly measure inflammation within the vascular wall, we can in the circulation in relation to measures such as CRP, fibrinogen, and PLA2.  We can attenuate inflammation by:
A. Identifying and removing its causes (diet, belly fat, leaky gut, food allergy, etc.)
B. Fish oil supplementation (please see our AV presentation) 1-4,000 mg/day.  EztrekÔ may replace fish oil in our armamentarium. In 2023 we will be conducting a 54-subject controlled trial of EztrekÔ vs. placebo, looking for six and twelve month effects on coronary artery calcium score and carotid artery intima-media thickness.
C. Turmeric (phytosomal for better absorption).
D. Pentoxifylline – this prescription agent is of value in all CV conditions, from heart failure to the prevention of vein graft closure.
E. Vitamin D promotes immune system integrity, both the ability to response do real infection and the ability to “stand down” after real infection has cleared – aim for a level between 50 and 80 ng/ml.
F. SPMs (Specific Pro-Resolving Mediators) are downstream fatty acid metabolites that “turn down” the inflammatory response and then “clean up” the debris.  Mother Nature generates these molecules after a legitimate microbe has been defeated.  Supplementing with SPMs (provided by Metagenics) will help you resolve inappropriate or non-microbial inflammation, and will likely be of value in atherosclerosis.

TMAO (Trimethylamine Oxide) is a pro-oxidant risk factor for atherosclerosis, atrial fib, stroke, and kidney disease.  One’s level involves an interaction between diet, GI tract flora, and the status of a specific liver enzyme, FMO3.  Carnitine (red meat) and phosphatidylcholine (meat, egg, and dairy) is converted by some but not all GI microbes into TMA (and fish provides TMA). FMO3 (Flavin Monooxygenase 3), the expression of which up regulates in the presence of toxins, converts TMA into TMAO.  TMAO is excreted via the kidneys, and thus kidney disease, which is contributed to by TMAO, is also a cause of high TMAO. We do not know which GI microbes are involved in TMA generation, and to this point probiotic therapy has not worked. Antibiotic therapy will lower TMAO, but levels will rebound as the GI flora reconstitutes.  TMAO above > 6.2 uM is associated with an increased risk of the above-described conditions.  We can address an elevated TMAO in multiple ways:
A. Dietary change – cutting back on red meat and egg intake.  TMAO may be the key link between animal protein intake and CV disease states.
B. Dealing with GI tract dysfunction.  We can carry out upper GI (SIBO-small intestinal bowel overgrowth) or lower GI (GI-MAP) testing, in relation to any GI symptoms you are experiencing, and then address any microbial overgrowth identified (again keeping in mind that we do not know which specific microbes are involved in TMAO generation).
C. Resveratrol and Jiaogulan interact with the GI tract wall to lower TMAO.
D. Carnitine is of definite value is heart failure and active coronary ischemia, but supplemental  carnitine can be converted into TMAO. PPC opens up arteries in humans but may also be converted into TMAO.  This is a vexing issue and here we need to weight the benefits of supplementation with the risks associated with elevated TMAO – a judgment call.  

Plaque Stabilization with Colchicine (please see our AV presentation).  Plaque activation shares a common pathway with acute gout, and both processes are blunted/prevented by colchicine.   Colchicine also inhibits NADPH Oxidase; thus, lowering oxidation stress. Colchicine will acutely lower inflammatory cytokine release in unstable coronary disease, and in patients with stable coronary disease colchicine lowers CRP and decreases three-year adverse event rate (in patients already on standard drug therapy) by 75%.  A potential down-side of colchicine is diarrhea, which typically resolves with a dose reduction. Pharmacists tell you that colchicine will delay the metabolism of your other agents, and there is biochemical truth to this, but in all of the studies supporting the use of colchicine, patients were already on multi-drug standard therapy; side-effects were low and benefits obvious (fewer heart attacks and strokes).

Vitamin K2 (discussed in part three of our Integrative Cardiology for Physicians Workshop AV presentation):  Vascular calcification, which can be quantitated with coronary calcium scoring, reflects the presence, extent, and duration of atherosclerosis.  Vascular calcification also relates to Vitamin K2 nutriture.  In the presence of vascular calcification, the artery wall generates Matrix GLA protein.  If activated (carboxylated) by K2, matrix GLA protein promotes removal of vascular calcium.  Conversely, if K2 is in short supply, and Matrix GLA protein is uncarboxylated, vascular calcification is accelerated (helping to explain why coronary calcification progresses at »20% per year even with LDL-lowering statin therapy).  K2 is also needed to keep calcium out of valves and joint tissue and in bone.  We get K2 from meat and dairy. Europeans with above-average dietary K2 intake, with or without familial hyperlipidemia, are less likely to develop vascular calcification and clinical atherosclerosis in comparison to individuals taking in less K2.  Europeans get K2 from meat and dairy (helping to explain the “French Paradox”).  In Europe, animals are fed grass and other K2 containing plants, while in the US the animals that we eat are fattened up with corn and soybean (along with antibiotics and hormones); thus, as a society we are K2 deficient.  To make matters worse, may of the drugs that we use, particular Warfarin (Coumadin) and statin drugs, lead to K2 deficiency.  That’s right – Statin drugs lead to K2 deficiency and accelerated vascular wall calcification. Warfarin anticoagulation has been linked to aortic stenosis and statins likely accelerate this process as well (and we seem to be seeing more aortic stenosis now vs. 20 years ago).  We can address this concern with K2 supplementation, 100 mcg/day as a preventive and 1000 mcg/day if you are taking a statin or if vascular calcification (or atherosclerosis) is known to be present. The optimal K2 dose has not been determined, and doses up to 35,000 mcg/day (used as a treatment for osteoporosis) are not associated with adverse effects.  We can also generate K2 from K1, which is obtained in the diet from greens (another benefit of a plant-based diet).  Neither K1 or K2 promotes clot formation.  This question comes up as Warfarin, which we can use as an anticoagulant, inhibits the recycling of K1 and K2.  K1 is used to generate pro-coagulation and anti-coagulation factors, and if we knock it out with Warfarin than an anti-coagulation effect occurs (“blood is thinned” as commonly stated), and vascular calcification is accelerated.  The newer oral anticoagulants work via a different mechansims and K1/K2 intake is not an issue.  Thus, neither K1 or K2 promotes clotting and are risk free (unless you are taking Warfarin). 

Hormonal Support: In men, low testosterone and/or elevated estradiol (please see our Testosterone AV presentation) is associated with an increased risk of atherosclerosis and other age-related metabolic disease states. Non-oral (thus pellet or IM) Testosterone replacement has been shown to be of value in essentially all CV conditions.  Standard oral (non-lipophilic) testosterone should never be used, as its metabolism in the liver leads to a pro-coagulant effect.  Topical testosterone is problematic, in that serum levels will underestimate the tissue effect, and with this method of delivery there is an increase tendency for the testosterone to be metabolized into estradiol and DHT (dihydrotestosterone), which work against us.  If IM testosterone is to be used, we favor a low dose administered twice a week. My favorite approach is slow-release pellet testosterone, typically placed every six months, which more closely mimics testicular testosterone release. Fat cells express aromatase, an enzyme that converts testosterone in to estradiol; thus, we will measure estradiol and if elevated treat you with low dose anastrozole (typically ½ to 1 mg/week) to blunt testosterone to estradiol conversion.

In women, estradiol is protective against vascular disease, particularly in women with elevated Lp(a) levels, and if begun at the time of menopause (please see our Estrogen Metabolism write-up).  We will complement estradiol with testosterone and progesterone (Mother Nature provides all three ovarian hormones so why shouldn’t we)?  Estradiol should never be given orally (as with testosterone, liver metabolism of estradiol leads to inflammation).  We will use only bio-identical hormones (PremPro involved the use of non-human hormones, adding unnecessary metabolic risk). We can evaluate how estrogen molecules are activated and metabolized, and then utilize specific supplements to maximize protective and minimize pro-inflammatory estrogen metabolism pathways.  As with testosterone, I favor pellet estradiol over topical, given the difficulty we have in monitoring estradiol effect with topical therapy (here we need to use salivary or 24-hour urine estradiol assessments).  I do acknowledge that there is no one best way to carry our HRT and that other practitioners utilize different approaches.

Heavy Metal Detoxification (please see website AV presentations and the Lead write-up in the Medical Topics section).  Progressive metal accumulation plays a key role in cardiovascular and kidney disease.  The evidence here is unassailable, and it has been demonstrated that metal detox improves patient outcome in chronic kidney disease and in chronic coronary disease (as documented in the Trial to Address Chelation Therapy – TACT, in which I was a Principal Investigator).  Chelation therapy pertains to the use of IV and/or oral agents that remove metals from our body.  Metals irreversibly inactivate enzymes systems, including our innate oxidant neutralizing defense systems, contributing to oxidative stress, and the disease sates that we experience with ageing (hypertension, vascular disease, kidney disease, and malignancy).  I got involved in chelation therapy 25 years ago, when patients with advanced coronary disease received chelation behind my back and got better!  Getting involved with chelation was the most important professional position that I have taken, but for this and other, like positions that I subsequently adopted, I steadily lost the friendship and support of 95% of the health care providers in NW Ohio (they were all my friends when I was the procedure and admitting king in my late 30s) and I have been subjected to harassment by state and federal agencies.  I did not back down.  I was right and they were wrong. I will recommend to all of you some form of metal detoxification.  I teach these methods to younger practioners, and I randomized more subjects into the TACT study than did any other cardiologist.  I have new professional and personal friends, a few of whom live in NW Ohio, and I am overwhelmed with health aware, highly motivated new patients, most of whom originate outside of the Toledo area.

Organic Pollutant Detoxification:  These agents, pesticides, dioxins, PCBs, Agent Orange, and related chemicals, accumulate in body fat, and then are carried by the LDL particle into your vascular wall, where they play a pro-oxidative role in vascular disease.  These molecules also stimulate the estrogen receptor (thus they are often referred to as “xenoestrogens”), leading to hormonal dysregualtion (menarche is occurring earlier and earlier in girls and male testosterone levels are falling).  We can estimate your toxin burden (lab testing) and then apply strategies to up regulate your body’s detox capability and help clear these fat-soluble toxins from your system.  Nrf-2 translocators (the classic example is sulforaphane) stimulate the generation of detox and anti-oxidant enzyme systems.  All of the major nutraceutical firms provide 10–24-day organic pollutant detox programs.  Sweating releases fat-soluble toxins, and here we can utilize exercise and far infrared sauna therapy.  The foot bath methodology opens up specific eccrine pores through which toxins (and uric acid) are drawn out from your body.  Olestra (the fake fat in fat free snacks) will pull fat-soluble toxins (including Agent Orange) from your body (unfortunately olestra is no longer available).

Detoxification is Your Responsibility:  If your body came with an owner’s manual, it would tell you that there is no place for toxicity in human health.  I have been alive for 67 years and in practice for 37 years and over this time frame have witnessed a steady decline in our collective health and vitality.  Many factors play a role, but key is the progressive accumulation of heavy metals and fat-soluble organic pollutants.  These molecules, to which we were not exposed to 100 years ago, inactivate enzyme systems, including those involved in detoxification and oxidative stress resolution, and the toxins themselves catalyze free radical generation.  The scientific link between toxin exposure/accumulation and disease is unassailable, but no one wants to recognize or address this issue (except on TV adds put out by class action attorneys who are suing manufacturers because people are suffering from toxin-induced disease states and here there is money to be made).  Politicians will not recognize the problem of toxicity, because then they would have to pay to deal with it. Don’t expect non-integrative health care providers to get involved.  Peer and regulatory pressure prevent this, and there is a lot of money to be made dealing with the health consequences of toxicity.  There are no patentable drugs available to remove toxins, so Big Pharma has no interest. Research dollars are just not available.  You put up the $32 million to fund the TACT study, which showed major benefits of EDTA chelation therapy in chronic coronary disease (and the medical community, NIH, Medicare, and the insurance industry just looked the other way).  Thus, it’s up to you. Read up on toxicity, and do your best to minimize toxin exposure.  If you are lucky enough to have a doctor who brings this issue to your attention, please listen and take action.  Or, you could be an average American, an entity upon whom we brave doctors translocate wealth ($100 K from birth to 65 and $250K on Medicare) from the future of our children and grandchildren and  into our pockets and those of our new masters in big medicine and big pharma (I know all about this. This is how I was taught to practice, and how I did practice the first 10 years of my career)!  If I can do better than so can you.

Fibrinolytic Supplementation:  In the pre-angioplasty/stent days, if you were experiencing a heart attack, we would treat you with an IV serine endopeptidase (streptokinase or TPA). These agents activate plasmin, an enzyme that degrades fibrin, thus dissolving (lysing) fibrin blood clots.  Lumbrokinase and Nattokinase are orally absorbable serine endopeptidases, and provide a qualitatively similar (but quantitatively less powerful) effect.  Of the two, Lumbrokinase has the most support in the literature (see our AV presentation), but we know that Nattokinase will prevent blood clots related to inactivity (studied on long-haul flights from NY to Europe). These agents are useful in the treatment of arterial disease.  Many of you want to take these agents as opposed to an oral anticoagulant to prevent atrial clot formation (with subsequent embolism) in atrial fib.  I typically advise against this if your clot forming potential is elevated, as we do not have studies documenting efficacy in this setting. I also typically advise against the concomitant use of an endopeptidase with an oral anticoagulant (as we do not have studies documenting that bleeding risk is not increased).  These agents can be used in conjunction with anti-platelet agents. Of the two, I prefer Lumbrokinase, 20 mg three times a day, over Nattokinase, 50-100 mg twice a day, but the latter is less expensive. These agents must be taken on an empty stomach (otherwise they will be used up digesting foodstuffs).

Nutritional Optimization:  Nearly all individuals experiencing health challenges are nutritionally deficient.  The SAD (Standard American Diet) is sub-standard, and leads to disease states, that we Doctors treat you with drugs that cause new nutritional deficiencies, leading to new disease states, which we address with more nutrient-depleting drugs and repetitive invasive procedures. This is, of course, insane, but this is what we do in America (again, what I did my first 10 years in practice).  You don’t need to do this!  Follow a clean, additive free diet, appropriate for your health status, and then undergo nutritional testing (such as the GenovaLabs NutrEval or Metabolix), such that we can identify any nutritional imbalances that persist and take corrective action with targeted supplementation.  If testing is not feasible (related to cost) then I will probably recommend a broad-spectrum nutrient program appropriate for your age and health status, based upon my experience and knowledge of the nutritional medicine literature.

Elevated Viscosity due to Erythrocytosis and/or Elevated Fibrinogen:  Viscosity refers to the thickness of our circulating blood.  Does it flow easily, like wine, or is it sluggish, like catsup?  Elevated blood viscosity leads to shearing stress on the endothelium, which at branch points leads to focal oxidative stress (and thus endothelial activation, lipid deposition, and WBC ingress).  The two key determinants of viscosity are the red cell count and one’s fibrinogen level.  Erythrocytosis, an elevated RBC, manifested as a blood Hematocrit > 51 is addressed by:
A. Identifying and removing its underlying cause, and
B. Periodic blood donation to the Red Cross or therapeutic phlebotomy (if the red Cross does not wish to take your blood 500 cc of blood can be removed and discarded), or
C. Physicians of yesteryear used leaching, but my hunch is you would prefer approaches A or B!

One time out of twenty, erythrocytosis is due to the bone marrow disorder Polycythemia Vera, which can be addressed with low level chemotherapy and periodic phlebotomy.  Low oxygenation leads to secondary erythrocytosis (if oxygen availability is low, the bone marrow turns out more red cells in an effort to transport the sparse oxygen to our cells).  We often see erythrocytosis in our patients with COPD (emphysema) and we expect it in the presence of sleep apnea.  In this setting, resolving sleep apnea (weight loss, CPAP, or dental appliance therapy) will resolve the viscosity issue.  Testosterone stimulates bone marrow RBC production, and thus we monitor for erythrocytosis in male patients receiving TRT.  Periodic phlebotomy may also be used to address iron overload, a key cause of oxidative stress. Blood donation thus has many benefits, and explains the longevity advantage that frequent blood donors enjoy.

Fibrinogen, generated in the liver, is converted in to fibrin, in the formation of a blood clot (thrombus), and thus elevated fibrinogen may contribute to abnormal clotting.  Fibrinogen also contributes to viscosity.  A fibrinogen > 350 is thus associated with an increased CV risk.  As a general rule, fibrinogen rises and falls (often in lock step with CRP) is relation to one’s inflammatory status. Steps to lower inflammation (such as weight loss) will typically lower CRP and fibrinogen levels.  We can also lower fibrinogen with Turmeric (and other anti-inflammatory nutritional blends provided by the major nutriceutical firms) and the anti-inflammatory drug Pentoxifylline.

Genomic Predisposition (please see our Methyl Cycle Nutrigenomics section) to CV disease is well appreciated, but dooms none of us to die.  Mother Nature never makes mistakes.  All of the genomic predisposition to CV disease identified to date help us defend against infection or death due to starvation or nutrient (iron and salt for sure) deprivation.  It is our job to understand how these genomic variations increase the CV risk of Modern Man, and then to creat work-arounds to lessen risk.  How we address genomic hyperlipidemia is discussed above.  If you are a genomic iron over absorber, we ask you to give blood to the Red Cross.  If you have trouble with methylation, we can overcome this with nutritional testing and corresponding nutritional support.  If you have neutralizing superoxide and other free radical species (just what you want when dealing with infection) then we bolster your anti-oxidant defense systems.  My personal patients with complicated disease states (and/or patients with enquiring minds) undergo genomic testing (see Getting Started – How to Obtain Your Genomic Profile), and then I analyze the data in relation to the individual’s health and nutritional status.

Rapamycin (see Dr. Greene’s website, rapamycintherapy.com).  The mTOR (mechanistic target of rapamycin) pathway mediates cellular proliferation and chemical mediator secretion.  mTOR is thus active in normal growth and development.  Following maturity, this pathway, which is upregulated by inflammatory cues, mediates inappropriate cellular growth and secretory activity.  Rapamycin inhibits mTOR, and thus inhibits undesirable cellular proliferation and generation of pro-inflammatory substances.  Rapamycin and related agents are used to prevent rejection of transplanted organs, to deal with certain forms of malignancy, and are released locally by drug eluting stents.  Restenosis (narrowing within stents) is not mediated by atherosclerotic plaque formation, but rather by a process termed neointimal hyperplasia, wherein immune cells and connective tissue cells proliferate and plug up the stented area (akin to a keloid scar on your skin).  Rapamycin inhibits this unwanted cellular proliferation, thus decreasing the risk of restenosis.  Rapamycin therapy in transplant patients is associated with insulin insensitivity and hyperlipidemia, but also provides an element of protection against atherosclerosis and malignancy.  This apparent paradox is explained by the presence of two mTOR pathways, type I and type II.  Type I works against us in atherosclerosis, while type II is protective against age-related metabolic dysregualtion (lipids, insulin insensitivity, and weight gain).  A single dose of rapamycin will inhibit mTOR type I for two weeks, while to knock out mTOR type II, daily rapamycin dosing is requited.  Thus, the intermittent use of Rapamycin (one dose every 1-3 weeks), has been proposed as a preventive and therapeutic in atherosclerosis and other age-related inflammatory/degenerative conditions.  The down side of non-daily Rapamycin (perhaps more theoretical than real) would be impaired immune vigilance 1-3 days after taking a dose, and thus one would not take Rapamycin if active infection is present.  Right now, a dozen of my patients have been taking Rapamycin for 6-12 months. Two experienced side-effects that resolved rapidly with treatment discontinuation, while the others seem to be benefitting (a subjective observation but one patient demonstrated carotid IMT regression).  Time will tell how well this novel approach is going to work.  The expert here is Dr. Alan Green, whose first Rapamycin patient was himself.  Dr. Green feels that the optimal dose of Rapamycin is 2-6 mg, taken every 1-3 weeks. His comment is that 3 mg every 10 days serves as a conservative dose, with 6 mg once a week as a more aggressive regimen (which Dr. Green has been taking since 2017). The key here is not the mg dose, but rather the dosing interval (to knock out mTOR 1 without inhibiting the beneficial mTOR 2).  Caloric restriction (being trim – minimal visceral fat), regular exercise, metformin (and thus presumably berberine which mimics metformin metabolically), and low dose alcohol will all inhibit mTOR type 1.  Dr. Green is taking Rapamycin in combination with senolytic therapy (designed to clear out old, dysfunctional cells), utilizing Quercetin and the pharmaceutical agent Dasatinib.  You can set up a consultation with Dr. Green through his website.

Peptide Vascular Bioregulation (search Khavison Peptide Bioregulators or read The Peptide Bioregulator Revolution by Marios Kyriazis MD) and peptide growth factor therapy in general is an everyday approach to health optimization in Russia and Eastern Europe, but remains little discussed in the US.  When we are young our organs generate peptides (short chains of amino acids) that mediate growth and development of the specific organ. As we age, growth factor generation attenuates, and so do our organs, both in size and function.  These growth factors, common to all mammals, can be obtained from animal sources or made in the lab.  If we take these peptides, function of the corresponding organ is enhanced.  Peptide growth factors are utilized not to treat a specific disease (as Mother Nature did not design us to be sick) but rather to support the functional status of an organ system experiencing stress in the context of aging.     There is a great deal of literature to support this approach, and this is open to all of you.

Stem Enhance Ultra (marketed by Cerule) stimulates our bone marrow to release uncommitted stem cells (demonstrated in humans), stimulating self-repair (demonstrated in animals).  The stem cells hone to organ systems or body regions under stress (they release distress factors).  This approach makes sense (and I think it has helped me with knee pain due to my 12 hour a week vigorous exercise habit).

NAD⁺/NMN supplementation stimulates the generation of mitochondria (our cellular fuel cells) and activates the PGC1-alpha pathway (which enhances energy production). IV NAD (Nicotinamide Adenine Dinucleotide) had been used in Psychiatry to help individuals de-habituate from narcotic pain meds and other addictive substances.   In animal models it speeds recovery from cardiac toxicity, and will likely help humans dealing with health challenges that involve faulty energy generation (essentially all non-infectious, non-traumatic disease states).  A course of treatment involves an all-day IV infusion over one to two weeks (very expensive).  Lifespan, written by Dr. David Sinclair, covers this concept in detail. Dr. Sinclair recommends a daily program that includes NMN (500-1000 mg), Resveratrol (500-1000 mg) and Quercetin (500 mg), all synergizing to increase mitochondrial expression.

Arterosil, a recently introduced CV supplement, is said to work at the level of the glycocalyx, the region overlying the endothelial layer of the vascular wall. Small studies discuses on the Arterosil website suggest a favorable effect of Arterosil on plaque composition and vascular function.  Outcome studies are not, to my knowledge, available (these take years and a lot of money).  I have just begun a handful of patients on Arterosil; time will tell if this approach will work in practice.

The Atherosclerosis Check List below will help you and I apply this science to your health. We can check each and every box, but obviously some steps will be more important than others, based upon your genomic and nutritional status, individual disease burden(s), preferences, resources, and whether we do or do not have the luxury of times. If you are my patient, then this Atherosclerosis Check List will become your Problem List within your medical record, and it is our shared responsibility to make sure that each of the major causes of atherosclerosis, and the corresponding neutralizing treatment(s), have been considered.  You don’t have to do all of this, but I need to bring up these concepts to you!

                                                                                                                                                                                                James C. Roberts MD, FACC, FAARFM 12/22

 
Atherosclerosis Check List

? Lipid Cholesterol Management          
? Lipoprotein (a)
? Oxidative Stress
? Endothelial Function and EndoPAT Assessment
? Hypertension
? Insulin Insensitivity, Diabesity, and Metabolic Syndrome            
? Reverse Cholesterol Transport with PPC
? Reverse Cholesterol Transport with Cyclodextrin (CavadexÔ)
? Homocysteine
? Inflammation Reduction
? TMAO
? Plaque stabilization with Colchicine          
? Vitamin K2
? Hormonal Support
? Heavy Metal Detoxification 
? Organic Pollutants
? Detoxification is Your Responsibility
? Fibrinolytic Supplementation
? Nutritional Optimization
? Elevated Viscosity due to Erythrocytosis and/or Elevated Fibrinogen 
? Genomic Predisposition
? Rapamycin          
? Peptide Vascular Bioregulation
? Stem Enhance Ultra
? NAD⁺/NMN
? Arterosil